Promethazine With Codeine

Promethazine With Codeine

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Questions & Answers

Side Effects & Adverse Reactions

Respiratory Depression in Children
The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients.

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients.

 Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed.

Codeine:

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine (see PRECAUTIONS -Nursing Mothers).

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see OVERDOSAGE).

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS).

When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

Codeine: Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.

Codeine may cause or aggravate constipation.

Administration of codeine may be accompanied by histamine release and should be used with caution in atopic children.

Head Injury And Increased Intracranial Pressure:

The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.

Asthma And Other Respiratory Conditions:

Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see CONTRAINDICATIONS). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function.

Hypotensive Effect:

Codeine may produce orthostatic hypotension in ambulatory patients.

Promethazine:
CNS Depression –

Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS - Information For Patients and Drug Interactions).

Respiratory Depression –

Promethazine may lead to potentially fatal respiratory depression.

Use of promethazine in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.

Lower Seizure Threshold –

Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression –

Promethazine should be used with caution in patients with bone marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome –

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered.

Respiratory Depression in Children
The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients.

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients.

 Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed.

Codeine:

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine (see PRECAUTIONS -Nursing Mothers).

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see OVERDOSAGE).

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS).

When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

Codeine: Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.

Codeine may cause or aggravate constipation.

Administration of codeine may be accompanied by histamine release and should be used with caution in atopic children.

Head Injury And Increased Intracranial Pressure:

The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.

Asthma And Other Respiratory Conditions:

Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see CONTRAINDICATIONS). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function.

Hypotensive Effect:

Codeine may produce orthostatic hypotension in ambulatory patients.

Head Injury And Increased Intracranial Pressure:

The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.

Asthma And Other Respiratory Conditions:

Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see CONTRAINDICATIONS). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function.

Hypotensive Effect:

Codeine may produce orthostatic hypotension in ambulatory patients.

Promethazine:
CNS Depression –

Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS - Information For Patients and Drug Interactions).

Respiratory Depression –

Promethazine may lead to potentially fatal respiratory depression.

Use of promethazine in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.

Lower Seizure Threshold –

Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression –

Promethazine should be used with caution in patients with bone marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome –

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered.

CNS Depression –

Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS - Information For Patients and Drug Interactions).

Respiratory Depression –

Promethazine may lead to potentially fatal respiratory depression.

Use of promethazine in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.

Lower Seizure Threshold –

Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression –

Promethazine should be used with caution in patients with bone marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome –

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered.

Administration of promethazine has been associated with reported cholestatic jaundice.

Legal Issues

There is currently no legal information available for this drug.

FDA Safety Alerts

There are currently no FDA safety alerts available for this drug.

Manufacturer Warnings

There is currently no manufacturer warning information available for this drug.

FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

Promethazine with codeine syrup is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

History

There is currently no drug history available for this drug.

Other Information

Each 5 mL (one teaspoonful), for oral administration contains: Promethazine hydrochloride 6.25 mg; codeine phosphate 10 mg. Alcohol 7%.

Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy; it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1)(salt) hemihydrate.

The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. It has a molecular weight of 406.37, a molecular formula of C18H21NO3•H3PO4•½H2O, and the following structural formula:

This is an image of the structural formula of Codeine Phosphate.

Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride.

Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol. It has a molecular weight of 320.88, a molecular formula of C17H20N2S•HCI, and the following structural formula:

This is an image of the structural formula of Promethazine.

Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy; it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1)(salt) hemihydrate.

The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. It has a molecular weight of 406.37, a molecular formula of C18H21NO3•H3PO4•½H2O, and the following structural formula:

This is an image of the structural formula of Codeine Phosphate.

Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride.

Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol. It has a molecular weight of 320.88, a molecular formula of C17H20N2S•HCI, and the following structural formula:

This is an image of the structural formula of Promethazine.

Promethazine With Codeine Manufacturers


  • Proficient Rx Lp
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Proficient Rx Lp]
  • Apotheca, Inc.
    Promethazine With Codeine Liquid [Apotheca, Inc.]
  • Physicians Total Care, Inc.
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Physicians Total Care, Inc.]
  • Rebel Distributors Corp
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Rebel Distributors Corp]
  • Lake Erie Medical & Surgical Supply Dba Quality Care Products Llc
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Lake Erie Medical & Surgical Supply Dba Quality Care Products Llc]
  • A-s Medication Solutions Llc
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [A-s Medication Solutions Llc]
  • Qualitest Pharmaceuticals
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Qualitest Pharmaceuticals]
  • Preferred Pharmaceuticals, Inc
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Preferred Pharmaceuticals, Inc]
  • Aidarex Pharmaceuticals Llc
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Aidarex Pharmaceuticals Llc]
  • Atlantic Biologicals Corps
    Promethazine With Codeine (Promethazine Hydrochloride And Codeine Phosphate) Syrup [Atlantic Biologicals Corps]

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