Midazolam Hydrochloride

Midazolam Hydrochloride Manufacturers

• Baxter Healthcare Corporation
  

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  Midazolam Hydrochloride | Baxter Healthcare Corporation

  

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  The 1 mL and 2 mL Midazolam Injection vials include a cautionary label that extends above the main label and highlights the drug name and strength per total volume. The purpose of the extended label is to prevent medication errors due to the different strengths of Midazolam Injection. Read the label and confirm you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this cautionary label prior to removing the flip-off cap.

  Midazolam is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see BOX WARNING and  WARNINGS.)

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam Injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring

  Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics

  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics

  For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  Usual Adult Dose Intramuscularly For preoperative sedation/anxiolysis/
  amnesia (induction of sleepiness or
  drowsiness and relief of apprehension
  and to impair memory
  of perioperative events). The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.
  
  For intramuscular use, midazolam
  should be injected deep in a
  large muscle mass. The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics. Intravenously Sedation/anxiolysis/amnesia for
  procedures (See INDICATIONS AND USAGE):
  Narcotic premedication results in less
  variability in patient response and a
  reduction in dosage of midazolam.
  For peroral procedures, the use of an
  appropriate topical anesthetic is
  recommended. For bronchoscopic
  procedures, the use of narcotic
  premedication is recommended.
  
  Midazolam 1 mg/mL formulation
  is recommended for
  sedation/anxiolysis/amnesia for
  procedures to facilitate slower
  injection. Both the 1 mg/mL and the
  5 mg/mL formulations may be
  diluted with 0.9% sodium chloride or
  5% dextrose in water.
  
  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.) 1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
  
  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.
  
  Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.
  
  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.
  
  3. Maintenance Dose:  Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.
  
  Induction of Anesthesia: For
  induction of general anesthesia,
  before administration of other
  anesthetic agents. Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.
  
  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
  
  Unpremedicated Patients
  In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.
  
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.
  
  Premedicated Patients
  When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.
  
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.
  
  Injectable midazolam can also
  be used during maintenance of
  anesthesia, for surgical procedures, as
  a component of balanced anesthesia.
  Effective narcotic premedication is
  especially recommended in such cases. Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.
  
  Continuous Infusion For continuous infusion, midazolam
  5 mg/mL formulation is
  recommended diluted to a
  concentration of 0.5 mg/mL with
  0.9% sodium chloride or 5%
  dextrose in water. Usual Adult Dose
  If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.10 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients.
  
  The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.
  
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate. Pediatric Patients UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction or hypoventilation is increased. For appropriate patient monitoring, see BOX WARNING, WARNINGS, Monitoring subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Assessment Categories Responsiveness Speech Facial
  Expression Eyes Composite
  Score Responds readily to name spoken in normal tone
  
  normal normal clear; no ptosis 5 (alert) Lethargic response to name spoken in normal tone
  
  mild slowing
  or thickening mild
  relaxation glazed or mild
  ptosis (less than
  half the eye) 4 Responds only after name is called loudly and/or repeatedly
  
  slurring or
  prominent slowing marked
  relaxation
  (slack jaw) glazed and
  marked ptosis
  (half the eye
  or more) 3 Responds only after mild prodding or shaking
  
  few
  recognizable
  words —— —— 2 Does not respond to mild prodding or shaking
  
  —— —— —— 1
  (deep sleep) FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF CHILDREN UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION OAA/S
  Score   Age
  Range
  (years) n 1 (deep sleep) 2 3 4 5 (alert) 1-2 16 6 (38%) 4 (25%) 3 (19%) 3 (19%) 0 >2-5 22 9 (41%) 5 (23%) 8 (36%) 0 0 >5-12 34 1 (3%) 6 (18%) 22 (65%) 5 (15%) 0 >12- 17 18 0 4 (22%) 14 (78%) 0 0 Total (1-17) 90 16 (18%) 19 (21%) 47 (52%) 8 (9%) 0 Intramuscularly For sedation/anxiolysis/amnesia prior
  to anesthesia or for procedures,
  intramuscular midazolam can be used
  to sedate pediatric patients to
  facilitate less traumatic insertion of an
  intravenous catheter for titration of
  additional medication. USUAL PEDIATRIC DOSE (NON-NEONATAL).
  Sedation after intramuscular midazolam is age and dose dependent; higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced. Intravenously by Intermittent Injection For sedation/anxiolysis/amnesia
  prior to and during procedures or
  prior to anesthesia. USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam HCl is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects; therefore, one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.
  
  1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology; therefore, the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation; therefore, titration with small increments to clinical effect and careful monitoring are essential.
  
  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
  
  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
  
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.
  
  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS). Continuous Intravenous Infusion For sedation/anxiolysis/amnesia in
  critical care settings. USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.
  
  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation. Continuous Intravenous Infusion For sedation in critical care settings. USUAL NEONATAL DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of Midazolam Injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see Usage in Preterm Infants and Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  Parenteral drug products should be inspected visually for particulate matter and
  discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Physicians Total Care, Inc.

  

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  The 1 mL and 2 mL Midazolam Injection vials include a cautionary label that extends above the main label and highlights the drug name and strength per total volume. The purpose of the extended label is to prevent medication errors due to the different strengths of Midazolam Injection. Read the label and confirm you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this cautionary label prior to removing the flip-off cap.

  Midazolam is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see BOX WARNING and  WARNINGS.)

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam Injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring

  Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics

  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics

  For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  Usual Adult Dose Intramuscularly For preoperative sedation/anxiolysis/
  amnesia (induction of sleepiness or
  drowsiness and relief of apprehension
  and to impair memory
  of perioperative events). The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.
  
  For intramuscular use, midazolam
  should be injected deep in a
  large muscle mass. The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics. Intravenously Sedation/anxiolysis/amnesia for
  procedures (See INDICATIONS AND USAGE):
  Narcotic premedication results in less
  variability in patient response and a
  reduction in dosage of midazolam.
  For peroral procedures, the use of an
  appropriate topical anesthetic is
  recommended. For bronchoscopic
  procedures, the use of narcotic
  premedication is recommended.
  
  Midazolam 1 mg/mL formulation
  is recommended for
  sedation/anxiolysis/amnesia for
  procedures to facilitate slower
  injection. Both the 1 mg/mL and the
  5 mg/mL formulations may be
  diluted with 0.9% sodium chloride or
  5% dextrose in water.
  
  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.) 1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
  
  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.
  
  Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.
  
  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.
  
  3. Maintenance Dose:  Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.
  
  Induction of Anesthesia: For
  induction of general anesthesia,
  before administration of other
  anesthetic agents. Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.
  
  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
  
  Unpremedicated Patients
  In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.
  
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.
  
  Premedicated Patients
  When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.
  
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.
  
  Injectable midazolam can also
  be used during maintenance of
  anesthesia, for surgical procedures, as
  a component of balanced anesthesia.
  Effective narcotic premedication is
  especially recommended in such cases. Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.
  
  Continuous Infusion For continuous infusion, midazolam
  5 mg/mL formulation is
  recommended diluted to a
  concentration of 0.5 mg/mL with
  0.9% sodium chloride or 5%
  dextrose in water. Usual Adult Dose
  If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.10 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients.
  
  The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.
  
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate. Pediatric Patients UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction or hypoventilation is increased. For appropriate patient monitoring, see BOX WARNING, WARNINGS, Monitoring subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Assessment Categories Responsiveness Speech Facial
  Expression Eyes Composite
  Score Responds readily to name spoken in normal tone
  
  normal normal clear; no ptosis 5 (alert) Lethargic response to name spoken in normal tone
  
  mild slowing
  or thickening mild
  relaxation glazed or mild
  ptosis (less than
  half the eye) 4 Responds only after name is called loudly and/or repeatedly
  
  slurring or
  prominent slowing marked
  relaxation
  (slack jaw) glazed and
  marked ptosis
  (half the eye
  or more) 3 Responds only after mild prodding or shaking
  
  few
  recognizable
  words —— —— 2 Does not respond to mild prodding or shaking
  
  —— —— —— 1
  (deep sleep) FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF CHILDREN UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION OAA/S
  Score   Age
  Range
  (years) n 1 (deep sleep) 2 3 4 5 (alert) 1-2 16 6 (38%) 4 (25%) 3 (19%) 3 (19%) 0 >2-5 22 9 (41%) 5 (23%) 8 (36%) 0 0 >5-12 34 1 (3%) 6 (18%) 22 (65%) 5 (15%) 0 >12- 17 18 0 4 (22%) 14 (78%) 0 0 Total (1-17) 90 16 (18%) 19 (21%) 47 (52%) 8 (9%) 0 Intramuscularly For sedation/anxiolysis/amnesia prior
  to anesthesia or for procedures,
  intramuscular midazolam can be used
  to sedate pediatric patients to
  facilitate less traumatic insertion of an
  intravenous catheter for titration of
  additional medication. USUAL PEDIATRIC DOSE (NON-NEONATAL).
  Sedation after intramuscular midazolam is age and dose dependent; higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced. Intravenously by Intermittent Injection For sedation/anxiolysis/amnesia
  prior to and during procedures or
  prior to anesthesia. USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam HCl is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects; therefore, one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.
  
  1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology; therefore, the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation; therefore, titration with small increments to clinical effect and careful monitoring are essential.
  
  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
  
  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
  
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.
  
  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS). Continuous Intravenous Infusion For sedation/anxiolysis/amnesia in
  critical care settings. USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.
  
  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation. Continuous Intravenous Infusion For sedation in critical care settings. USUAL NEONATAL DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of Midazolam Injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see Usage in Preterm Infants and Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  Parenteral drug products should be inspected visually for particulate matter and
  discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Cardinal Health

  

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  The 1 mL and 2 mL Midazolam Injection vials include a cautionary label that extends above the main label and highlights the drug name and strength per total volume. The purpose of the extended label is to prevent medication errors due to the different strengths of Midazolam Injection. Read the label and confirm you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this cautionary label prior to removing the flip-off cap.

  Midazolam is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see BOX WARNING and  WARNINGS.)

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam Injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring

  Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics

  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics

  For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  Usual Adult Dose Intramuscularly For preoperative sedation/anxiolysis/
  amnesia (induction of sleepiness or
  drowsiness and relief of apprehension
  and to impair memory
  of perioperative events). The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.
  
  For intramuscular use, midazolam
  should be injected deep in a
  large muscle mass. The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics. Intravenously Sedation/anxiolysis/amnesia for
  procedures (See INDICATIONS AND USAGE):
  Narcotic premedication results in less
  variability in patient response and a
  reduction in dosage of midazolam.
  For peroral procedures, the use of an
  appropriate topical anesthetic is
  recommended. For bronchoscopic
  procedures, the use of narcotic
  premedication is recommended.
  
  Midazolam 1 mg/mL formulation
  is recommended for
  sedation/anxiolysis/amnesia for
  procedures to facilitate slower
  injection. Both the 1 mg/mL and the
  5 mg/mL formulations may be
  diluted with 0.9% sodium chloride or
  5% dextrose in water.
  
  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.) 1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
  
  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.
  
  Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.
  
  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.
  
  3. Maintenance Dose:  Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.
  
  Induction of Anesthesia: For
  induction of general anesthesia,
  before administration of other
  anesthetic agents. Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.
  
  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
  
  Unpremedicated Patients
  In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.
  
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.
  
  Premedicated Patients
  When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.
  
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.
  
  Injectable midazolam can also
  be used during maintenance of
  anesthesia, for surgical procedures, as
  a component of balanced anesthesia.
  Effective narcotic premedication is
  especially recommended in such cases. Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.
  
  Continuous Infusion For continuous infusion, midazolam
  5 mg/mL formulation is
  recommended diluted to a
  concentration of 0.5 mg/mL with
  0.9% sodium chloride or 5%
  dextrose in water. Usual Adult Dose
  If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.10 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients.
  
  The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.
  
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate. Pediatric Patients UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction or hypoventilation is increased. For appropriate patient monitoring, see BOX WARNING, WARNINGS, Monitoring subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Assessment Categories Responsiveness Speech Facial
  Expression Eyes Composite
  Score Responds readily to name spoken in normal tone
  
  normal normal clear; no ptosis 5 (alert) Lethargic response to name spoken in normal tone
  
  mild slowing
  or thickening mild
  relaxation glazed or mild
  ptosis (less than
  half the eye) 4 Responds only after name is called loudly and/or repeatedly
  
  slurring or
  prominent slowing marked
  relaxation
  (slack jaw) glazed and
  marked ptosis
  (half the eye
  or more) 3 Responds only after mild prodding or shaking
  
  few
  recognizable
  words —— —— 2 Does not respond to mild prodding or shaking
  
  —— —— —— 1
  (deep sleep) FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF CHILDREN UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION OAA/S
  Score   Age
  Range
  (years) n 1 (deep sleep) 2 3 4 5 (alert) 1-2 16 6 (38%) 4 (25%) 3 (19%) 3 (19%) 0 >2-5 22 9 (41%) 5 (23%) 8 (36%) 0 0 >5-12 34 1 (3%) 6 (18%) 22 (65%) 5 (15%) 0 >12- 17 18 0 4 (22%) 14 (78%) 0 0 Total (1-17) 90 16 (18%) 19 (21%) 47 (52%) 8 (9%) 0 Intramuscularly For sedation/anxiolysis/amnesia prior
  to anesthesia or for procedures,
  intramuscular midazolam can be used
  to sedate pediatric patients to
  facilitate less traumatic insertion of an
  intravenous catheter for titration of
  additional medication. USUAL PEDIATRIC DOSE (NON-NEONATAL).
  Sedation after intramuscular midazolam is age and dose dependent; higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced. Intravenously by Intermittent Injection For sedation/anxiolysis/amnesia
  prior to and during procedures or
  prior to anesthesia. USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam HCl is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects; therefore, one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.
  
  1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology; therefore, the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation; therefore, titration with small increments to clinical effect and careful monitoring are essential.
  
  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
  
  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.
  
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.
  
  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS). Continuous Intravenous Infusion For sedation/anxiolysis/amnesia in
  critical care settings. USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.
  
  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation. Continuous Intravenous Infusion For sedation in critical care settings. USUAL NEONATAL DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of Midazolam Injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see Usage in Preterm Infants and Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  Parenteral drug products should be inspected visually for particulate matter and
  discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Dispensing Solutions, Inc.

  

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  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSAGE

  INTRAMUSCULARLY

  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/ hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation.

  Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS
  

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name

  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name

  spoken in normal tone

  mild slowing

  or thickening

  mild relaxation

  glazed or mild ptosis

  (less than half the eye)

  4

  Responds only after name is

  called loudly and/or repeatedly

  slurring or

  prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis

  (half the eye or more)

  3

  Responds only after mild

  prodding or shaking

  few recognizable

  words

  −

  −

  2

  Does not respond to mild

  prodding or shaking

  −

  −

  −

  1 (deep sleep)

  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC

  PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range

  (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Dispensing Solutions, Inc.

  

  ---

  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  INTRAMUSCULARLY

  For preoperative sedation/ anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  
  
  

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, MONITORING. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)
  

  Assessment Categories

  
  

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  
  

  Responds readily to name spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  
  

  Lethargic response to name spoken in normal tone

  mild slowing or thickening

  mild relaxation

  glazed or mild ptosis (less than half the eye)

  4

  
  

  Responds only after name is called loudly and/or repeatedly

  slurring or prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis (half the eye or more)

  3

  
  

  Responds only after mild prodding or shaking

  few recognizable words

  —

  —

  2

  
  

  Does not respond to mild prodding or shaking

  —

  —

  —

  1 (deep sleep)

  
  
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE
  STUDY OF CHILDREN UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  
  Age Range
  (years)
  n
  OAA/S Score
  

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  
  

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Hospira, Inc.

  

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  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  INTRAMUSCULARLY

  For preoperative sedation/ anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  
  
  

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, MONITORING. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)
  

  Assessment Categories

  
  

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  
  

  Responds readily to name spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  
  

  Lethargic response to name spoken in normal tone

  mild slowing or thickening

  mild relaxation

  glazed or mild ptosis (less than half the eye)

  4

  
  

  Responds only after name is called loudly and/or repeatedly

  slurring or prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis (half the eye or more)

  3

  
  

  Responds only after mild prodding or shaking

  few recognizable words

  —

  —

  2

  
  

  Does not respond to mild prodding or shaking

  —

  —

  —

  1 (deep sleep)

  
  
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE
  STUDY OF CHILDREN UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  
  Age Range
  (years)
  n
  OAA/S Score
  

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  
  

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Hospira, Inc.

  

  ---

  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSAGE

  INTRAMUSCULARLY

  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/ hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation.

  Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS
  

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name

  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name

  spoken in normal tone

  mild slowing

  or thickening

  mild relaxation

  glazed or mild ptosis

  (less than half the eye)

  4

  Responds only after name is

  called loudly and/or repeatedly

  slurring or

  prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis

  (half the eye or more)

  3

  Responds only after mild

  prodding or shaking

  few recognizable

  words

  −

  −

  2

  Does not respond to mild

  prodding or shaking

  −

  −

  −

  1 (deep sleep)

  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC

  PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range

  (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  No Recall

  More Info
• Hospira, Inc.
  

  ×

  Midazolam Hydrochloride | Hospira, Inc.

  

  ---

  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with Lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  INTRAMUSCULARLY

  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

   

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

   

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Healthy Adults Below the Age of 60: Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

   

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Assessment Categories
  Responsiveness
  Speech
  Facial Expression
  Eyes
  Composite Score
  

  Responds readily to name

  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name

  spoken in normal tone

  mild slowing

  or thickening

  mild relaxation

  glazed or mild ptosis

  (less than half the eye)

  4

  Responds only after name is

  called loudly and/or repeatedly

  slurring or

  prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis

  (half the eye or more)

  3

  Responds only after mild

  prodding or shaking

  few recognizable

  words

  −

  −

  2

  Does not respond to mild

  prodding or shaking

  −

  −

  −

  1 (deep sleep)

  
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION Age Range (years)
  n
  OAA/S Score
  1 (deep sleep)
  2
  3
  4
  5 (alert)
  

  1-2

  16

  6 (38%)

  4 (25%)

  3 (19%)

  3 (19%)

  0

  >2-5

  22

  9 (41%)

  5 (23%)

  8 (36%)

  0

  0

  >5-12

  34

  1 (3%)

  6 (18%)

  22 (65%)

  5 (15%)

  0

  >12-17

  18

  0

  4 (22%)

  14 (78%)

  0

  0

  Total (1-17)

  90

  16 (18%)

  19 (21%)

  47 (52%)

  8 (9%)

  0

  
  
  

  INTRAMUSCULARLY

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY INTERMITTENT INJECTION

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

   

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  Pediatric patients less than 6 months of age: limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  Pediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  Pediatric patients 12 to 16 years of age: should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS INTRAVENOUS INFUSION

  For sedation/anxiolysis/amnesia in critical care settings.

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

   

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS INTRAVENOUS INFUSION

  For sedation in critical care settings.

  USUAL NEONATAL DOSE

   

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  
  

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Hospira, Inc.

  

  ---

  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with Lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  
  
  

  USUAL ADULT DOSE

  INTRAMUSCULARLY

  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events). For intramuscular use, midazolam should be injected deep in a large muscle mass.

  
  

   

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  
  

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  
  

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

   

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  
  

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  1.    Healthy Adults Below the Age of 60: Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  
  

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  
  

  2.    Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  
  

  Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of   2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  
  

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  
  

  3.    Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  
  

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  
  

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  
  

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  
  

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  
  

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  
  

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  
  

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  
  

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

   

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  
  

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  
  
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name

  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name

  spoken in normal tone

  mild slowing

  or thickening

  mild relaxation

  glazed or mild ptosis

  (less than half the eye)

  4

  Responds only after name is called loudly and/or repeatedly

  slurring or

  prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis

  (half the eye or more)

  3

  Responds only after mild

  prodding or shaking

  few recognizable

  words

  –

  –

  2

  Does not respond to mild

  prodding or shaking

  
  

  –

  –

  –

  1 (deep sleep)

  
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6 (38%)

  4 (25%)

  3 (19%)

  3 (19%)

  0

  >2-5

  22

  9 (41%)

  5 (23%)

  8 (36%)

  0

  0

  >5-12

  34

  1 (3%)

  6 (18%)

  22 (65%)

  5 (15%)

  0

  >12-17

  18

  0

  4 (22%)

  14 (78%)

  0

  0

  Total (1-17)

  90

  16 (18%)

  19 (21%)

  47 (52%)

  8 (9%)

  0

  
  
  

  INTRAMUSCULARLY

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  
  

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  For sedation/anxiolysis/amnesia

  prior to and during procedures

  or prior to anesthesia.

   

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  
  

  1.     Pediatric patients less than 6 months of age: limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  
  

  2.     Pediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  
  

  3.     Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  
  

  4.     Pediatric patients 12 to 16 years of age: should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  
  
  

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  
  

  CONTINUOUS INTRAVENOUS INFUSION

  For sedation/anxiolysis/amnesia in critical care settings.

  
  

   

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  
  

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS INTRAVENOUS INFUSION

  For sedation in critical care settings.

   

  USUAL NEONATAL DOSE

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Wockhardt Usa Llc.

  

  ---

  Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam.  BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING. DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNINGand WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS).

  Midazolam hydrochloride injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).      

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE
  INTRAMUSCULARLY
  For preoperative sedation/anxiolysis/ amnesia (induction of sleepiness or drowsiness and relief of apprehension
  and to impair memory of perioperative events).
  For intramuscular use, midazolam
  hydrochloride should be injected deep in a large muscle mass.
  The recommended premedication dose of midazolam for good risk (ASA Physical 
  Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM 
  (approximately 5 mg IM) administered up to 1 hour before surgery.
  The dose must be individualized and reduced when IM midazolam is administered to patients
  with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60
  or more years of age, and patients who have received concomitant narcotics or other CNS
  depressants (see ADVERSE REACTIONS). 
  In a study of patients 60 years or older, who did not receive concomitant administration 
  of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during
  the preoperative period. The dose of 1 mg IM midazolam hydrochloride may suffice for some
  older patients if the anticipated intensity and duration of sedation is less critical. As with any
  potential respiratory depressant, these patients require observation for signs of cardiorespiratory
  depression after receiving IM midazolam.
  Onset is within 15 minutes, peaking at 30 to 60 minutes. it can be administered concomitantly
  with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.
  INTRAVENOUSLY
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): 
  Narcotic premedication results In less variability in patient response and a
  reduction in dosage of midazolam. For peroral procedures, the use of an 
  appropriate topical anesthetic is recommended. For bronchoscopic 
  procedures, the use of narcotic premedication is recommended.
  
  
  Midazolam hydrochloride 1 mg/mL formulation is recommended for 
  sedation/anxiolysis/amnesia for procedures to facilitate slower injection. 
  Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% 
  sodium chloride or 5% dextrose in water.
  When used for sedation/anxiolysis/ amnesia for a procedure, dosage must be individualized and 
  titrated. Midazolam hydrochloride should always be titrated slowly; administer over at least 2 
  minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. 
  Individual response will vary with age, physical status and concomitant medications, but may also 
  vary independent of these factors. (See WARNINGS concerning cardiac/ 
  respiratory arrest/airway obstruction/ hypoventilation.)
  
  
  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of 
  slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be 
  given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the 
  sedative effect. If further titration is necessary, continue to titrate, using small increments, to the 
  appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully 
  evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the 
  desired endpoint.
  If narcotic premeditation or other CNS depressants are used, patients will require 
  approximately 30% less midazolam than unpremeditated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of 
  hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic 
  disease states or decreased pulmonary reserve, and because the peak effect may take longer in 
  these patients, increments should be smaller and the rate of injection slower. Titrate slowly to the 
  desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 
  1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an 
  additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is 
  necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an 
  additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater 
  than 3.5 mg are not usually necessary.
  If concomitant CNS depressant premedications are used in these patients, they will require at 
  least 50% less midazolam than healthy young unpremedicated patients.
  
  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may be 
  given in increments of 25% of the dose used to first reach the sedative endpoint, but again only 
  by slow titration, especially in the elderly and chronically ill or debilitated patient. These 
  additional doses should be given only after a thorough clinical evaluation clearly indicates the 
  need for additional sedation.
  Induction of Anesthesia:
  For induction of general anesthesia, before administration of other anesthetic 
  agents.
  Individual response to the drug is variable, particularly when a narcotic premeditation is not 
  used. The dosage should be titrated to the desired effect according to the patient's age and clinical 
  status.
  When midazolam is used before other intravenous agents for induction of anesthesia, 
  the initial dose of each agent may be significantly reduced, at times to as low as 25% 
  of the usual initial dose of the individual agents.
  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 
  55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 
  20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, 
  increments of approximately 25% of the patient's initial dose may be used; induction may instead 
  be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be 
  used for induction, but such larger doses may prolong recovery.
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an 
  initial dose of 0.3 mg/kg is recommended. 
  Unpremedicated patients with severe systemic disease or other debilitation usually require less 
  midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, 
  as little as 0.15 mg/kg may suffice.
  Premedicated Patients: When the patient has received sedative or narcotic premedication, 
  particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 
  seconds and allowing 2 minutes for effect, will usually suffice.
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the 
  age of 55 years.
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg 
  IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 
  mg/kg lM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative 
  premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg 
  orally). Except for intravenous fentanyl, administered 5 minutes before induction, all 
  other premedications should be administered approximately 1 hour prior to the time 
  anticipated for midazolam induction.
  Injectable midazolam hydrochloride can also be used during maintenance of 
  anesthesia, for surgical procedures, as a component of balanced anesthesia. 
  Effective narcotic premedication is especially recommended in such cases.
  Incremental injections of approximately 25% of the induction dose should be given in response to 
  signs of lightening of anesthesia and repeated as necessary.
  CONTINUOUS INFUSION
  Far continuous infusion, midazolam hydrochloride 5 mg/mL formulation is 
  recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride 
  or 5% dextrose in water.
  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg 
  (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several 
  minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is 
  achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 
  mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some 
  patients. The lowest recommended doses should be used in patients with residual effects from 
  anesthetic drugs, or in those concurrently receiving other sedatives or opioids. 
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired 
  level of sedation, taking into account the patient's age, clinical status and current medications. In 
  general, midazolam should be infused at the lowest rate that produces the desired level of 
  sedation. 
  Assessment of sedation should be performed at regular intervals and the midazolam infusion rate 
  adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of 
  sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid 
  changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 
  10% to 25% every few hours to find the minimum effective infusion rate. Finding the 
  minimum effective infusion rate decreases the potential accumulation of midazolam and 
  provides for the most rapid recovery once the infusion is terminated. Patients who exhibit 
  agitation, hypertension, or tachycardia in response to noxious stimulation, but who are 
  otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. 
  Addition of an opioid will generally reduce the minimum effective midazolam hydrochloride 
  infusion rate.
  PEDIATRIC PATIENTS
  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE 
  INCREMENTS OF MIDAZOLAM HYDROCHLORIDE ON A MG/KG BASIS. 
  As a group, pediatric patients generally require higher dosages of midazolam hydrochloride 
  (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher 
  dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables 
  below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body 
  weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for 
  respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate 
  patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, 
  MONITORING. The health care practitioner who uses this medication in pediatric patients 
  should be aware of and follow accepted professional guidelines for pediatric sedation 
  appropriate to their situation.
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (0AA/S)
  Assessment Categories
  Responsiveness
  Speech
  Facial Expression
  Eyes
  Composite Score
  Responds readily to name spoken in normal tone
  normal
  normal
  clear, no ptosis
  5 (alert)
  Lethargic response to name spoken in normal tone
  mild slowing or thickening
  mild relaxation
  glazed or mild ptosis (less than  half the eye)
  4
  Responds only after name is called loudly and/or repeatedly
  slurring or prominent slowing
  marked relaxation (slack jaw)
  glazed and marked ptosis (half the eye or more)
  3
  Responds only after mild prodding or shaking
  few recognizable words
  -
  -
  2
  Does not respond to mild prodding or shaking
  -
  -
  -
  1 (deep sleep)
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING
  PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  Age Range
  (years)
  n
  OAA/S Score
  
  
  1 (deep sleep)
  2
  3
  4
  5 (alert)
  1-2
  16
  6 (38%)
  4 (25%)
  3 (19%)
  3 (19%)
  0
  >2-5
  22
  9 (41%)
  5 (23%)
  8 (36%)
  0
  0
  >5-12
  34
  1 (3%)
  6 (18%)
  22 (65%)
  5 (15%)
  0
  >12-17
  18
  0
  4 (22%)
  14 (78%)
  0
  0
  Total (1-17)
  90
  16 (18%)
  19 (21%)
  47 (52%)
  8 (9%)
  0
  INTRAMUSCULARLY
  For sedation/anxiolysis /amnesia prior to anesthesia or for procedures, intramuscular 
  midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion 
  of an intravenous catheter for titration of additional medication.
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  Sedation after intramuscular midazolam is age and dose dependent: higher doses may 
  result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are 
  usually effective and do not prolong emergence from general anesthesia. For 
  more anxious patients, doses up to 0.5 mg/kg have been used. Although not 
  systematically studied, the total dose usually does not exceed 10 mg. If 
  midazolam is given with an opioid, the initial dose of each must be reduced.
  
  INTRAVENOUSLY BY 
  INTERMITTENT INJECTION
  For sedation/anxiolysis/amnesia prior to and during procedures or prior to 
  anesthesia.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation /anxiolysis needed for pediatric 
  patients depends on the type of procedure to be performed. For example, simple light 
  sedation/anxiolysis in the preoperative period is quite different from the deep 
  sedation and analgesia required for an endoscopic procedure in a child. For this 
  reason, there is a broad range of dosage. For all pediatric patients, regardless of the 
  indications for sedation/anxiolysis, it is vital to titrate midazolam hydrochloride 
  and other concomitant medications slowly to the desired clinical effect. The initial 
  dose of midazolam should be administered over 2 to 3 minutes. Since midazolam 
  hydrochloride is water soluble, it takes approximately three times longer than 
  diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 
  minutes to fully evaluate the sedative effect before initiating a procedure or repeating a 
  dose. If further sedation is necessary, continue to titrate with small increments 
  until the appropriate level of sedation is achieved. If other medications capable of 
  depressing the CNS are coadministered, the peak effect of those concomitant 
  medications must be considered and the dose of midazolam adjusted. The 
  importance of drug titration to effect is vital to the safe sedation/anxiolysis of the 
  pediatric patient. The total dose of midazolam will depend on patient 
  response, the type and duration of the procedure, as well as the type and dose of 
  concomitant medications.
  
  1.  Pediatric patients less than 6 months of age: Limited information is available in 
  non-intubated pediatric patients less than 6 months of age. It is uncertain when the 
  patient transfers from neonatal physiology to pediatric physiology, therefore the 
  dosing recommendations are unclear, Pediatric patients less than 6 months of age 
  are particularly vulnerable to airway obstruction and hypoventilation, therefore 
  titration with small increments to clinical effect and careful monitoring are essential.
  
  2.  Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total 
  dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does 
  not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated 
  with the higher doses.
  
  3.  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose 
  up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not 
  exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with 
  the higher doses.
  
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged 
  sedation may be associated with higher doses; some patients in this age range will 
  require higher than recommended adult doses but the total dose usually does not 
  exceed 10 mg. 
  
  The dose of midazolam hydrochloride must be reduced in patients premedicated with 
  opioid or other sedative agents including midazolam. Higher risk or debilitated 
  patients may require lower dosages whether or not concomitant sedating 
  medications have been administered (see WARNINGS).
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation/anxiolysis/amnesia in critical care settings.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered 
  over at least 2 to 3 minutes can be used to establish the desired clinical effect IN 
  PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be 
  administered as a rapid intravenous dose.) This loading dose may be followed by a 
  continuous intravenous infusion to maintain the effect. An infusion of 
  midazolam hydrochloride injection has been used in patients whose trachea was 
  intubated but who were allowed to breathe spontaneously. Assisted ventilation is 
  recommended for pediatric patients who are receiving other central nervous system 
  depressant medications such as opioids. Based on pharmacokinetic parameters and 
  reported clinical experience, continuous intravenous infusions of midazolam should 
  be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of 
  infusion can be increased or decreased (generally by 25% of the initial or 
  subsequent infusion rate) as required, or supplemental intravenous doses of 
  midazolam hydrochloride can be administered to increase or maintain the 
  desired effect. Frequent assessment at regular intervals using standard 
  pain/sedation scales is recommended. Drug elimination may be delayed in patients 
  receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, 
  Drug Interactions section) and in patients with liver dysfunction, low 
  cardiac output (especially those requiring inotropic support), and in neonates. 
  Hypotension may be observed in patients who are critically ill, particularly those 
  receiving opioids and/or when midazolam is rapidly administered. 
  When initiating an infusion with midazolam in hemodynamically 
  compromised patients, the usual loading dose of midazolam hydrochloride should 
  be titrated in small increments and the patient monitored for hemodynamic 
  instability, e.g., hypotension. These patients are also vulnerable to the 
  respiratory depressant effects of midazolam and require careful monitoring of 
  respiratory rate and oxygen saturation.
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation in critical care settings.
  
  USUAL  NEONATAL  DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and 
  term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous 
  infusions of midazolam hydrochloride injection should be initiated at a rate of 
  0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 
  mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be 
  used in neonates, rather the infusion may be run more rapidly for the first several 
  hours to establish therapeutic plasma levels. The rate of infusion should be 
  carefully and frequently reassessed, particularly after the first 24 hours so as to 
  administer the lowest possible effective dose and reduce the potential for drug 
  accumulation. Hypotension may be observed in patients who are critically ill 
  and in preterm and term infants, particularly those receiving fentanyl and/or 
  when midazolam is administered rapidly. Due to an increased risk of apnea, extreme 
  caution is advised when sedating preterm and former preterm patients whose trachea 
  is not intubated.
  

  Note:  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Wockhardt Usa Llc.

  

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  Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam.  BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING. DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNINGand WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS).

  Midazolam hydrochloride injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).      

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE
  INTRAMUSCULARLY
  For preoperative sedation/anxiolysis/ amnesia (induction of sleepiness or 
  drowsiness and relief of apprehension and to impair memory of perioperative 
  events).
  For intramuscular use, midazolam hydrochloride should be injected deep in 
  a large muscle mass.
  
  
  The recommended premedication dose of midazolam for good risk (ASA Physical 
  Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM 
  (approximately 5 mg IM) administered up to 1 hour before surgery.
  The dose must be individualized and reduced when IM midazolam is 
  administered to patients with chronic obstructive pulmonary disease, other higher 
  risk surgical patients, patients 60 or more years of age, and patients who have 
  received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS).
  In a study of patients 60 years or older, who did not receive concomitant administration
  of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation
  during the preoperative period. The dose of 1 mg IM midazolam hydrochloride may
  suffice for some older patients if the anticipated intensity and duration of
  sedation is less critical. As with any potential respiratory depressant, these 
  patients require observation for signs of cardiorespiratory depression after receiving
  IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. 
  It can be administered concomitantly with atropine sulfate or scopolamine 
  hydrochloride and reduced doses of narcotics.
  
  INTRAVENOUSLY
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): 
  Narcotic premedication results in less variability in patient response and a 
  reduction in dosage of midazolam. For peroral procedures, the use of an 
  appropriate topical anesthetic is recommended. For bronchoscopic 
  procedures, the use of narcotic premedication is recommended.
  
  
  
  Midazolam hydrochloride 1 mg/mL formulation is recommended for 
  sedation/anxiolysis/amnesia for procedures to facilitate slower injection. 
  Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% 
  sodium chloride or 5% dextrose in water.
  
  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be 
  individualized and titrated. Midazolam hydrochloride should always be titrated 
  slowly; administer over at least 2 minutes and allow an additional 2 or more minutes 
  to fully evaluate the sedative effect.
  Individual response will vary with age, physical status and concomitant 
  medications, but may also vary independent of these factors. (See WARNINGS 
  concerning cardiac/respiratory arrest/ airway obstruction/hypoventilation.)
  
  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the 
  initiation of slurred speech. Some patients may respond to as little as 1 mg. No more 
  than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 
  or more minutes to fully evaluate the sedative effect. If further titration is 
  necessary, continue to titrate, using small increments, to the appropriate level of 
  sedation. Wait an additional 2 or more minutes after each increment to fully 
  evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary 
  to reach the desired endpoint.
        If narcotic premeditation or other CNS depressants are used, patients will require 
  approximately 30% less midazolam than unpremeditated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically III Patients: 
  Because the danger of hypoventilation, airway obstruction, or apnea is greater in 
  elderly patients and those with chronic disease states or decreased pulmonary 
  reserve, and because the peak effect may take longer in these patients, increments 
  should be smaller and the rate of injection slower.
        Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some 
  patients may respond to as little as 1 mg. No more than 1.5 mg should be given over 
  a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully 
  evaluate the sedative effect. If additional titration is necessary, it should be given at a 
  rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more 
  minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 
  mg are not usually necessary.
        If concomitant CNS depressant premedications are used in these patients, 
  they will require at least 50% less midazolam than healthy young 
  unpremedicated patients.
  
  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may 
  be given in increments of 25% of the dose used to first reach the sedative endpoint, 
  but again only by slow titration, especially in the elderly and chronically ill or 
  debilitated patient. These additional doses should be given only after a thorough 
  clinical evaluation clearly indicates the need for additional sedation.
  
  Induction of Anesthesia:
  For induction of general anesthesia, before administration of other anesthetic 
  agents.
  
  Individual response to the drug is variable, particularly when a narcotic premeditation 
  is not used. The dosage should be titrated to the desired effect according to the patient's 
  age and clinical status.
  When midazolam is used before other intravenous agents for induction of 
  anesthesia, the initial dose of each agent may be significantly reduced, at times to as 
  low as 25% of the usual initial dose of the individual agents.
  Unpremedicated Patients: In the absence of premedication, an average adult under the 
  age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for 
  induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. 
  If needed to complete induction, increments of approximately 25% of the patient's 
  initial dose may be used; induction may instead be completed with inhalational 
  anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, 
  but such larger doses may prolong recovery.
  Unpremedicated patients over the age of 55 years usually require less midazolam for 
  induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients 
  with severe systemic disease or other debilitation usually require less midazolam 
  for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, 
  as little as 0.15 mg/kg may suffice.
  Premedicated Patients: When the patient has received sedative or narcotic 
  premedication, particularly narcotic premedication, the range of recommended 
  doses is 0.15 to 0.35 mg/kg.
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 
  to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) 
  surgical patients over the age of 55 years. In some patients with severe systemic 
  disease or debilitation, as little as 0.15 mg/kg may suffice.
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 
  to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage 
  individualized, up to 0.15 mg/kg lM), and meperidine (dosage individualized, up to 1 
  mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and 
  sodium secobarbital (200 mg orally). 
  Except for intravenous fentanyl, administered 5 minutes before induction, 
  all other premedications should be administered approximately 1 hour prior to 
  the time anticipated for midazolam induction.
  
  Injectable midazolam hydrochloride can also be used during maintenance of 
  anesthesia, for surgical procedures, as a component of balanced anesthesia. 
  Effective narcotic premedication is especially recommended in such cases.
  
  CONTINUOUS INFUSION
  Far continuous infusion, midazolam hydrochloride 5 mg/mL formulation is 
  recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride 
  or 5% dextrose in water.
  
  Incremental injections of approximately 25% of the induction dose should be given 
  in response to signs of lightening of anesthesia and repeated as necessary.
  
  
  
  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 
  to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or 
  infused over several minutes. This dose may be repeated at 10 to 15 minute 
  intervals until adequate sedation is achieved. For maintenance of sedation, the 
  usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or 
  maintenance infusion rates may occasionally be required in some patients. 
  The lowest recommended doses should be used in patients with residual effects from 
  anesthetic drugs, or in those concurrently receiving other sedatives or opioids. 
  Individual response to midazolam is variable. The infusion rate should be 
  titrated to the desired level of sedation, taking into account the patient's age, 
  clinical status and current medications. In general, midazolam should be infused at 
  the lowest rate that produces the desired level of sedation. Assessment of sedation 
  should be performed at regular intervals and the midazolam infusion rate adjusted 
  up or down by 25% to 50% of the initial infusion rate so as to assure adequate 
  titration of sedation level. Larger adjustments or even a small incremental 
  dose may be necessary if rapid changes in the level of sedation are indicated. In 
  addition, the infusion rate should be decreased by 10% to 25% every few hours 
  to find the minimum effective infusion rate. Finding the minimum effective infusion 
  rate decreases the potential accumulation of midazolam and provides for the most rapid 
  recovery once the infusion is terminated. 
  Patients who exhibit agitation, hypertension, or tachycardia in response to 
  noxious stimulation, but who are otherwise adequately sedated, may benefit from 
  concurrent administration of an opioid analgesic. Addition of an opioid will 
  generally reduce the minimum effective midazolam hydrochloride infusion rate.
  
  PEDIATRIC PATIENTS
  
  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY 
  RECEIVE INCREMENTS OF MIDAZOLAM HYDROCHLORIDE 
  ON A MG/KG BASIS. As a group, pediatric patients generally require higher 
  dosages of midazolam hydrochloride (mg/kg) than do adults. Younger (less than 
  six years) pediatric patients may require higher dosages (mg/kg) than older pediatric 
  patients, and may require close monitoring (see tables below). In obese PEDIATRIC 
  PATIENTS, the dose should be calculated based on ideal body weight. When 
  midazolam is given in conjunction with opioids or other sedatives, the potential for 
  respiratory depression, airway obstruction, or hypoventilation is increased. For 
  appropriate patient monitoring, see Boxed WARNING, WARNINGS, and 
  DOSAGE AND ADMINISTRATION, MONITORING. The health care 
  practitioner who uses this medication in pediatric patients should be aware of and 
  follow accepted professional guidelines for pediatric sedation appropriate to their 
  situation.
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (0AA/S)
  Assessment Categories
  Responsiveness
  Speech
  Facial Expression
  Eyes
  Composite Score
  Responds readily to name spoken in normal tone
  normal
  normal
  clear, no ptosis
  5 (alert)
  Lethargic response to name spoken in normal tone
  mild slowing or thickening
  mild relaxation
  glazed or mild ptosis (less than  half the eye)
  4
  Responds only after name is called loudly and/or repeatedly
  slurring or prominent slowing
  marked relaxation (slack jaw)
  glazed and marked ptosis (half the eye or more)
  3
  Responds only after mild prodding or shaking
  few recognizable words
  -
  -
  2
  Does not respond to mild prodding or shaking
  -
  -
  -
  1 (deep sleep)
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING
  PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  Age Range
  (years)
  n
  OAA/S Score
  
  
  1 (deep sleep)
  2
  3
  4
  5 (alert)
  1-2
  16
  6 (38%)
  4 (25%)
  3 (19%)
  3 (19%)
  0
  >2-5
  22
  9 (41%)
  5 (23%)
  8 (36%)
  0
  0
  >5-12
  34
  1 (3%)
  6 (18%)
  22 (65%)
  5 (15%)
  0
  >12-17
  18
  0
  4 (22%)
  14 (78%)
  0
  0
  Total (1-17)
  90
  16 (18%)
  19 (21%)
  47 (52%)
  8 (9%)
  0
  
  INTRAMUSCULARLY
  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular
  midazolam can be used to sedate pediatric patients to facilitate less traumatic
  insertion of an intravenous catheter for titration of additional medication.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  Sedation after intramuscular midazolam is age and dose dependent: higher doses may 
  result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are 
  usually effective and do not prolong emergence from general anesthesia. For 
  more anxious patients, doses up to 0.5 mg/kg have been used. Although not 
  systematically studied, the total dose usually does not exceed 10 mg. If 
  midazolam is given with an opioid, the initial dose of each must be reduced.
  
  INTRAVENOUSLY BY INTERMITTENT INJECTION
  For sedation/anxiolysis/amnesia prior to and during procedures or prior to 
  anesthesia.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation/anxiolysis needed for pediatric 
  patients depends on the type of procedure to be performed. For example, simple light 
  sedation/anxiolysis in the preoperative period is quite different from the deep 
  sedation and analgesia required for an endoscopic procedure in a child. For this 
  reason, there is a broad range of dosage. For all pediatric patients, regardless of the 
  indications for sedation/anxiolysis, it is vital to titrate midazolam hydrochloride and 
  other concomitant medications slowly to the desired clinical effect. The initial dose of 
  midazolam should be administered over 2 to 3 minutes. Since midazolam hydrochloride 
  is water soluble, it takes approximately three times longer than diazepam to achieve 
  peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully 
  evaluate the sedative effect before initiating a procedure or repeating a dose. If further 
  sedation is necessary, continue to titrate with small increments until the appropriate 
  level of sedation is achieved. If other medications capable of depressing the CNS 
  are coadministered, the peak effect of those concomitant medications must be 
  considered and the dose of midazolam adjusted. The importance of drug titration to 
  effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of 
  midazolam will depend on patient response, the type and duration of the procedure, as 
  well as the type and dose of concomitant medications.
  
  1. Pediatric patients less than 6 months of age: Limited information is available in 
  non-intubated pediatric patients less than 6 months of age. It is uncertain when the 
  patient transfers from neonatal physiology to pediatric physiology, therefore the dosing 
  recommendations are unclear pediatric patients less than 6 months of age are 
  particularly vulnerable to airway obstruction and hypoventilation, therefore 
  titration with small increments to clinical effect and careful monitoring are essential. 
  2.  Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total 
  dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does 
  not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated 
  with the higher doses.
  3.  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose 
  up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not 
  exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with 
  the higher doses.
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults: Prolonged 
  sedation may be associated with higher doses; some patients in this age range will 
  require higher than recommended adult doses but the total dose usually does not 
  exceed 10 mg. 
  
  The dose of midazolam hydrochloride must be reduced in patients premedicated with 
  opioid or other sedative agents including midazolam. Higher risk or debilitated 
  patients may require lower dosages whether or not concomitant sedating medications 
  have been administered (see WARNINGS).
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation/anxiolysis/amnesia in critical care settings.
  
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over 
  at least 2 to 3 minutes can be used to establish the desired clinical effect IN 
  PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be 
  administered as a rapid intravenous dose.) This loading dose may be followed by a 
  continuous intravenous infusion to maintain the effect. An infusion of midazolam 
  hydrochloride injection has been used in patients whose trachea was intubated but 
  who were allowed to breathe spontaneously. Assisted ventilation is recommended for 
  pediatric patients who are receiving other central nervous system depressant 
  medications such as opioids. Based on pharmacokinetic parameters and reported 
  clinical experience, continuous intravenous infusions of midazolam should be initiated 
  at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be 
  increased or decreased (generally by 25% of the initial or subsequent infusion rate) as 
  required, or supplemental intravenous doses of midazolam hydrochloride can be 
  administered to increase or maintain the desired effect Frequent assessment at 
  regular intervals using standard pain/sedation scales is recommended. Drug 
  elimination may be delayed in patients receiving erythromycin and/or other P450-3A4
  enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients 
  with liver dysfunction, low cardiac output (especially those requiring inotropic 
  support), and in neonates. Hypotension may be observed in patients who are critically ill, 
  particularly those receiving opioids and/or when midazolam is rapidly administered. 
  When initiating an infusion with midazolam in hemodynamically compromised patients, 
  the usual loading dose of midazolam hydrochloride should be titrated in small 
  increments and the patient monitored for hemodynamic instability, e.g., hypotension. 
  These patients are also vulnerable to the respiratory depressant effects of midazolam 
  and require careful monitoring of respiratory rate and oxygen saturation.
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation in critical care settings.
  
  
  USUAL  NEONATAL  DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and 
  term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous 
  infusions of midazolam hydrochloride injection should be initiated at a rate of 0.03 
  mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in 
  neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather 
  the infusion may be run more rapidly for the first several hours to establish therapeutic 
  plasma levels. The rate of infusion should be carefully and frequently reassessed, 
  particularly after the first 24 hours so as to administer the lowest possible effective 
  dose and reduce the potential for drug accumulation. This is particularly important 
  because of the potential for adverse effects related to metabolism of the benzyl alcohol 
  (see WARNINGS: Usage in Preterm Infants and Neonates). Hypotension may 
  be observed in patients who are critically ill and in preterm and term infants, particularly 
  those receiving fentanyl and/or when midazolam is administered rapidly. Due to 
  an increased risk of apnea, extreme caution is advised when sedating preterm and 
  former preterm patients whose trachea is not intubated.
  

  Note:  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Wockhardt Limited

  

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  Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam.  BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING. DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNINGand WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS).

  Midazolam hydrochloride injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).      

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE
  INTRAMUSCULARLY
  For preoperative sedation/anxiolysis/ amnesia (induction of sleepiness or drowsiness and relief of apprehension
  and to impair memory of perioperative events).
  For intramuscular use, midazolam
  hydrochloride should be injected deep in a large muscle mass.
  The recommended premedication dose of midazolam for good risk (ASA Physical 
  Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM 
  (approximately 5 mg IM) administered up to 1 hour before surgery.
  The dose must be individualized and reduced when IM midazolam is administered to patients
  with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60
  or more years of age, and patients who have received concomitant narcotics or other CNS
  depressants (see ADVERSE REACTIONS). 
  In a study of patients 60 years or older, who did not receive concomitant administration 
  of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during
  the preoperative period. The dose of 1 mg IM midazolam hydrochloride may suffice for some
  older patients if the anticipated intensity and duration of sedation is less critical. As with any
  potential respiratory depressant, these patients require observation for signs of cardiorespiratory
  depression after receiving IM midazolam.
  Onset is within 15 minutes, peaking at 30 to 60 minutes. it can be administered concomitantly
  with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.
  INTRAVENOUSLY
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): 
  Narcotic premedication results In less variability in patient response and a
  reduction in dosage of midazolam. For peroral procedures, the use of an 
  appropriate topical anesthetic is recommended. For bronchoscopic 
  procedures, the use of narcotic premedication is recommended.
  
  
  Midazolam hydrochloride 1 mg/mL formulation is recommended for 
  sedation/anxiolysis/amnesia for procedures to facilitate slower injection. 
  Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% 
  sodium chloride or 5% dextrose in water.
  When used for sedation/anxiolysis/ amnesia for a procedure, dosage must be individualized and 
  titrated. Midazolam hydrochloride should always be titrated slowly; administer over at least 2 
  minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. 
  Individual response will vary with age, physical status and concomitant medications, but may also 
  vary independent of these factors. (See WARNINGS concerning cardiac/ 
  respiratory arrest/airway obstruction/ hypoventilation.)
  
  
  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of 
  slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be 
  given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the 
  sedative effect. If further titration is necessary, continue to titrate, using small increments, to the 
  appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully 
  evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the 
  desired endpoint.
  If narcotic premeditation or other CNS depressants are used, patients will require 
  approximately 30% less midazolam than unpremeditated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of 
  hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic 
  disease states or decreased pulmonary reserve, and because the peak effect may take longer in 
  these patients, increments should be smaller and the rate of injection slower. Titrate slowly to the 
  desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 
  1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an 
  additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is 
  necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an 
  additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater 
  than 3.5 mg are not usually necessary.
  If concomitant CNS depressant premedications are used in these patients, they will require at 
  least 50% less midazolam than healthy young unpremedicated patients.
  
  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may be 
  given in increments of 25% of the dose used to first reach the sedative endpoint, but again only 
  by slow titration, especially in the elderly and chronically ill or debilitated patient. These 
  additional doses should be given only after a thorough clinical evaluation clearly indicates the 
  need for additional sedation.
  Induction of Anesthesia:
  For induction of general anesthesia, before administration of other anesthetic 
  agents.
  Individual response to the drug is variable, particularly when a narcotic premeditation is not 
  used. The dosage should be titrated to the desired effect according to the patient's age and clinical 
  status.
  When midazolam is used before other intravenous agents for induction of anesthesia, 
  the initial dose of each agent may be significantly reduced, at times to as low as 25% 
  of the usual initial dose of the individual agents.
  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 
  55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 
  20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, 
  increments of approximately 25% of the patient's initial dose may be used; induction may instead 
  be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be 
  used for induction, but such larger doses may prolong recovery.
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an 
  initial dose of 0.3 mg/kg is recommended. 
  Unpremedicated patients with severe systemic disease or other debilitation usually require less 
  midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, 
  as little as 0.15 mg/kg may suffice.
  Premedicated Patients: When the patient has received sedative or narcotic premedication, 
  particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 
  seconds and allowing 2 minutes for effect, will usually suffice.
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the 
  age of 55 years.
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg 
  IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 
  mg/kg lM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative 
  premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg 
  orally). Except for intravenous fentanyl, administered 5 minutes before induction, all 
  other premedications should be administered approximately 1 hour prior to the time 
  anticipated for midazolam induction.
  Injectable midazolam hydrochloride can also be used during maintenance of 
  anesthesia, for surgical procedures, as a component of balanced anesthesia. 
  Effective narcotic premedication is especially recommended in such cases.
  Incremental injections of approximately 25% of the induction dose should be given in response to 
  signs of lightening of anesthesia and repeated as necessary.
  CONTINUOUS INFUSION
  Far continuous infusion, midazolam hydrochloride 5 mg/mL formulation is 
  recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride 
  or 5% dextrose in water.
  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg 
  (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several 
  minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is 
  achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 
  mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some 
  patients. The lowest recommended doses should be used in patients with residual effects from 
  anesthetic drugs, or in those concurrently receiving other sedatives or opioids. 
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired 
  level of sedation, taking into account the patient's age, clinical status and current medications. In 
  general, midazolam should be infused at the lowest rate that produces the desired level of 
  sedation. 
  Assessment of sedation should be performed at regular intervals and the midazolam infusion rate 
  adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of 
  sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid 
  changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 
  10% to 25% every few hours to find the minimum effective infusion rate. Finding the 
  minimum effective infusion rate decreases the potential accumulation of midazolam and 
  provides for the most rapid recovery once the infusion is terminated. Patients who exhibit 
  agitation, hypertension, or tachycardia in response to noxious stimulation, but who are 
  otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. 
  Addition of an opioid will generally reduce the minimum effective midazolam hydrochloride 
  infusion rate.
  PEDIATRIC PATIENTS
  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE 
  INCREMENTS OF MIDAZOLAM HYDROCHLORIDE ON A MG/KG BASIS. 
  As a group, pediatric patients generally require higher dosages of midazolam hydrochloride 
  (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher 
  dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables 
  below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body 
  weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for 
  respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate 
  patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, 
  MONITORING. The health care practitioner who uses this medication in pediatric patients 
  should be aware of and follow accepted professional guidelines for pediatric sedation 
  appropriate to their situation.
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (0AA/S)
  Assessment Categories
  Responsiveness
  Speech
  Facial Expression
  Eyes
  Composite Score
  Responds readily to name spoken in normal tone
  normal
  normal
  clear, no ptosis
  5 (alert)
  Lethargic response to name spoken in normal tone
  mild slowing or thickening
  mild relaxation
  glazed or mild ptosis (less than  half the eye)
  4
  Responds only after name is called loudly and/or repeatedly
  slurring or prominent slowing
  marked relaxation (slack jaw)
  glazed and marked ptosis (half the eye or more)
  3
  Responds only after mild prodding or shaking
  few recognizable words
  -
  -
  2
  Does not respond to mild prodding or shaking
  -
  -
  -
  1 (deep sleep)
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING
  PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  Age Range
  (years)
  n
  OAA/S Score
  
  
  1 (deep sleep)
  2
  3
  4
  5 (alert)
  1-2
  16
  6 (38%)
  4 (25%)
  3 (19%)
  3 (19%)
  0
  >2-5
  22
  9 (41%)
  5 (23%)
  8 (36%)
  0
  0
  >5-12
  34
  1 (3%)
  6 (18%)
  22 (65%)
  5 (15%)
  0
  >12-17
  18
  0
  4 (22%)
  14 (78%)
  0
  0
  Total (1-17)
  90
  16 (18%)
  19 (21%)
  47 (52%)
  8 (9%)
  0
  INTRAMUSCULARLY
  For sedation/anxiolysis /amnesia prior to anesthesia or for procedures, intramuscular 
  midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion 
  of an intravenous catheter for titration of additional medication.
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  Sedation after intramuscular midazolam is age and dose dependent: higher doses may 
  result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are 
  usually effective and do not prolong emergence from general anesthesia. For 
  more anxious patients, doses up to 0.5 mg/kg have been used. Although not 
  systematically studied, the total dose usually does not exceed 10 mg. If 
  midazolam is given with an opioid, the initial dose of each must be reduced.
  
  INTRAVENOUSLY BY 
  INTERMITTENT INJECTION
  For sedation/anxiolysis/amnesia prior to and during procedures or prior to 
  anesthesia.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation /anxiolysis needed for pediatric 
  patients depends on the type of procedure to be performed. For example, simple light 
  sedation/anxiolysis in the preoperative period is quite different from the deep 
  sedation and analgesia required for an endoscopic procedure in a child. For this 
  reason, there is a broad range of dosage. For all pediatric patients, regardless of the 
  indications for sedation/anxiolysis, it is vital to titrate midazolam hydrochloride 
  and other concomitant medications slowly to the desired clinical effect. The initial 
  dose of midazolam should be administered over 2 to 3 minutes. Since midazolam 
  hydrochloride is water soluble, it takes approximately three times longer than 
  diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 
  minutes to fully evaluate the sedative effect before initiating a procedure or repeating a 
  dose. If further sedation is necessary, continue to titrate with small increments 
  until the appropriate level of sedation is achieved. If other medications capable of 
  depressing the CNS are coadministered, the peak effect of those concomitant 
  medications must be considered and the dose of midazolam adjusted. The 
  importance of drug titration to effect is vital to the safe sedation/anxiolysis of the 
  pediatric patient. The total dose of midazolam will depend on patient 
  response, the type and duration of the procedure, as well as the type and dose of 
  concomitant medications.
  
  1.  Pediatric patients less than 6 months of age: Limited information is available in 
  non-intubated pediatric patients less than 6 months of age. It is uncertain when the 
  patient transfers from neonatal physiology to pediatric physiology, therefore the 
  dosing recommendations are unclear, Pediatric patients less than 6 months of age 
  are particularly vulnerable to airway obstruction and hypoventilation, therefore 
  titration with small increments to clinical effect and careful monitoring are essential.
  
  2.  Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total 
  dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does 
  not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated 
  with the higher doses.
  
  3.  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose 
  up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not 
  exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with 
  the higher doses.
  
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged 
  sedation may be associated with higher doses; some patients in this age range will 
  require higher than recommended adult doses but the total dose usually does not 
  exceed 10 mg. 
  
  The dose of midazolam hydrochloride must be reduced in patients premedicated with 
  opioid or other sedative agents including midazolam. Higher risk or debilitated 
  patients may require lower dosages whether or not concomitant sedating 
  medications have been administered (see WARNINGS).
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation/anxiolysis/amnesia in critical care settings.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered 
  over at least 2 to 3 minutes can be used to establish the desired clinical effect IN 
  PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be 
  administered as a rapid intravenous dose.) This loading dose may be followed by a 
  continuous intravenous infusion to maintain the effect. An infusion of 
  midazolam hydrochloride injection has been used in patients whose trachea was 
  intubated but who were allowed to breathe spontaneously. Assisted ventilation is 
  recommended for pediatric patients who are receiving other central nervous system 
  depressant medications such as opioids. Based on pharmacokinetic parameters and 
  reported clinical experience, continuous intravenous infusions of midazolam should 
  be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of 
  infusion can be increased or decreased (generally by 25% of the initial or 
  subsequent infusion rate) as required, or supplemental intravenous doses of 
  midazolam hydrochloride can be administered to increase or maintain the 
  desired effect. Frequent assessment at regular intervals using standard 
  pain/sedation scales is recommended. Drug elimination may be delayed in patients 
  receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, 
  Drug Interactions section) and in patients with liver dysfunction, low 
  cardiac output (especially those requiring inotropic support), and in neonates. 
  Hypotension may be observed in patients who are critically ill, particularly those 
  receiving opioids and/or when midazolam is rapidly administered. 
  When initiating an infusion with midazolam in hemodynamically 
  compromised patients, the usual loading dose of midazolam hydrochloride should 
  be titrated in small increments and the patient monitored for hemodynamic 
  instability, e.g., hypotension. These patients are also vulnerable to the 
  respiratory depressant effects of midazolam and require careful monitoring of 
  respiratory rate and oxygen saturation.
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation in critical care settings.
  
  USUAL  NEONATAL  DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and 
  term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous 
  infusions of midazolam hydrochloride injection should be initiated at a rate of 
  0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 
  mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be 
  used in neonates, rather the infusion may be run more rapidly for the first several 
  hours to establish therapeutic plasma levels. The rate of infusion should be 
  carefully and frequently reassessed, particularly after the first 24 hours so as to 
  administer the lowest possible effective dose and reduce the potential for drug 
  accumulation. Hypotension may be observed in patients who are critically ill 
  and in preterm and term infants, particularly those receiving fentanyl and/or 
  when midazolam is administered rapidly. Due to an increased risk of apnea, extreme 
  caution is advised when sedating preterm and former preterm patients whose trachea 
  is not intubated.
  

  Note:  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Wockhardt Limited

  

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  Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam.  BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING. DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNINGand WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS).

  Midazolam hydrochloride injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).      

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE
  INTRAMUSCULARLY
  For preoperative sedation/anxiolysis/ amnesia (induction of sleepiness or 
  drowsiness and relief of apprehension and to impair memory of perioperative 
  events).
  For intramuscular use, midazolam hydrochloride should be injected deep in 
  a large muscle mass.
  
  
  The recommended premedication dose of midazolam for good risk (ASA Physical 
  Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM 
  (approximately 5 mg IM) administered up to 1 hour before surgery.
  The dose must be individualized and reduced when IM midazolam is 
  administered to patients with chronic obstructive pulmonary disease, other higher 
  risk surgical patients, patients 60 or more years of age, and patients who have 
  received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS).
  In a study of patients 60 years or older, who did not receive concomitant administration
  of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation
  during the preoperative period. The dose of 1 mg IM midazolam hydrochloride may
  suffice for some older patients if the anticipated intensity and duration of
  sedation is less critical. As with any potential respiratory depressant, these 
  patients require observation for signs of cardiorespiratory depression after receiving
  IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. 
  It can be administered concomitantly with atropine sulfate or scopolamine 
  hydrochloride and reduced doses of narcotics.
  
  INTRAVENOUSLY
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): 
  Narcotic premedication results in less variability in patient response and a 
  reduction in dosage of midazolam. For peroral procedures, the use of an 
  appropriate topical anesthetic is recommended. For bronchoscopic 
  procedures, the use of narcotic premedication is recommended.
  
  
  
  Midazolam hydrochloride 1 mg/mL formulation is recommended for 
  sedation/anxiolysis/amnesia for procedures to facilitate slower injection. 
  Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% 
  sodium chloride or 5% dextrose in water.
  
  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be 
  individualized and titrated. Midazolam hydrochloride should always be titrated 
  slowly; administer over at least 2 minutes and allow an additional 2 or more minutes 
  to fully evaluate the sedative effect.
  Individual response will vary with age, physical status and concomitant 
  medications, but may also vary independent of these factors. (See WARNINGS 
  concerning cardiac/respiratory arrest/ airway obstruction/hypoventilation.)
  
  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the 
  initiation of slurred speech. Some patients may respond to as little as 1 mg. No more 
  than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 
  or more minutes to fully evaluate the sedative effect. If further titration is 
  necessary, continue to titrate, using small increments, to the appropriate level of 
  sedation. Wait an additional 2 or more minutes after each increment to fully 
  evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary 
  to reach the desired endpoint.
        If narcotic premeditation or other CNS depressants are used, patients will require 
  approximately 30% less midazolam than unpremeditated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically III Patients: 
  Because the danger of hypoventilation, airway obstruction, or apnea is greater in 
  elderly patients and those with chronic disease states or decreased pulmonary 
  reserve, and because the peak effect may take longer in these patients, increments 
  should be smaller and the rate of injection slower.
        Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some 
  patients may respond to as little as 1 mg. No more than 1.5 mg should be given over 
  a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully 
  evaluate the sedative effect. If additional titration is necessary, it should be given at a 
  rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more 
  minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 
  mg are not usually necessary.
        If concomitant CNS depressant premedications are used in these patients, 
  they will require at least 50% less midazolam than healthy young 
  unpremedicated patients.
  
  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may 
  be given in increments of 25% of the dose used to first reach the sedative endpoint, 
  but again only by slow titration, especially in the elderly and chronically ill or 
  debilitated patient. These additional doses should be given only after a thorough 
  clinical evaluation clearly indicates the need for additional sedation.
  
  Induction of Anesthesia:
  For induction of general anesthesia, before administration of other anesthetic 
  agents.
  
  Individual response to the drug is variable, particularly when a narcotic premeditation 
  is not used. The dosage should be titrated to the desired effect according to the patient's 
  age and clinical status.
  When midazolam is used before other intravenous agents for induction of 
  anesthesia, the initial dose of each agent may be significantly reduced, at times to as 
  low as 25% of the usual initial dose of the individual agents.
  Unpremedicated Patients: In the absence of premedication, an average adult under the 
  age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for 
  induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. 
  If needed to complete induction, increments of approximately 25% of the patient's 
  initial dose may be used; induction may instead be completed with inhalational 
  anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, 
  but such larger doses may prolong recovery.
  Unpremedicated patients over the age of 55 years usually require less midazolam for 
  induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients 
  with severe systemic disease or other debilitation usually require less midazolam 
  for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, 
  as little as 0.15 mg/kg may suffice.
  Premedicated Patients: When the patient has received sedative or narcotic 
  premedication, particularly narcotic premedication, the range of recommended 
  doses is 0.15 to 0.35 mg/kg.
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 
  to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) 
  surgical patients over the age of 55 years. In some patients with severe systemic 
  disease or debilitation, as little as 0.15 mg/kg may suffice.
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 
  to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage 
  individualized, up to 0.15 mg/kg lM), and meperidine (dosage individualized, up to 1 
  mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and 
  sodium secobarbital (200 mg orally). 
  Except for intravenous fentanyl, administered 5 minutes before induction, 
  all other premedications should be administered approximately 1 hour prior to 
  the time anticipated for midazolam induction.
  
  Injectable midazolam hydrochloride can also be used during maintenance of 
  anesthesia, for surgical procedures, as a component of balanced anesthesia. 
  Effective narcotic premedication is especially recommended in such cases.
  
  CONTINUOUS INFUSION
  Far continuous infusion, midazolam hydrochloride 5 mg/mL formulation is 
  recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride 
  or 5% dextrose in water.
  
  Incremental injections of approximately 25% of the induction dose should be given 
  in response to signs of lightening of anesthesia and repeated as necessary.
  
  
  
  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 
  to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or 
  infused over several minutes. This dose may be repeated at 10 to 15 minute 
  intervals until adequate sedation is achieved. For maintenance of sedation, the 
  usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or 
  maintenance infusion rates may occasionally be required in some patients. 
  The lowest recommended doses should be used in patients with residual effects from 
  anesthetic drugs, or in those concurrently receiving other sedatives or opioids. 
  Individual response to midazolam is variable. The infusion rate should be 
  titrated to the desired level of sedation, taking into account the patient's age, 
  clinical status and current medications. In general, midazolam should be infused at 
  the lowest rate that produces the desired level of sedation. Assessment of sedation 
  should be performed at regular intervals and the midazolam infusion rate adjusted 
  up or down by 25% to 50% of the initial infusion rate so as to assure adequate 
  titration of sedation level. Larger adjustments or even a small incremental 
  dose may be necessary if rapid changes in the level of sedation are indicated. In 
  addition, the infusion rate should be decreased by 10% to 25% every few hours 
  to find the minimum effective infusion rate. Finding the minimum effective infusion 
  rate decreases the potential accumulation of midazolam and provides for the most rapid 
  recovery once the infusion is terminated. 
  Patients who exhibit agitation, hypertension, or tachycardia in response to 
  noxious stimulation, but who are otherwise adequately sedated, may benefit from 
  concurrent administration of an opioid analgesic. Addition of an opioid will 
  generally reduce the minimum effective midazolam hydrochloride infusion rate.
  
  PEDIATRIC PATIENTS
  
  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY 
  RECEIVE INCREMENTS OF MIDAZOLAM HYDROCHLORIDE 
  ON A MG/KG BASIS. As a group, pediatric patients generally require higher 
  dosages of midazolam hydrochloride (mg/kg) than do adults. Younger (less than 
  six years) pediatric patients may require higher dosages (mg/kg) than older pediatric 
  patients, and may require close monitoring (see tables below). In obese PEDIATRIC 
  PATIENTS, the dose should be calculated based on ideal body weight. When 
  midazolam is given in conjunction with opioids or other sedatives, the potential for 
  respiratory depression, airway obstruction, or hypoventilation is increased. For 
  appropriate patient monitoring, see Boxed WARNING, WARNINGS, and 
  DOSAGE AND ADMINISTRATION, MONITORING. The health care 
  practitioner who uses this medication in pediatric patients should be aware of and 
  follow accepted professional guidelines for pediatric sedation appropriate to their 
  situation.
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (0AA/S)
  Assessment Categories
  Responsiveness
  Speech
  Facial Expression
  Eyes
  Composite Score
  Responds readily to name spoken in normal tone
  normal
  normal
  clear, no ptosis
  5 (alert)
  Lethargic response to name spoken in normal tone
  mild slowing or thickening
  mild relaxation
  glazed or mild ptosis (less than  half the eye)
  4
  Responds only after name is called loudly and/or repeatedly
  slurring or prominent slowing
  marked relaxation (slack jaw)
  glazed and marked ptosis (half the eye or more)
  3
  Responds only after mild prodding or shaking
  few recognizable words
  -
  -
  2
  Does not respond to mild prodding or shaking
  -
  -
  -
  1 (deep sleep)
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING
  PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  Age Range
  (years)
  n
  OAA/S Score
  
  
  1 (deep sleep)
  2
  3
  4
  5 (alert)
  1-2
  16
  6 (38%)
  4 (25%)
  3 (19%)
  3 (19%)
  0
  >2-5
  22
  9 (41%)
  5 (23%)
  8 (36%)
  0
  0
  >5-12
  34
  1 (3%)
  6 (18%)
  22 (65%)
  5 (15%)
  0
  >12-17
  18
  0
  4 (22%)
  14 (78%)
  0
  0
  Total (1-17)
  90
  16 (18%)
  19 (21%)
  47 (52%)
  8 (9%)
  0
  
  INTRAMUSCULARLY
  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular
  midazolam can be used to sedate pediatric patients to facilitate less traumatic
  insertion of an intravenous catheter for titration of additional medication.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  Sedation after intramuscular midazolam is age and dose dependent: higher doses may 
  result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are 
  usually effective and do not prolong emergence from general anesthesia. For 
  more anxious patients, doses up to 0.5 mg/kg have been used. Although not 
  systematically studied, the total dose usually does not exceed 10 mg. If 
  midazolam is given with an opioid, the initial dose of each must be reduced.
  
  INTRAVENOUSLY BY INTERMITTENT INJECTION
  For sedation/anxiolysis/amnesia prior to and during procedures or prior to 
  anesthesia.
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation/anxiolysis needed for pediatric 
  patients depends on the type of procedure to be performed. For example, simple light 
  sedation/anxiolysis in the preoperative period is quite different from the deep 
  sedation and analgesia required for an endoscopic procedure in a child. For this 
  reason, there is a broad range of dosage. For all pediatric patients, regardless of the 
  indications for sedation/anxiolysis, it is vital to titrate midazolam hydrochloride and 
  other concomitant medications slowly to the desired clinical effect. The initial dose of 
  midazolam should be administered over 2 to 3 minutes. Since midazolam hydrochloride 
  is water soluble, it takes approximately three times longer than diazepam to achieve 
  peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully 
  evaluate the sedative effect before initiating a procedure or repeating a dose. If further 
  sedation is necessary, continue to titrate with small increments until the appropriate 
  level of sedation is achieved. If other medications capable of depressing the CNS 
  are coadministered, the peak effect of those concomitant medications must be 
  considered and the dose of midazolam adjusted. The importance of drug titration to 
  effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of 
  midazolam will depend on patient response, the type and duration of the procedure, as 
  well as the type and dose of concomitant medications.
  
  1. Pediatric patients less than 6 months of age: Limited information is available in 
  non-intubated pediatric patients less than 6 months of age. It is uncertain when the 
  patient transfers from neonatal physiology to pediatric physiology, therefore the dosing 
  recommendations are unclear pediatric patients less than 6 months of age are 
  particularly vulnerable to airway obstruction and hypoventilation, therefore 
  titration with small increments to clinical effect and careful monitoring are essential. 
  2.  Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total 
  dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does 
  not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated 
  with the higher doses.
  3.  Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose 
  up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not 
  exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with 
  the higher doses.
  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults: Prolonged 
  sedation may be associated with higher doses; some patients in this age range will 
  require higher than recommended adult doses but the total dose usually does not 
  exceed 10 mg. 
  
  The dose of midazolam hydrochloride must be reduced in patients premedicated with 
  opioid or other sedative agents including midazolam. Higher risk or debilitated 
  patients may require lower dosages whether or not concomitant sedating medications 
  have been administered (see WARNINGS).
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation/anxiolysis/amnesia in critical care settings.
  
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over 
  at least 2 to 3 minutes can be used to establish the desired clinical effect IN 
  PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be 
  administered as a rapid intravenous dose.) This loading dose may be followed by a 
  continuous intravenous infusion to maintain the effect. An infusion of midazolam 
  hydrochloride injection has been used in patients whose trachea was intubated but 
  who were allowed to breathe spontaneously. Assisted ventilation is recommended for 
  pediatric patients who are receiving other central nervous system depressant 
  medications such as opioids. Based on pharmacokinetic parameters and reported 
  clinical experience, continuous intravenous infusions of midazolam should be initiated 
  at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be 
  increased or decreased (generally by 25% of the initial or subsequent infusion rate) as 
  required, or supplemental intravenous doses of midazolam hydrochloride can be 
  administered to increase or maintain the desired effect Frequent assessment at 
  regular intervals using standard pain/sedation scales is recommended. Drug 
  elimination may be delayed in patients receiving erythromycin and/or other P450-3A4
  enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients 
  with liver dysfunction, low cardiac output (especially those requiring inotropic 
  support), and in neonates. Hypotension may be observed in patients who are critically ill, 
  particularly those receiving opioids and/or when midazolam is rapidly administered. 
  When initiating an infusion with midazolam in hemodynamically compromised patients, 
  the usual loading dose of midazolam hydrochloride should be titrated in small 
  increments and the patient monitored for hemodynamic instability, e.g., hypotension. 
  These patients are also vulnerable to the respiratory depressant effects of midazolam 
  and require careful monitoring of respiratory rate and oxygen saturation.
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation in critical care settings.
  
  
  USUAL  NEONATAL  DOSE
  Based on pharmacokinetic parameters and reported clinical experience in preterm and 
  term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous 
  infusions of midazolam hydrochloride injection should be initiated at a rate of 0.03 
  mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in 
  neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather 
  the infusion may be run more rapidly for the first several hours to establish therapeutic 
  plasma levels. The rate of infusion should be carefully and frequently reassessed, 
  particularly after the first 24 hours so as to administer the lowest possible effective 
  dose and reduce the potential for drug accumulation. This is particularly important 
  because of the potential for adverse effects related to metabolism of the benzyl alcohol 
  (see WARNINGS: Usage in Preterm Infants and Neonates). Hypotension may 
  be observed in patients who are critically ill and in preterm and term infants, particularly 
  those receiving fentanyl and/or when midazolam is administered rapidly. Due to 
  an increased risk of apnea, extreme caution is advised when sedating preterm and 
  former preterm patients whose trachea is not intubated.
  

  Note:  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | General Injectables & Vaccines, Inc

  

  ---

  Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT T0 WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS). Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS). Midazolam hydrochloride injection should only be administered IM or IV (see WARNINGS). Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS). Midazolam Hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine
  sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/ mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.
  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).
  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting. Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam. Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).
  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.
  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  INTRAMUSCULARLY
  For preoperative sedation/anxiolysis/ amnesia (induction of
  sleepiness or drowsiness and relief of apprehension and to impair
  memory of perioperative events).
  For intramuscular use, midazolam hydrochloride should be
  injected deep in a large muscle mass.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  The recommended premedication dose of midazolam for good
  risk (ASA Physical Status I and II) adult patients below the age
  of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM)
  administered up to 1 hour before surgery.
  The dose must be individualized and reduced when IM
  midazolam is administered to patients with chronic obstructive
  pulmonary disease, other higher risk surgical patients, patients
  60 or more years of age, and patients who have received
  concomitant narcotics or other CNS depressants (see ADVERSE
  REACTIONS). In a study of patients 60 years or older, who did
  not receive concomitant administration of narcotics, 2 to 3 mg
  (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation
  during the preoperative period. The dose of 1 mg IM midazolam
  may suffice for some older patients if the anticipated intensity
  and duration of sedation is less critical. As with any potential
  respiratory depressant, these patients require observation for signs
  of cardiorespiratory depression after receiving IM midazolam.
  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be
  administered concomitantly with atropine sulfate or scopolamine
  hydrochloride and reduced doses of narcotics.
  INTRAVENOUSLY
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS
  AND USAGE): Narcotic premedication results in less variability
  in patient response and a reduction in dosage of midazolam. For
  peroral procedures, the use of an appropriate topical anesthetic is
  recommended. For bronchoscopic procedures, the use of narcotic
  premedication is recommended.Midazolam hydrochloride 1 mg/mL
  formulation is recommended for sedation/anxiolysis/amnesia for
  procedures to facilitate slowerinjection. Both the 1 mg/mL and the
  5 mg/mL formulations may be diluted with 0.9% sodium chloride
  or 5% dextrose in water.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  When used for sedation/anxiolysis/amnesia for a procedure,
  dosage must be individualized and titrated. Midazolam
  hydrochloride should always be titrated slowly; administer over at
  least 2 minutes and allow an additional 2 or more minutes to fully
  evaluate the sedative effect. Individual response will vary with
  age, physical status and concomitant medications, but may also
  vary independent of these factors. (See WARNINGS concerning
  cardiac/respiratory arrest/airway obstruction/ hypoventilation.)
  
  1. Healthy Adults Below the Age of 60: Titrate slowly to the
  desired effect, (e.g., the initiation of slurred speech). Some
  patients may respond to as little as 1 mg. No more than 2.5
  mg should be given over a period of at least 2 minutes. Wait
  an additional 2 or more minutes to fully evaluate the sedative
  effect. If further titration is necessary, continue to titrate, using
  small increments, to the appropriate level of sedation. Wait
  an additional 2 or more minutes after each increment to fully
  evaluate the sedative effect. A total dose greater than 5 mg is
  not usually necessary to reach the desired endpoint.
  If narcotic premedication or other CNS depressants are used,
  patients will require approximately 30% less midazolam than
  unpremedicated patients.
  
  2. Patients Age 60 or Older, and Debilitated or Chronically
  III Patients: Because the danger of hypoventilation, airway
  obstruction, or apnea is greater in elderly patients and those
  with chronic disease states or decreased pulmonary reserve,
  and because the peak effect may take longer in these patients,
  increments should be smaller and the rate of injection slower.
  Titrate slowly to the desired effect, (e.g., the initiation of
  slurred speech). Some patients may respond to as little as 1
  mg. No more than 1.5 mg should be given over a period of
  no less than 2 minutes. Wait an additional 2 or more minutes
  to fully evaluate the sedative effect. If additional titration is
  necessary, it should be given at a rate of no more than 1 mg
  over a period of 2 minutes, waiting an additional 2 or more
  minutes each time to fully evaluate the sedative effect. Total
  doses greater than 3.5 mg are not usually necessary.
  If concomitant CNS depressant premedications are used in
  these patients, they will require at least 50% less midazolam
  than healthy young unpremedicated patients.
  
  3. Maintenance Dose: Additional doses to maintain the desired
  level of sedation may be given in increments of 25% of the
  dose used to first reach the sedative endpoint, but again only
  by slow titration, especially in the elderly and chronically ill
  or debilitated patient. These additional doses should be given
  only after a thorough clinical evaluation clearly indicates the
  need for additional sedation.
  Induction of Anesthesia:
  For induction of general anesthesia, before administration of other
  anesthetic agents.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  Individual response to the drug is variable, particularly when a
  narcotic premedication is not used. The dosage should be titrated
  to the desired effect according to the patient’s age and clinical
  status.
  When midazolam is used before other intravenous agents for
  induction of anesthesia, the initial dose of each agent may be
  significantly reduced, at times to as low as 25% of the usual initial
  dose of the individual agents.
  Unpremedicated Patients: In the absence of premedication, an
  average adult under the age of 55 years will usually require an
  initial dose of 0.3 to 0.35 mg/kg for induction, administered over
  20 to 30 seconds and allowing 2 minutes for effect. If needed
  to complete induction, increments of approximately 25% of the
  patient’s initial dose may be used; induction may instead be
  completed with inhalational anesthetics. In resistant cases, up to
  0.6 mg/kg total dose may be used for induction, but such larger
  doses may prolong recovery.
  Unpremedicated patients over the age of 55 years usually require
  less midazolam for induction; an initial dose of 0.3 mg/kg is
  recommended. Unpremedicated patients with severe systemic
  disease or other debilitation usually require less midazolam for
  induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice;
  in some cases, as little as 0.15 mg/kg may suffice.
  Premedicated Patients: When the patient has received sedative or
  narcotic premedication, particularly narcotic premedication, the
  range of recommended doses is 0.15 to 0.35 mg/kg.
  In average adults below the age of 55 years, a dose of 0.25 mg/
  kg, administered over 20 to 30 seconds and allowing 2 minutes for
  effect, will usually suffice.
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA
  I and II) surgical patients over the age of 55 years.
  In some patients with severe systemic disease or debilitation, as
  little as 0.15 mg/kg may suffice.
  Narcotic premedication frequently used during clinical trials
  included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes
  before induction), morphine (dosage individualized, up to 0.15
  mg/kg IM), and meperidine (dosage individualized, up to 1 mg/
  kg IM). Sedative premedications were hydroxyzine pamoate (100
  mg orally) and sodium secobarbital (200 mg orally). Except for
  intravenous fentanyl, administered 5 minutes before induction,
  all other premedications should be administered approximately
  1 hour prior to the time anticipated for midazolam induction.
  
  
  Injectable midazolam hydrochloride can also be used
  during maintenance of anesthesia, for surgical procedures,
  as a component of balanced anesthesia. Effective narcotic
  premedication is especially recommended in such cases.
  Incremental injections of approximately 25% of the induction dose
  should be given in response to signs of lightening of anesthesia
  and repeated as necessary.
  
  
  
  
  
  CONTINUOUS INFUSION
  For continuous infusion, midazolam hydrochloride 5 mg/mL
  formulation is recommended diluted to a concentration of 0.5 mg/
  mL with 0.9% sodium chloride or 5% dextrose in water. Usual Adult Dose: If a loading dose is necessary to rapidly
  initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4
  mg for a typical adult) may be given slowly or infused over
  several minutes. This dose may be repeated at 10 to 15 minute
  intervals until adequate sedation is achieved. For maintenance
  of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/
  kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion
  rates may occasionally be required in some patients. The lowest
  recommended doses should be used in patients with residual
  effects from anesthetic drugs, or in those concurrently receiving
  other sedatives or opioids.
  Individual response to midazolam is variable. The infusion rate
  should be titrated to the desired level of sedation, taking into
  account the patient’s age, clinical status and current medications.
  In general, midazolam should be infused at the lowest rate that
  produces the desired level of sedation.
  
  
  Assessment of sedation should be performed at regular intervals
  and the midazolam infusion rate adjusted up or down by 25% to
  50% of the initial infusion rate so as to assure adequate titration
  of sedation level. Larger adjustments or even a small incremental
  dose may be necessary if rapid changes in the level of sedation
  are indicated. In addition, the infusion rate should be decreased
  by 10% to 25% every few hours to find the minimum effective
  infusion rate. Finding the minimum effective infusion rate
  decreases the potential accumulation of midazolam and provides
  for the most rapid recovery once the infusion is terminated.
  Patients who exhibit agitation, hypertension, or tachycardia in
  response to noxious stimulation, but who are otherwise adequately
  sedated, may benefit from concurrent administration of an
  opioid analgesic. Addition of an opioid will generally reduce the
  minimum effective midazolam hydrochloride infusion rate.
  
  
  PEDIATRIC PATIENTS
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS
  GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM
  HYDROCHLORIDE ON A MG/KG BASIS. As a group,
  pediatric patients generally require higher dosages of midazolam
  hydrochloride (mg/kg) than do adults. Younger (less than six
  years) pediatric patients may require higher dosages (mg/kg)
  than older pediatric patients, and may require close monitoring
  (see tables below). In obese PEDIATRIC PATIENTS, the
  dose should be calculated based on ideal body weight. When
  midazolam is given in conjunction with opioids or other sedatives,
  the potential for respiratory depression, airway obstruction, or
  hypoventilation is increased. For appropriate patient monitoring,
  see Boxed WARNING, WARNINGS, and DOSAGE AND
  ADMINISTRATION, Monitoring. The health care practitioner
  who uses this medication in pediatric patients should be aware of
  and follow accepted professional guidelines for pediatric sedation
  appropriate to their situation.
  
  OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Responsiveness Speech Facial Expression Eyes Composite Score Responds readily to name
  spoken in normal tone
  normal
  normal
  clear, no ptosis
  5 (alert)
  Lethargic response to name
  spoken in normal tone
  mild slowing
  or thickening
  mild relaxation
  glazed or mild ptosis
  (less than half the eye)
  4
  Responds only after name is
  called loudly and/or repeatedly
  slurring or
  prominent slowing
  marked relaxation
  (slack jaw)
  glazed and marked ptosis
  3
  Responds only after mild
  prodding or shaking
  few recognizable
  words
  -
  -
  2
  Does not respond to mild
  prodding or shaking
  -
  -
  -
  1 (deep sleep)
  
  FREQUENCY OF OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION Age Range
  (years)
  n
  
  OAA/S Score
  
  
  
  
  
  1(deep sleep)
  2
  3
  4
  5 (alert)
  1-2
  16
  6
  (38%)
  4
  (25%)
  3
  (19%)
  3
  (19%)
  0
  greater than 2-5
  22
  9
  (41%)
  5
  (23%)
  8
  (36%)
  0
  0
  greater than 5-12
  34
  1
  (3%)
  6
  (18%)
  22
  (65%)
  5
  (15%)
  0
  greater than 12-17
  18
  0
  4
  (22%)
  14
   (78%)
  0
  0
  Total (1-17
  90
  16
  (18%)
  19
  (21%)
  47
  (52%)
  8
  (9%)
  0
  
  
  INTRAMUSCULARLY
  For sedation/anxiolysis/amnesia prior to anesthesia or for
  procedures, intramuscular midazolam can be used to sedate
  pediatric patients to facilitate less traumatic insertion of an
  intravenous catheter for titration of additional medication.
  
  
  
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  Sedation after intramuscular midazolam is age and dose
  dependent: higher doses may result in deeper and more prolonged
  sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do
  not prolong emergence from general anesthesia. For more anxious
  patients, doses up to 0.5 mg/kg have been used. Although not
  systematically studied, the total dose usually does not exceed 10
  mg. If midazolam is given with an opioid, the initial dose of each
  must be reduced.
  
  INTRAVENOUSLY BY
  INTERMITTENT INJECTION
  For sedation/anxiolysis/amnesia prior to and during procedures or
  prior to anesthesia.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  It should be recognized that the depth of sedation/anxiolysis
  needed for pediatric patients depends on the type of procedure to
  be performed. For example, simple light sedation/anxiolysis in
  the preoperative period is quite different from the deep sedation
  and analgesia required for an endoscopic procedure in a child.
  For this reason, there is a broad range of dosage. For all pediatric
  patients, regardless of the indications for sedation/anxiolysis, it
  is vital to titrate midazolam hydrochloride and other concomitant
  medications slowly to the desired clinical effect. The initial dose
  of midazolam should be administered over 2 to 3 minutes. Since
  midazolam hydrochloride is water soluble, it takes approximately
  three times longer than diazepam to achieve peak EEG effects,
  therefore one must wait an additional 2 to 3 minutes to fully
  evaluate the sedative effect before initiating a procedure or
  repeating a dose. If further sedation is necessary, continue to
  titrate with small increments until the appropriate level of sedation
  is achieved. If other medications capable of depressing the
  CNS are coadministered, the peak effect of those concomitant
  medications must be considered and the dose of midazolam
  adjusted. The importance of drug titration to effect is vital to the
  safe sedation/anxiolysis of the pediatric patient. The total dose of
  midazolam will depend on patient response, the type and duration
  of the procedure, as well as the type and dose of concomitant
  medications.
  
  1. Pediatric patients less than 6 months of age: Limited
  information is available in non-intubated pediatric patients
  less than 6 months of age. It is uncertain when the patient
  transfers from neonatal physiology to pediatric physiology,
  therefore the dosing recommendations are unclear. Pediatric
  patients less than 6 months of age are particularly vulnerable to
  airway obstruction and hypoventilation, therefore titration with
  small increments to clinical effect and careful monitoring are
  essential.
  
  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05
  to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary
  to reach the desired endpoint but usually does not exceed 6
  mg. Prolonged sedation and risk of hypoventilation may be
  associated with the higher doses.
  
  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025
  to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to
  reach the desired endpoint but usually does not exceed 10
  mg. Prolonged sedation and risk of hypoventilation may be
  associated with the higher doses.
  
  4. Pediatric patients 12 to 16 years of age: Should be dosed
  as adults. Prolonged sedation may be associated with higher
  doses; some patients in this age range will require higher than
  recommended adult doses but the total dose usually does not
  exceed 10 mg.
  
  The dose of midazolam hydrochloride must be reduced in patients
  premedicated with opioid or other sedative agents including
  midazolam. Higher risk or debilitated patients may require lower
  dosages whether or not concomitant sedating medications have
  been administered (see WARNINGS).
  
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation/anxiolysis/amnesia in critical care settings.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  USUAL PEDIATRIC DOSE (NON-NEONATAL)
  To initiate sedation, an intravenous loading dose of 0.05 to 0.2
  mg/kg administered over at least 2 to 3 minutes can be used
  to establish the desired clinical effect IN PATIENTS WHOSE
  TRACHEA IS INTUBATED. (Midazolam should not be
  administered as a rapid intravenous dose.) This loading dose may
  be followed by a continuous intravenous infusion to maintain
  the effect. An infusion of midazolam hydrochloride injection
  has been used in patients whose trachea was intubated but who
  were allowed to breathe spontaneously. Assisted ventilation
  is recommended for pediatric patients who are receiving other
  central nervous system depressant medications such as opioids.
  Based on pharmacokinetic parameters and reported clinical
  experience, continuous intravenous infusions of midazolam should
  be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min).
  The rate of infusion can be increased or decreased (generally
  by 25% of the initial or subsequent infusion rate) as required,
  or supplemental intravenous doses of midazolam hydrochloride
  can be administered to increase or maintain the desired effect.
  Frequent assessment at regular intervals using standard pain/
  sedation scales is recommended. Drug elimination may be
  delayed in patients receiving erythromycin and/or other P450-3A4
  enzyme inhibitors (see PRECAUTIONS, Drug Interactions
  section) and in patients with liver dysfunction, low cardiac output
  (especially those requiring inotropic support), and in neonates.
  Hypotension may be observed in patients who are critically ill,
  particularly those receiving opioids and/or when midazolam is
  rapidly administered.
  When initiating an infusion with midazolam in hemodynamically
  compromised patients, the usual loading dose of midazolam
  hydrochloride should be titrated in small increments and the
  patient monitored for hemodynamic instability, e.g., hypotension.
  These patients are also vulnerable to the respiratory depressant
  effects of midazolam and require careful monitoring of respiratory
  rate and oxygen saturation.
  
  
  CONTINUOUS
  INTRAVENOUS INFUSION
  For sedation in critical care settings.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  USUAL NEONATAL DOSE
  Based on pharmacokinetic parameters and reported clinical
  experience in preterm and term neonates WHOSE TRACHEA
  WAS INTUBATED, continuous intravenous infusions of
  midazolam hydrochloride injection should be initiated at a rate
  of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates less than32 weeks and
  0.06 mg/kg/hr (1 mcg/kg/min) in neonates more than 32 weeks. Intravenous
  loading doses should not be used in neonates, rather the infusion
  may be run more rapidly for the first several hours to establish
  therapeutic plasma levels. The rate of infusion should be carefully
  and frequently reassessed, particularly after the first 24 hours so
  as to administer the lowest possible effective dose and reduce the
  potential for drug accumulation. Hypotension may be observed
  in patients who are critically ill and in preterm and term infants,
  particularly those receiving fentanyl and/or when midazolam is
  administered rapidly. Due to an increased risk of apnea, extreme
  caution is advised when sedating preterm and former preterm
  patients whose trachea is not intubated.
  
  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
  

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  Midazolam Hydrochloride | Cardinal Health

  

  ---

  Midazolamhydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE- THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS.Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental(see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS).

  Midazolam hydrochloride should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  MONITORING

  Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics

  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics

  For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

   

  USUAL ADULT DOSE INTRAMUSCULARLY   For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).   For intramuscular use, midazolam hydrochloride should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam. 

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

  INTRAVENOUSLY   Sedation /anxiolysis/amnesia for procedures (see INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

   

    Midazolam hydrochloride mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  Healthy Adults Below the Age of 6: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients Patients Age 60 or Older, and Debilitated or Chronically Ill Patient: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.
  Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.
  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients. Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.   Induction of Anesthesia:   For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient's age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient's initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery. 

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

   

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

   

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

   

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

   

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

   

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

    Injectable midazolam hydrochloride can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommneded in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION   For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

   

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

   

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring see Boxed WARNING, WARNINGS, MONITORING subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Assessment Categories
  Responsiveness
  Speech Facial Expression
  Eyes
  Composite Score Responds readily to name spoken in normal tone normal normal clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone mild slowing or thickening mild relaxation glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly slurring or prominent slowing marked relaxation (slack jaw) glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking few recognizable words
  ----
  ---- 2 Does not respond to mild prodding or shaking
  
  ----
  ----
  ---- 1 (deep
  sleep) FREQUENCY OF OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION Age Range (years)
  n
  OAA/S Score 1
  (deep sleep) 2 3 4 5 (alert) 1-2 16 6
  (38%) 4
  (25%) 3
  (19%) 3
  (19%) 0 >2-5 22 9
  (41%) 5
  (23%) 8
  (36%) 0 0 >5-12 34 1
  (3%) 6
  (18%) 22
  (65%) 5
  (15%) 0 >12-17 18 0 4
  (22%) 14
  (78%) 0 0 Total (1-17) 90 16
  (18%) 19
  (21%) 47
  (52%) 8
  (9%) 0 INTRAMUSCULARLY   For sedation/anxiolysis/ amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication. USUAL PEDIATRIC DOSE (NON-NEONATAL)

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY INTERMITTENT INJECTION   For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia. USUAL PEDIATRIC DOSE (NON-NEONATAL)

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam hydrochloride is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects; therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  Pediatric Patients Less Than 6 Months of Age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential. Pediatric Patients 6 Months to 5 Years of Age: Initial dose 0.05 to 0.1 mg/kg; total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. Pediatric Patients 6 to 12 Years of Age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. Pediatric Patients 12 to 16 Years of Age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS INTRAVENOUS INFUSION   For sedation/anxiolysis/amnesia in critical care settings. USUAL PEDIATRIC DOSE (NON-NEONATAL)

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam hydrochloride injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS: Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam hydrochloride in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability (e.g., hypotension). These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS INTRAVENOUS INFUSION   For sedation in critical care settings. USUAL NEONATAL DOSE

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS: Usage in Preterm Infants and Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | A-s Medication Solutions Llc

  

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  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  INTRAMUSCULARLY

  For preoperative sedation/ anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  1. Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect, e.g., the initiation of slurred speech. Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  3. Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  
  
  

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, MONITORING. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)
  

  Assessment Categories

  
  

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  
  

  Responds readily to name spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  
  

  Lethargic response to name spoken in normal tone

  mild slowing or thickening

  mild relaxation

  glazed or mild ptosis (less than half the eye)

  4

  
  

  Responds only after name is called loudly and/or repeatedly

  slurring or prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis (half the eye or more)

  3

  
  

  Responds only after mild prodding or shaking

  few recognizable words

  —

  —

  2

  
  

  Does not respond to mild prodding or shaking

  —

  —

  —

  1 (deep sleep)

  
  
  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE
  STUDY OF CHILDREN UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
  
  Age Range
  (years)
  n
  OAA/S Score
  

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  
  

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  1. Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  2. Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  3. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  4. Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Cardinal Health

  

  ---

  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with Lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  
  

  INTRAMUSCULARLY
  
  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).
  For intramuscular use, midazolam should be injected deep in a large muscle mass.

   
  
  
  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.
  
  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

  
  

  INTRAVENOUSLY
  
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  
  
  
  

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  
  

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  
  

  1.           Healthy Adults Below the Age of 60: Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
  
  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.
  
  2.           Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.
  
  Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.
  
  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.
  
  3.           Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  
  

  Induction of Anesthesia:
  
  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.
  
  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
  
  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.
  
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.
  
  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.
  
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  
  

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  
  

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  
  
  

  CONTINUOUS INFUSION
  
  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  
  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.
  
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  
  

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  
  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name
  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name
  spoken in normal tone

  mild slowing
  or thickening

  mild relaxation

  glazed or mild ptosis
  (less than half the eye)

  4

  Responds only after name is
  called loudly and/or
  repeatedly

  slurring or
  prominent slowing

  marked relaxation
  (slack jaw)

  glazed and marked ptosis
  (half the eye or more)

  3

  Responds only after mild
  prodding or shaking

  few recognizable
  words

  –

  –

  2

  Does not respond to mild
  prodding or shaking

  –

  –

  –

  1 (deep sleep)

  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range
  (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6 (38%)

  4 (25%)

  3 (19%)

  3 (19%)

  0

  >2-5

  22

  9 (41%)

  5 (23%)

  8 (36%)

  0

  0

  >5-12

  34

  1 (3%)

  6 (18%)

  22 (65%)

  5 (15%)

  0

  >12-17

  18

  0

  4 (22%)

  14 (78%)

  0

  0

  Total (1-17)

  90

  16 (18%)

  19 (21%)

  47 (52%)

  8 (9%)

  0

  
  

  INTRAMUSCULARLY

  
  

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  
  

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  
  

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  
  

  INTRAVENOUSLY BY INTERMITTENT INJECTION

  
  

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  
  
  
  
  
  

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  
  

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  
  

  1.           Pediatric patients less than 6 months of age: limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.

  
  

  2.           Pediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  
  

  3.           Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

  
  

  4.           Pediatric patients 12 to 16 years of age: should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  
  

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  
  

  CONTINUOUS INTRAVENOUS INFUSION

  
  

  For sedation/anxiolysis/amnesia in critical care settings.

  
  

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  
  
  

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  
  

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  
  
  

  CONTINUOUS INTRAVENOUS INFUSION

  
  

  For sedation in critical care settings.

  USUAL NEONATAL DOSE

  
  
  

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Ranbaxy Pharmaceuticlas Inc

  

  ---

  Midazolam hydrochloride syrup is indicated for use as a single dose (0.25 to 1 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients. Midazolam hydrochloride syrup is not intended for chronic administration.

  Monitoring

  Midazolam hydrochloride syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Continuous monitoring of respiratory and cardiac function is required.

  Midazolam hydrochloride syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional. Midazolam hydrochloride syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

  Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation (see PRECAUTIONS: Drug Interactions). This is especially true in pediatric patients. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  Midazolam hydrochloride syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression. Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

  When midazolam hydrochloride syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see WARNINGS and Monitoring subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg. In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need (see WARNINGS and PRECAUTIONS). The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg. A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical. For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam hydrochloride syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants. As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam hydrochloride syrup. In obese pediatric patients, the dose should be calculated based on ideal body weight. Midazolam hydrochloride syrup has not been studied, nor is it intended for chronic use.

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  Midazolam Hydrochloride | Cardinal Health

  

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  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSAGE

  INTRAMUSCULARLY

  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/ hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

    Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.   If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.   Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.   Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.   If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.   Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation.

  Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS
  

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name

  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name

  spoken in normal tone

  mild slowing

  or thickening

  mild relaxation

  glazed or mild ptosis

  (less than half the eye)

  4

  Responds only after name is

  called loudly and/or repeatedly

  slurring or

  prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis

  (half the eye or more)

  3

  Responds only after mild

  prodding or shaking

  few recognizable

  words

  −

  −

  2

  Does not respond to mild

  prodding or shaking

  −

  −

  −

  1 (deep sleep)

  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC

  PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range

  (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

    Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.   Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.   Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.   Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Cardinal Health

  

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  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSAGE

  INTRAMUSCULARLY

  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).

  For intramuscular use, midazolam should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine and reduced doses of narcotics.

  INTRAVENOUSLY

  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/ hypoventilation.)

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

    Healthy Adults Below the Age of 60: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.   If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.   Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.   Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.   If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.   Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.

  Induction of Anesthesia:

  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION

  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation.

  Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS
  

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name

  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name

  spoken in normal tone

  mild slowing

  or thickening

  mild relaxation

  glazed or mild ptosis

  (less than half the eye)

  4

  Responds only after name is

  called loudly and/or repeatedly

  slurring or

  prominent slowing

  marked relaxation

  (slack jaw)

  glazed and marked ptosis

  (half the eye or more)

  3

  Responds only after mild

  prodding or shaking

  few recognizable

  words

  −

  −

  2

  Does not respond to mild

  prodding or shaking

  −

  −

  −

  1 (deep sleep)

  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC

  PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range

  (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6

  (38%)

  4

  (25%)

  3

  (19%)

  3

  (19%)

  0

  >2-5

  22

  9

  (41%)

  5

  (23%)

  8

  (36%)

  0

  0

  >5-12

  34

  1

  (3%)

  6

  (18%)

  22

  (65%)

  5

  (15%)

  0

  >12-17

  18

  0

  4

  (22%)

  14

  (78%)

  0

  0

  Total (1-17)

  90

  16

  (18%)

  19

  (21%)

  47

  (52%)

  8

  (9%)

  0

  
  

  INTRAMUSCULARLY

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY

  INTERMITTENT INJECTION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

    Pediatric patients less than 6 months of age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential.   Pediatric patients 6 months to 5 years of age: Initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.   Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.   Pediatric patients 12 to 16 years of age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  For sedation/anxiolysis/amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions section) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS

  INTRAVENOUS INFUSION

  USUAL NEONATAL DOSE

  For sedation in critical care settings.

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Hospira, Inc.

  

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  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with Lactated Ringer’s solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring: Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  USUAL ADULT DOSE

  
  

  INTRAMUSCULARLY
  
  For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).
  For intramuscular use, midazolam should be injected deep in a large muscle mass.

   
  
  
  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.
  
  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.
  
  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

  
  

  INTRAVENOUSLY
  
  Sedation/anxiolysis/amnesia for procedures (See INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

  
  
  
  

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  
  

  Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  
  Healthy Adults Below the Age of 60: Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.

  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients.

  Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.

  Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.

  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients.

  Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.
  

  Induction of Anesthesia:
  
  For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient’s age and clinical status.
  
  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
  
  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient’s initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.
  
  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.
  
  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
  
  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.
  
  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.
  
  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
  
  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

  
  

  Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.

  
  

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  
  
  

  CONTINUOUS INFUSION
  
  For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  
  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.
  
  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

  
  

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see Boxed WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  
  OBSERVER’S ASSESSMENT OF ALERTNESS/ SEDATION (OAA/S)

  Assessment Categories

  Responsiveness

  Speech

  Facial Expression

  Eyes

  Composite Score

  Responds readily to name
  spoken in normal tone

  normal

  normal

  clear, no ptosis

  5 (alert)

  Lethargic response to name
  spoken in normal tone

  mild slowing
  or thickening

  mild relaxation

  glazed or mild ptosis
  (less than half the eye)

  4

  Responds only after name is
  called loudly and/or
  repeatedly

  slurring or
  prominent slowing

  marked relaxation
  (slack jaw)

  glazed and marked ptosis
  (half the eye or more)

  3

  Responds only after mild
  prodding or shaking

  few recognizable
  words

  –

  –

  2

  Does not respond to mild
  prodding or shaking

  –

  –

  –

  1 (deep sleep)

  _______________________________________________________________________________________

  FREQUENCY OF OBSERVER’S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION

  Age Range
   (years)

  n

  OAA/S Score

  1 (deep sleep)

  2

  3

  4

  5 (alert)

  1-2

  16

  6 (38%)

  4 (25%)

  3 (19%)

  3 (19%)

  0

  >2-5

  22

  9 (41%)

  5 (23%)

  8 (36%)

  0

  0

  >5-12

  34

  1 (3%)

  6 (18%)

  22 (65%)

  5 (15%)

  0

  >12-17

  18

  0

  4 (22%)

  14 (78%)

  0

  0

  Total (1-17)

  90

  16 (18%)

  19 (21%)

  47 (52%)

  8 (9%)

  0

  
  

  INTRAMUSCULARLY

  
  

  For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.

  
  

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  
  

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  
  

  INTRAVENOUSLY BY
  INTERMITTENT INJECTION

  
  

  For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.

  
  
  
  
  
  

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  
  

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects, therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  
  Pediatric patients less than 6 months of age: limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential. Pediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. Pediatric patients 12 to 16 years of age: should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  
  

  CONTINUOUS INTRAVENOUS INFUSION

  
  

  For sedation/anxiolysis/amnesia in critical care settings.

  
  

  USUAL PEDIATRIC DOSE (NON-NEONATAL)

  
  
  

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS, Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  
  

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  
  
  

  CONTINUOUS INTRAVENOUS INFUSION

  
  

  For sedation in critical care settings.

  USUAL NEONATAL DOSE

  
  
  

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS, Usage In Preterm Infants And Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Midazolam Hydrochloride | Cardinal Health

  

  ---

  Midazolamhydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE- THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS.Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental(see Boxed WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS).

  Midazolam hydrochloride should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam hydrochloride Injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  MONITORING

  Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).

  Adults and Pediatrics

  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics

  For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

   

  USUAL ADULT DOSE INTRAMUSCULARLY   For preoperative sedation/anxiolysis/amnesia (induction of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).   For intramuscular use, midazolam hydrochloride should be injected deep in a large muscle mass.

  The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.

  The dose must be individualized and reduced when IM midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam. 

  Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.

  INTRAVENOUSLY   Sedation /anxiolysis/amnesia for procedures (see INDICATIONS AND USAGE): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.

   

    Midazolam hydrochloride mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  When used for sedation/anxiolysis/amnesia for a procedure, dosage must be individualized and titrated. Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors. (See WARNINGS concerning cardiac/respiratory arrest/airway obstruction/hypoventilation.)

  Healthy Adults Below the Age of 6: Titrate slowly to the desired effect, (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If further titration is necessary, continue to titrate, using small increments, to the appropriate level of sedation. Wait an additional 2 or more minutes after each increment to fully evaluate the sedative effect. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint.
  If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less midazolam than unpremedicated patients Patients Age 60 or Older, and Debilitated or Chronically Ill Patient: Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, increments should be smaller and the rate of injection slower.
  Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect. If additional titration is necessary, it should be given at a rate of no more than 1 mg over a period of 2 minutes, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect. Total doses greater than 3.5 mg are not usually necessary.
  If concomitant CNS depressant premedications are used in these patients, they will require at least 50% less midazolam than healthy young unpremedicated patients. Maintenance Dose: Additional doses to maintain the desired level of sedation may be given in increments of 25% of the dose used to first reach the sedative endpoint, but again only by slow titration, especially in the elderly and chronically ill or debilitated patient. These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.   Induction of Anesthesia:   For induction of general anesthesia, before administration of other anesthetic agents.

  Individual response to the drug is variable, particularly when a narcotic premedication is not used. The dosage should be titrated to the desired effect according to the patient's age and clinical status.

  When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

  Unpremedicated Patients: In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient's initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery. 

  Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.

   

  Premedicated Patients: When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.

   

  In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.

   

  The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.

   

  In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.

   

  Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.

    Injectable midazolam hydrochloride can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommneded in such cases.

  Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.

  CONTINUOUS INFUSION   For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.

  Usual Adult Dose: If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.

   

  Individual response to midazolam is variable. The infusion rate should be titrated to the desired level of sedation, taking into account the patient’s age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.

  PEDIATRIC PATIENTS

   

  UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring see Boxed WARNING, WARNINGS, MONITORING subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

  OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S) Assessment Categories
  Responsiveness
  Speech Facial Expression
  Eyes
  Composite Score Responds readily to name spoken in normal tone normal normal clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone mild slowing or thickening mild relaxation glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly slurring or prominent slowing marked relaxation (slack jaw) glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking few recognizable words
  ----
  ---- 2 Does not respond to mild prodding or shaking
  
  ----
  ----
  ---- 1 (deep
  sleep) FREQUENCY OF OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION Age Range (years)
  n
  OAA/S Score 1
  (deep sleep) 2 3 4 5 (alert) 1-2 16 6
  (38%) 4
  (25%) 3
  (19%) 3
  (19%) 0 >2-5 22 9
  (41%) 5
  (23%) 8
  (36%) 0 0 >5-12 34 1
  (3%) 6
  (18%) 22
  (65%) 5
  (15%) 0 >12-17 18 0 4
  (22%) 14
  (78%) 0 0 Total (1-17) 90 16
  (18%) 19
  (21%) 47
  (52%) 8
  (9%) 0 INTRAMUSCULARLY   For sedation/anxiolysis/ amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication. USUAL PEDIATRIC DOSE (NON-NEONATAL)

  Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.

  INTRAVENOUSLY BY INTERMITTENT INJECTION   For sedation/anxiolysis/amnesia prior to and during procedures or prior to anesthesia. USUAL PEDIATRIC DOSE (NON-NEONATAL)

  It should be recognized that the depth of sedation/anxiolysis needed for pediatric patients depends on the type of procedure to be performed. For example, simple light sedation/anxiolysis in the preoperative period is quite different from the deep sedation and analgesia required for an endoscopic procedure in a child. For this reason, there is a broad range of dosage. For all pediatric patients, regardless of the indications for sedation/anxiolysis, it is vital to titrate midazolam and other concomitant medications slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. Since midazolam hydrochloride is water soluble, it takes approximately three times longer than diazepam to achieve peak EEG effects; therefore one must wait an additional 2 to 3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. If other medications capable of depressing the CNS are coadministered, the peak effect of those concomitant medications must be considered and the dose of midazolam adjusted. The importance of drug titration to effect is vital to the safe sedation/anxiolysis of the pediatric patient. The total dose of midazolam will depend on patient response, the type and duration of the procedure, as well as the type and dose of concomitant medications.

  Pediatric Patients Less Than 6 Months of Age: Limited information is available in non-intubated pediatric patients less than 6 months of age. It is uncertain when the patient transfers from neonatal physiology to pediatric physiology, therefore the dosing recommendations are unclear. Pediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful monitoring are essential. Pediatric Patients 6 Months to 5 Years of Age: Initial dose 0.05 to 0.1 mg/kg; total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint but usually does not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. Pediatric Patients 6 to 12 Years of Age: Initial dose 0.025 to 0.05 mg/kg; total dose up to 0.4 mg/kg may be needed to reach the desired endpoint but usually does not exceed 10 mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses. Pediatric Patients 12 to 16 Years of Age: Should be dosed as adults. Prolonged sedation may be associated with higher doses; some patients in this age range will require higher than recommended adult doses but the total dose usually does not exceed 10 mg.

  The dose of midazolam must be reduced in patients premedicated with opioid or other sedative agents including midazolam. Higher risk or debilitated patients may require lower dosages whether or not concomitant sedating medications have been administered (see WARNINGS).

  CONTINUOUS INTRAVENOUS INFUSION   For sedation/anxiolysis/amnesia in critical care settings. USUAL PEDIATRIC DOSE (NON-NEONATAL)

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam hydrochloride injection has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450-3A4 enzyme inhibitors (see PRECAUTIONS: Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

  When initiating an infusion with midazolam hydrochloride in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability (e.g., hypotension). These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

  CONTINUOUS INTRAVENOUS INFUSION   For sedation in critical care settings. USUAL NEONATAL DOSE

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS: Usage in Preterm Infants and Neonates). Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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