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Duopa

Duopa

2.1 DUOPA Daily Dose

DUOPA is administered over a 16-hour infusion period. The daily dose is determined by individualized patient titration and composed of:
A Morning Dose A Continuous Dose Extra Doses
The maximum recommended daily dose of DUOPA is 2000 mg of the levodopa component (i.e., one cassette per day) administered over 16 hours. At the end of the daily 16-hour infusion, patients will disconnect the pump from the PEG-J and take their night-time dose of oral immediate-release carbidopa-levodopa tablets.

Treatment with DUOPA is initiated in 3 steps [see Dosage and Administration (2.2)]:
Conversion of patients to oral immediate-release carbidopa-levodopa tablets in preparation for DUOPA treatment. Calculation and administration of the DUOPA starting dose (Morning Dose and Continuous Dose) for Day 1. Titration of the dose as needed based on individual clinical response and tolerability.
Extra Doses

DUOPA has an extra dose function that can be used to manage acute “Off” symptoms that are not controlled by the Morning Dose and the Continuous Dose administered over 16 hours. The extra dose function should be set at 1 mL (20 mg of levodopa) when starting DUOPA. If the amount of the extra dose needs to be adjusted, it is typically done in 0.2 mL increments. The extra dose frequency should be limited to one extra dose every 2 hours. Administration of frequent extra doses may cause or worsen dyskinesias.

Once no further adjustments are required to the DUOPA Morning Dose, Continuous Dose, or Extra Dose, this dosing regimen should be administered daily. Over time, additional changes may be necessary based on the patient’s clinical response and tolerability.

2.2 Initiation and Titration Instructions

Prepare for DUOPA Treatment

Prior to initiating DUOPA, convert patients from all other forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio). Patients should remain on a stable dose of their concomitant medications taken for the treatment of Parkinson's disease before initiation of DUOPA infusion.

Healthcare providers should ensure patients take their oral Parkinson's disease medications the morning of the PEG-J procedure.

Determine the DUOPA Starting Dose for Day 1

The steps for determining the initial DUOPA daily dosing (Morning Dose and Continuous Dose) for Day 1 are outlined below.
Step 1: Calculate and administer the DUOPA Morning Dose for Day 1 a. Determine the total amount of levodopa (in milligrams) in the first dose of oral immediate-release carbidopa-levodopa that was taken by the patient on the previous day. b. Convert the oral levodopa dose from milligrams to milliliters by multiplying the oral dose by 0.8 and dividing by 20 mg/mL. This calculation will provide the Morning Dose of DUOPA in milliliters. c. Add 3 milliliters to the Morning Dose to fill (prime) the intestinal tube to obtain the Total Morning Dose. d. The Total Morning Dose is usually administered over 10 to 30 minutes. e. Program the pump to deliver the Total Morning Dose. Step 2: Calculate and administer the DUOPA Continuous Dose for Day 1 a. Determine the amount of oral immediate-release levodopa that the patient received from oral immediate-release carbidopa-levodopa doses throughout the previous day (16 waking hours), in milligrams. Do not include the doses of oral immediate-release carbidopa-levodopa taken at night when calculating the levodopa amount. b. Subtract the first oral levodopa dose in milligrams taken by the patient on the previous day (determined in Step 1 (a)) from the total oral levodopa dose in milligrams taken over 16 waking hours (determined in Step 2 (a)). Divide the result by 20 mg/mL. This is the dose of DUOPA administered as a Continuous Dose (in mL) over 16 hours. c. The hourly infusion rate (mL per hour) is obtained by dividing the Continuous Dose by 16 (hours). This value will be programmed into the pump as the continuous rate. d. If persistent or numerous “Off” periods occur during the 16-hour infusion, consider increasing the Continuous Dose or using the Extra Dose function. If dyskinesia or DUOPA-related adverse reactions occur, consider decreasing the Continuous Dose or stopping the infusion until the adverse reactions subside.
DUOPA Titration

The daily dose of DUOPA can be titrated as needed, based on the patient’s individual clinical response and tolerability after Day 1 of DUOPA treatment and until a stable daily dose is maintained. Adjustments to concomitant Parkinson’s disease medications may be needed. In the controlled trial, the average number of titration days required to establish a stable Morning and Continuous Dose was 5 days. Additional dose adjustments may be necessary over time based on the patient level of activity and disease progression.

The recommendations for adjusting the DUOPA Morning and Continuous Doses are provided below.

Morning Dose Adjustment

If there was an inadequate clinical response within 1 hour of the Morning Dose on the preceding day, adjust the Morning Dose (excluding the 3 mL to fill the tube) as follows:
If the Morning Dose on the preceding day was less than or equal to 6 mL, increase the Morning Dose by 1 mL. If the Morning Dose on the preceding day was greater than 6 mL, increase the Morning Dose by 2 mL.
If the patient experienced dyskinesias or DUOPA-related adverse reactions within 1 hour of the Morning Dose on the preceding day, decrease the Morning Dose by 1 mL.

Continuous Dose Adjustment

Consider increasing the Continuous Dose based on the number and volume of Extra Doses of DUOPA (i.e., total amount of levodopa component) that were needed for the previous day and the patient’s clinical response.

Consider decreasing the Continuous Dose if the patient experienced troublesome dyskinesia, or other troublesome DUOPA-related adverse reactions on the preceding day:
For troublesome adverse reactions lasting for a period of one hour or more, decrease the Continuous Dose by 0.3 mL per hour. For troublesome adverse reactions lasting for two or more periods of one hour or more, decrease the Continuous Dose by 0.6 mL per hour.
2.3 Administration Information
DUOPA should be used at room temperature. Take one DUOPA cassette out of the refrigerator and out of the carton 20 minutes prior to use; failure to use the product at room temperature may result in the patient not receiving the right amount of medication. DUOPA is delivered as a 16-hour infusion through either a naso-jejunal tube for short-term administration or through a PEG-J for long-term administration. The cassettes are for single-use only and should not be used for longer than 16 hours, even if some drug product remains. An opened cassette should not be re-used. The PEG-J should be disconnected from the pump at the end of the daily 16-hour administration period and flushed with room temperature potable water with a syringe.
Long-term administration of DUOPA requires placement of a PEG-J outer transabdominal tube and inner jejunal tube by percutaneous endoscopic gastrostomy. DUOPA is dispensed from medication cassette reservoirs that are specifically designed to be connected to the CADD®-Legacy 1400 pump.

Establishment of the transabdominal port should be performed by a gastroenterologist or other healthcare provider experienced in this procedure. See Table 1 for the recommended tubing sets for PEG-J administration.

For short-term, temporary administration of DUOPA prior to PEG-J tube placement, treatment may be initiated by a naso-jejunal tube with observation of the patient’s clinical response. See Table 2 for the recommended tubing sets for naso-jejunal administration.
Table 1. Recommended Tubing Sets for Long-Term PEG-J DUOPA Administration Product Name Manufacturer AbbVie PEG 15 and 20 FrAbbVie J AbbVie Inc. AbbVie Inc. EndoVive™ Standard PEG Kit – Pull MethodEndoVive™ Two-Port Through the PEG Jejunal Feeding Tube Kit Boston Scientific Corp.Boston Scientific Corp. Table 2. Recommended Tubing Sets for Short-Term Naso-Jejunal DUOPA Administration Product Name Manufacturer AbbVie NJ AbbVie Inc. NJFT-10 Wilson-Cook Medical, Inc. Kangaroo™ Naso-Jejunal Feeding Tube Covidien Kangaroo™ Covidien
2.4 Discontinuation of DUOPA

Avoid sudden discontinuation or rapid dose reduction in patients taking DUOPA.

If patients need to discontinue DUOPA, the dose should be tapered or patients should be switched to oral immediate-release carbidopa-levodopa tablets [see Warnings and Precautions (5.7)].

When using a PEG-J tube, DUOPA can be discontinued by withdrawing the tube and letting the stoma heal. The removal of the tube should only be performed by a qualified healthcare provider.
Cardizem La

Cardizem La

CARDIZEM LA Tablets are an extended-release formulation intended for once-a-day administration.

Patients controlled on diltiazem alone or in combination with other medications may be switched to CARDIZEM LA Tablets once-a-day at the nearest equivalent total daily dose. Higher doses of CARDIZEM LA Tablets once-a-day dosage may be needed in some patients. Patients should be closely monitored. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited general clinical experience with doses above 360 mg, but the safety and efficacy of doses as high as 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.

The tablet should be swallowed whole and not chewed or crushed.

Hypertension.

Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The dosage range studied in clinical trials was 120 to 540 mg once daily. The dosage may be titrated to a maximum of 540 mg daily.

CARDIZEM LA Tablets should be taken about the same time once each day either in the morning or at bedtime. The time of dosing should be considered when making dose adjustments based on trough effects.

Angina.

Dosage for the treatment of angina should be individualized based on response. The initial dose of 180 mg once daily may be increased at intervals of 7 to 14 days if adequate response is not obtained. CARDIZEM LA doses above 360 mg appear to confer no additional benefit.

CARDIZEM LA can be given once daily, either in the evening or in the morning.

Concomitant Use with Other Cardiovascular Agents
• Sublingual NTG. May be taken as required to abort acute anginal attacks during Diltiazem Hydrochloride Extended-Release therapy. • Prophylactic Nitrate Therapy. Diltiazem Hydrochloride Extended-Release Tablets may be safely coadministered with short-and long-acting nitrates. • Beta-blockers (see WARNINGS and PRECAUTIONS). • Antihypertensives. CARDIZEM LA has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of Diltiazem Hydrochloride Extended-Release Tablets or the concomitant antihypertensives may need to be adjusted when adding one to the other.
Creon

Creon

CREON is not interchangeable with other pancrelipase products.

CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

2.1 Administration

Infants (up to 12 months)

CREON should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce. Administration should be followed by breast milk or formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.

Children and Adults

CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents should not be crushed or chewed. Capsules should be swallowed whole.

For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth.

2.2 Dosage

Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the recommendations of the Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided in the following paragraphs, except for infants. Although the Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule. Therefore, the recommended dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.

Infants (up to 12 months)

CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding. Do not mix CREON capsule contents directly into formula or breast milk prior to administration [see Administration (2.1)].

Children Older than 12 Months and Younger than 4 Years

Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Children 4 Years and Older and Adults

Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack. The total daily dose should reflect approximately three meals plus two or three snacks per day.

Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.

Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy

The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.

In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat per day [see Clinical Studies (14.2)]. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.

Limitations on Dosing

Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
Tricor

Tricor

2.1 General Considerations

Patients should be placed on an appropriate lipid-lowering diet before receiving TRICOR, and should continue this diet during treatment with TRICOR. TRICOR tablets can be given without regard to meals.

The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of TRICOR if lipid levels fall significantly below the targeted range.

Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 145 mg once daily.

2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia

The initial dose of TRICOR is 145 mg once daily.

2.3 Severe Hypertriglyceridemia

The initial dose is 48 to 145 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 145 mg once daily.

2.4 Impaired Renal Function

Treatment with TRICOR should be initiated at a dose of 48 mg per day in patients having mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of TRICOR should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Geriatric Patients

Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5)].
Zemplar

Zemplar

The currently accepted target range for iPTH levels in CKD Stage 5 patients is no more than 1.5 to 3 times the non-uremic upper limit of normal.

The recommended initial dose of Zemplar is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg) administered as a bolus dose no more frequently than every other day at any time during dialysis.

If a satisfactory response is not observed, the dose may be increased by 2 to 4 mcg at 2- to 4-week intervals. During any dose adjustment period, serum calcium and phosphorus levels should be monitored more frequently, and if an elevated calcium level or a Ca × P product greater than 75 is noted, the drug dosage should be immediately reduced or interrupted until these parameters are normalized. Then, Zemplar should be reinitiated at a lower dose. If a patient is on a calcium-based phosphate binder, the dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. Zemplar doses may need to be decreased as the PTH levels decrease in response to therapy. Thus, incremental dosing must be individualized.

The following table is a suggested approach in dose titration:
Suggested Dosing Guidelines PTH Level Zemplar Dose the same or increasing increase decreasing by < 30% increase decreasing by > 30%, < 60% maintain decreasing by > 60% decrease one and one-half to three times upper limit of normal maintain
The influence of mild to moderately impaired hepatic function on paricalcitol pharmacokinetics is sufficiently small that no dosing adjustment is required.

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

After initial vial use, the contents of the multi-dose vial remain stable up to seven days when stored at controlled room temperature (see HOW SUPPLIED). Discard unused portion of the single-dose vial.
Gengraf

Gengraf

Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP). Gengraf® and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision.

The daily dose of Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED]) should always be given in two divided doses (BID). It is recommended that Gengraf® be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

Specific Populations

Renal Impairment in Kidney, Liver, and Heart Transplantation

Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. (See WARNINGS and PRECAUTIONS)

Renal Impairment in Rheumatoid Arthritis and Psoriasis

Patients with impaired renal function should not receive cyclosporine. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS)

Hepatic Impairment

The clearance of cyclosporine may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (See WARNINGS and PRECAUTIONS).

Newly Transplanted Patients

The initial oral dose of Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED]) can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Gengraf® varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Gengraf® is the same as the initial oral dose of Sandimmune®. Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® in US transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Gengraf® dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration. (See Blood Concentration Monitoring in Transplant Patients, below) If cyclosporine trough blood concentrations are used, the target range is the same for Gengraf® as for Sandimmune®. Using the same trough concentration target range for Gengraf® as for Sandimmune® results in greater cyclosporine exposure when Gengraf® is administered. (See Pharmacokinetics, Absorption) Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Gengraf® doses may be sufficient as maintenance therapy.

Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

Conversion from Sandimmune® (Cyclosporine) to Gengraf® Capsules (Cyclosporine Capsules, USP [MODIFIED]) in Transplant Patients

In transplanted patients who are considered for conversion to Gengraf® from Sandimmune® (cyclosporine), Gengraf® should be started with the same daily dose as was previously used with Sandimmune® (cyclosporine) (1:1 dose conversion). The Gengraf® dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Gengraf® as for Sandimmune® (cyclosporine) results in greater cyclosporine exposure when Gengraf® is administered. (See Pharmacokinetics, Absorption) Patients with suspected poor absorption of Sandimmune® (cyclosporine) require different dosing strategies. (See Transplant Patients with Poor Absorption of Sandimmune®(cyclosporine), below) In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Gengraf®. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Gengraf® must be adjusted accordingly.

Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine)

Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune® (cyclosporine) may have poor or inconsistent absorption of cyclosporine from Sandimmune® (cyclosporine). After conversion to Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED]), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Gengraf®, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Gengraf® at doses greater than 10 mg/kg/day. The dose of Gengraf® should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

Rheumatoid Arthritis

The initial dose of Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED]) is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued. (See WARNINGS and PRECAUTIONS, Drug Interactions) Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5-0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Gengraf® therapy should be discontinued.

Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient's pretreatment level) or clinically significant laboratory abnormalities. (See WARNINGS and PRECAUTIONS)

If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Gengraf® should be discontinued. The same initial dose and dosage range should be used if Gengraf® is combined with the recommended dose of methotrexate. Most patients can be treated with Gengraf® doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week. (See CLINICAL PHARMACOLOGY, Clinical Trials)

There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

Psoriasis

The initial dose of Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED]) should be 2.5 mg/kg/day. Gengraf® should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient's dosage should be increased at 2-week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4.0 mg/kg/day.

Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥25% above the patient's pretreatment level), or clinically significant laboratory abnormalities.

If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, Gengraf® should be discontinued. (See Special Monitoring of Psoriasis Patients)

Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Gengraf® indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient's maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of Gengraf® should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long term experience with Gengraf® in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long term management of patients with this life long disease.

Blood Concentration Monitoring in Transplant Patients

Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

Specific Populations

Renal Impairment in Kidney, Liver, and Heart Transplantation

Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. (See WARNINGS and PRECAUTIONS)

Renal Impairment in Rheumatoid Arthritis and Psoriasis

Patients with impaired renal function should not receive cyclosporine. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS)

Hepatic Impairment

The clearance of cyclosporine may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (See WARNINGS and PRECAUTIONS).
Simcor

Simcor

2.1 Recommended Dosing

SIMCOR should be taken as a single daily dose at bedtime, with a low fat snack. Patients not currently on niacin extended-release and patients currently on niacin products other than niacin extended-release should start SIMCOR at a single 500/20 mg tablet daily at bedtime. Patients already taking simvastatin 20 to 40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime [see Warnings and Precautions (5.3)]. The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks - see Table 1.
* After Week 8, titrate to patient response and tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 mg daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended. Table 1. Recommended niacin extended-release dosing Week(s) Daily dose of niacin extended-release Initial Titration Schedule 1 to 4 500 mg 5 to 8 1000 mg * 1500 mg * 2000 mg
The recommended maintenance dose for SIMCOR is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on patient tolerability and lipid levels. The efficacy and safety of doses of SIMCOR greater than 2000/40 mg daily have not been studied and are therefore not recommended.

If SIMCOR therapy is discontinued for an extended period of time (> 7 days), re-titration as tolerated is recommended. SIMCOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.

Due to the increased risk of hepatotoxicity with other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin, SIMCOR should only be substituted for equivalent doses of niacin extended-release (NIASPAN).

Flushing [see Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken approximately 30 minutes prior to SIMCOR dose). Flushing, pruritus, and gastrointestinal distress are also reduced by gradually increasing the dose of niacin (refer to Table 1) and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of SIMCOR ingestion.

2.2 Coadministration with Other Drugs

Patients taking Amiodarone, Amlodipine or Ranolazine
The dose of SIMCOR should not exceed 1000/20 mg/day [see Warnings and Precautions (5.2), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].
2.3 Chinese Patients Taking SIMCOR

Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when prescribing SIMCOR in doses that exceed 1000/20 mg/day to Chinese patients. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Warnings and Precautions (5.2)].

2.1 Recommended Dosing

SIMCOR should be taken as a single daily dose at bedtime, with a low fat snack. Patients not currently on niacin extended-release and patients currently on niacin products other than niacin extended-release should start SIMCOR at a single 500/20 mg tablet daily at bedtime. Patients already taking simvastatin 20 to 40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime [see Warnings and Precautions (5.3)]. The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks - see Table 1.
* After Week 8, titrate to patient response and tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 mg daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended. Table 1. Recommended niacin extended-release dosing Week(s) Daily dose of niacin extended-release Initial Titration Schedule 1 to 4 500 mg 5 to 8 1000 mg * 1500 mg * 2000 mg
The recommended maintenance dose for SIMCOR is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on patient tolerability and lipid levels. The efficacy and safety of doses of SIMCOR greater than 2000/40 mg daily have not been studied and are therefore not recommended.

If SIMCOR therapy is discontinued for an extended period of time (> 7 days), re-titration as tolerated is recommended. SIMCOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.

Due to the increased risk of hepatotoxicity with other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin, SIMCOR should only be substituted for equivalent doses of niacin extended-release (NIASPAN).

Flushing [see Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken approximately 30 minutes prior to SIMCOR dose). Flushing, pruritus, and gastrointestinal distress are also reduced by gradually increasing the dose of niacin (refer to Table 1) and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of SIMCOR ingestion.

2.2 Coadministration with Other Drugs

Patients taking Amiodarone, Amlodipine or Ranolazine
The dose of SIMCOR should not exceed 1000/20 mg/day [see Warnings and Precautions (5.2), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].
2.3 Chinese Patients Taking SIMCOR

Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when prescribing SIMCOR in doses that exceed 1000/20 mg/day to Chinese patients. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Warnings and Precautions (5.2)].
Erythrocin Stearate

Erythrocin Stearate

Optimal serum levels of erythromycin are reached when ERYTHROCIN STEARATE (erythromycin stearate) is taken in the fasting state or immediately before meals.

Adults

The usual dosage is 250 mg every 6 hours; or 500 mg every 12 hours. Dosage may be increased up to 4 g per day according to the severity of the infection. However, twice-a-day dosing is not recommended when doses larger than 1 g daily are administered.

Children

Age, weight, and severity of the infection are important factors in determining the proper dosage. The usual dosage is 30 to 50 mg/kg/day, in equally divided doses. For more severe infections this dosage may be doubled but should not exceed 4 g per day.

In the treatment of streptococcal infections of the upper respiratory tract (e.g., tonsillitis or pharyngitis), the therapeutic dosage of erythromycin should be administered for at least ten days.

The American Heart Association suggests a dosage of 250 mg of erythromycin orally, twice a day in long-term prophylaxis of streptococcal upper respiratory tract infections for the prevention of recurring attacks of rheumatic fever in patients allergic to penicillin and sulfonamides.3

Conjunctivitis of the Newborn Caused by Chlamydia trachomatis

Oral erythromycin suspension 50 mg/kg/day in 4 divided doses for at least 2 weeks.3

Pneumonia of Infancy Caused by Chlamydia trachomatis

Although the optimal duration of therapy has not been established, the recommended therapy is oral erythromycin suspension 50 mg/kg/day in 4 divided doses for at least 3 weeks.

Urogenital Infections During Pregnancy Due to Chlamydia trachomatis

Although the optimal dose and duration of therapy have not been established, the suggested treatment is 500 mg of erythromycin by mouth four times a day or two erythromycin 333 mg tablets orally every 8 hours on an empty stomach for at least 7 days. For women who cannot tolerate this regimen, a decreased dose of one erythromycin 500 mg tablet orally every 12 hours, one 333 mg tablet orally every 8 hours or 250 mg by mouth four times a day should be used for at least 14 days.5

For Adults With Uncomplicated Urethral, Endocervical, or Rectal Infections Caused by Chlamydia trachomatis, When Tetracycline is Contraindicated or Not Tolerated

500 mg of erythromycin by mouth four times a day or two 333 mg tablets orally every 8 hours for at least 7 days.5

For Patients With Nongonococcal Urethritis Caused by Ureaplasma urealyticum When Tetracycline is Contraindicated or Not Tolerated

500 mg of erythromycin by mouth four times a day or two 333 mg tablets orally every 8 hours for at least seven days.5

Primary Syphilis

30 to 40 g given in divided doses over a period of 10 to 15 days.

Acute Pelvic Inflammatory Disease Caused by N. gonorrhoeae

500 mg Erythrocin Lactobionate-I.V. (erythromycin lactobionate for injection, USP) every 6 hours for 3 days, followed by 500 mg of erythromycin base orally every 12 hours, or 333 mg of erythromycin base orally every 8 hours for 7 days.

Intestinal Amebiasis

Adults

500 mg every 12 hours, 333 mg every 8 hours or 250 mg every 6 hours for 10 to 14 days.

Children

30 to 50 mg/kg/day in divided doses for 10 to 14 days.

Pertussis

Although optimal dosage and duration have not been established, doses of erythromycin utilized in reported clinical studies were 40 to 50 mg/kg/day, given in divided doses for 5 to 14 days.

Legionnaires' Disease

Although optimal dosage has not been established, doses utilized in reported clinical data were 1 to 4 g daily in divided doses.
Nimbex

Nimbex

NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS – Pediatric Use)

NIMBEX SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY.

The dosage information provided below is intended as a guide only. Doses of NIMBEX should be individualized (see CLINICAL PHARMACOLOGY - Individualization of Dosages). The use of a peripheral nerve stimulator will permit the most advantageous use of NIMBEX, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

Adults

Initial Doses

One of two intubating doses of NIMBEX may be chosen, based on the desired time to tracheal intubation and the anticipated length of surgery. In addition to the dose of neuromuscular blocking agent, the presence of co-induction agents (e.g., fentanyl and midazolam) and the depth of anesthesia are factors that can influence intubation conditions. Doses of 0.15 (3 × ED95) and 0.20 (4 × ED95) mg/kg NIMBEX, as components of a propofol/nitrous oxide/oxygen induction-intubation technique, may produce generally GOOD or EXCELLENT conditions for intubation in 2.0 and 1.5 minutes, respectively. Similar intubation conditions may be expected when these doses of NIMBEX are administered as components of a thiopental/nitrous oxide/oxygen induction-intubation technique. In two intubation studies using thiopental or propofol and midazolam and fentanyl as co-induction agents, EXCELLENT intubation conditions were most frequently achieved with the 0.2 mg/kg compared to 0.15 mg/kg dose of cisatracurium. The clinically effective durations of action for 0.15 and 0.20 mg/kg NIMBEX during propofol anesthesia are 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively. Lower doses may result in a longer time for the development of satisfactory intubation conditions. Doses up to 8 × ED95 NIMBEX have been safely administered to healthy adult patients and patients with serious cardiovascular disease. These larger doses are associated with longer clinically effective durations of action (see CLINICAL PHARMACOLOGY).

Because slower times to onset of complete neuromuscular block were observed in elderly patients and patients with renal dysfunction, extending the interval between administration of NIMBEX and the intubation attempt for these patients may be required to achieve adequate intubation conditions.

A dose of 0.03 mg/kg NIMBEX is recommended for maintenance of neuromuscular block during prolonged surgical procedures. Maintenance doses of 0.03 mg/kg each sustain neuromuscular block for approximately 20 minutes. Maintenance dosing is generally required 40 to 50 minutes following an initial dose of 0.15 mg/kg NIMBEX and 50 to 60 minutes following an initial dose of 0.20 mg/kg NIMBEX, but the need for maintenance doses should be determined by clinical criteria. For shorter or longer durations of action, smaller or larger maintenance doses may be administered.

Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (Minimum Alveolar Concentration) may prolong the clinically effective duration of action of initial and maintenance doses. The magnitude of these effects may depend on the duration of administration of the volatile agents. Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of NIMBEX and therefore, no adjustment to the initial dose should be necessary when NIMBEX is administered shortly after initiation of volatile agents. In long surgical procedures during enflurane or isoflurane anesthesia, less frequent maintenance dosing or lower maintenance doses of NIMBEX may be necessary. No adjustments to the initial dose of NIMBEX are required when used in patients receiving propofol anesthesia.

Children

Initial Doses

The recommended dose of NIMBEX for children 2 to 12 years of age is 0.10-0.15 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.10 mg/kg NIMBEX produces maximum neuromuscular block in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) and clinically effective block for 28 minutes (range: 21 to 38 minutes). When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg NIMBEX produces maximum neuromuscular block in about 3.0 minutes (range: 1.5 to 8.0 minutes) and clinically effective block (time to 25% recovery) for 36 minutes (range: 29 to 46 minutes).

Infants

Initial Doses

The recommended dose of NIMBEX for intubation of infants 1 month to 23 months is 0.15 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg NIMBEX produces maximum neuromuscular block in about 2.0 minutes (range: 1.3 to 3.4 minutes) and clinically effective block (time to 25% recovery) for about 43 minutes (range: 34 to 58 minutes).

Use by Continuous Infusion

Infusion in the Operating Room (OR)

After administration of an initial bolus dose of NIMBEX, a diluted solution of NIMBEX can be administered by continuous infusion to adults and children aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures. Infusion of NIMBEX should be individualized for each patient. The rate of administration should be adjusted according to the patient's response as determined by peripheral nerve stimulation. Accurate dosing is best achieved using a precision infusion device.

Infusion of NIMBEX should be initiated only after early evidence of spontaneous recovery from the initial bolus dose. An initial infusion rate of 3 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 1 to 2 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under opioid/nitrous oxide/oxygen anesthesia.

Reduction of the infusion rate by up to 30% to 40% should be considered when NIMBEX is administered during stable isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen at the 1.25 MAC level). Greater reductions in the infusion rate of NIMBEX may be required with longer durations of administration of isoflurane or enflurane.

The rate of infusion of atracurium required to maintain adequate surgical relaxation in patients undergoing coronary artery bypass surgery with induced hypothermia (25° to 28°C) is approximately half the rate required during normothermia. Based on the structural similarity between NIMBEX and atracurium, a similar effect on the infusion rate of NIMBEX may be expected.

Spontaneous recovery from neuromuscular block following discontinuation of infusion of NIMBEX may be expected to proceed at a rate comparable to that following administration of a single bolus dose.

Infusion in the Intensive Care Unit (ICU)

The principles for infusion of NIMBEX in the OR are also applicable to use in the ICU. An infusion rate of approximately 3 mcg/kg/min (range: 0.5 to 10.2 mcg/kg/min) should provide adequate neuromuscular block in adult patients in the ICU. There may be wide interpatient variability in dosage requirements and these may increase or decrease with time (see PRECAUTIONS - Long-Term Use in the Intensive Care Unit [ICU]). Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly re-establish neuromuscular block prior to reinstitution of the infusion.

Infusion Rate Tables

The amount of infusion solution required per minute will depend upon the concentration of NIMBEX in the infusion solution, the desired dose of NIMBEX, and the patient's weight. The contribution of the infusion solution to the fluid requirements of the patient also must be considered. Tables 10 and 11 provide guidelines for delivery, in mL/hr (equivalent to microdrops/minute when 60 microdrops = 1 mL), of NIMBEX solutions in concentrations of 0.1 mg/mL (10 mg/100 mL) or 0.4 mg/mL (40 mg/100 mL).
Table 10. Infusion Rates of NIMBEX for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia for a Concentration of 0.1 mg/mL Drug Delivery Rate (mcg/kg/min) 1.0 1.5 2.0 3.0 5.0 Patient Weight (kg) Infusion Delivery Rate (mL/hr) 10 6 9 12 18 30 45 27 41 54 81 135 70 42 63 84 126 210 100 60 90 120 180 300 Table 11. Infusion Rates of NIMBEX for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia for a Concentration of 0.4 mg/mL Drug Delivery Rate (mcg/kg/min) 1.0 1.5 2.0 3.0 5.0 Patient Weight (kg) Infusion Delivery Rate (mL/hr) 10 1.5 2.3 3.0 4.5 7.5 45 6.8 10.1 13.5 20.3 33.8 70 10.5 15.8 21.0 31.5 52.5 100 15.0 22.5 30.0 45.0 75.0
NIMBEX Injection Compatibility and Admixtures

Y-site Administration

NIMBEX Injection is acidic (pH = 3.25 to 3.65) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g., barbiturate solutions).

Studies have shown that NIMBEX Injection is compatible with:
5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP SUFENTA® (sufentanil citrate) Injection, diluted as directed ALFENTA® (alfentanil hydrochloride) Injection, diluted as directed SUBLIMAZE® (fentanyl citrate) Injection, diluted as directed VERSED® (midazolam hydrochloride) Injection, diluted as directed Droperidol Injection, diluted as directed
NIMBEX Injection is not compatible with DIPRIVAN® (propofol) Injection or TORADOL® (ketorolac) Injection for Y-site administration. Studies of other parenteral products have not been conducted.

Dilution Stability

NIMBEX Injection diluted in 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or 5% Dextrose and 0.9% Sodium Chloride Injection, USP to 0.1 mg/mL may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency. Dilutions to 0.1 mg/mL or 0.2 mg/mL in 5% Dextrose and Lactated Ringer's Injection may be stored under refrigeration for 24 hours.

NIMBEX Injection should not be diluted in Lactated Ringer's Injection, USP due to chemical instability.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear, or contain visible particulates, should not be used. NIMBEX Injection is a colorless to slightly yellow or greenish-yellow solution.
Gengraf

Gengraf

Gengraf® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune®. Gengraf® and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision.

The daily dose of Gengraf® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) should always be given in two divided doses (BID). It is recommended that Gengraf® be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

Specific Populations

Renal Impairment in Kidney, Liver, and Heart Transplantation

Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. (See WARNINGS and PRECAUTIONS)

Renal Impairment in Rheumatoid Arthritis and Psoriasis

Patients with impaired renal function should not receive cyclosporine. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS)

Hepatic Impairment

The clearance of cyclosporine may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (See WARNINGS and PRECAUTIONS).

Newly Transplanted Patients

The initial oral dose of Gengraf® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Gengraf® varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Gengraf® is the same as the initial oral dose of Sandimmune®. Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® in US transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Gengraf® dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration. (See Blood Concentration Monitoring in Transplant Patients, below) If cyclosporine trough blood concentrations are used, the target range is the same for Gengraf® as for Sandimmune®. Using the same trough concentration target range for Gengraf® as for Sandimmune® results in greater cyclosporine exposure when Gengraf® is administered. (See Pharmacokinetics, Absorption) Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Gengraf® doses may be sufficient as maintenance therapy.

Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

Conversion From Sandimmune® Oral Solution (Cyclosporine Oral Solution, USP) To Gengraf® Oral Solution (Cyclosporine Oral Solution, USP [MODIFIED]) in Transplant Patients

In transplanted patients who are considered for conversion to Gengraf® from Sandimmune® (cyclosporine), Gengraf® should be started with the same daily dose as was previously used with Sandimmune® (cyclosporine) (1:1 dose conversion). The Gengraf® dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Gengraf® as for Sandimmune® (cyclosporine) results in greater cyclosporine exposure when Gengraf® is administered. (See Pharmacokinetics, Absorption) Patients with suspected poor absorption of Sandimmune® (cyclosporine) require different dosing strategies. (See Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine), below) In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Gengraf®. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Gengraf® must be adjusted accordingly.

Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine)

Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune® (cyclosporine) may have poor or inconsistent absorption of cyclosporine from Sandimmune® (cyclosporine). After conversion to Gengraf® Oral Solution (cyclosporine oral solution, USP [MODIFIED]), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Gengraf®, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Gengraf® at doses greater than 10 mg/kg/day. The dose of Gengraf® should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

Rheumatoid Arthritis

The initial dose of Gengraf® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued. (See WARNINGS and PRECAUTIONS, Drug Interactions) Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5-0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Gengraf® therapy should be discontinued.

Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient's pretreatment level) or clinically significant laboratory abnormalities. (See WARNINGS and PRECAUTIONS)

If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Gengraf® should be discontinued. The same initial dose and dosage range should be used if Gengraf® is combined with the recommended dose of methotrexate. Most patients can be treated with Gengraf® doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week. (See CLINICAL PHARMACOLOGY, Clinical Trials)

There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

Psoriasis

The initial dose of Gengraf® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) should be 2.5 mg/kg/day. Gengraf® should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient's dosage should be increased at 2-week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4.0 mg/kg/day.

Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥25% above the patient's pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, Gengraf® should be discontinued. (See Special Monitoring of Psoriasis Patients)

Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Gengraf® indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient's maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of Gengraf® should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long term experience with Gengraf® in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long term management of patients with this life long disease.

Gengraf® Oral Solution (Cyclosporine Oral Solution, USP [MODIFIED])-

Recommendations for Administration

To make Gengraf® (cyclosporine oral solution, [MODIFIED]) more palatable, it should be diluted with orange or apple juice that is at room temperature. Patients should avoid switching diluents frequently. Grapefruit juice affects metabolism of cyclosporine and should be avoided. The combination of Gengraf® solution with milk can be unpalatable. The effect of milk on the bioavailability of cyclosporine when administered as Gengraf® Oral Solution (cyclosporine oral solution, [MODIFIED]) has not been evaluated.

Take the prescribed amount of Gengraf® from the container using the dosing syringe supplied, and transfer the solution to a glass of orange or apple juice. Stir well and drink at once. Do not allow diluted oral solution to stand before drinking. Use a glass container (not plastic). Rinse the glass with more diluent to ensure that the total dose is consumed. After use, dry the outside of the dosing syringe with a clean towel and store in a clean, dry place. Do not rinse the dosing syringe with water or other cleaning agents. If the syringe requires cleaning, it must be completely dry before resuming use.

Blood Concentration Monitoring in Transplant Patients

Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

Specific Populations

Renal Impairment in Kidney, Liver, and Heart Transplantation

Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. (See WARNINGS and PRECAUTIONS)

Renal Impairment in Rheumatoid Arthritis and Psoriasis

Patients with impaired renal function should not receive cyclosporine. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS)

Hepatic Impairment

The clearance of cyclosporine may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (See WARNINGS and PRECAUTIONS).
Survanta

Survanta

For intratracheal administration only.

SURVANTA should be administered by or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants.

Marked improvements in oxygenation may occur within minutes of administration of SURVANTA. Therefore, frequent and careful clinical observation and monitoring of systemic oxygenation are essential to avoid hyperoxia.

Review of audiovisual instructional materials describing dosage and administration procedures is recommended before using SURVANTA. Materials are available upon request from AbbVie Inc.

Dosage

Each dose of SURVANTA is 100 mg of phospholipids/kg birth weight (4 mL/kg). The SURVANTA Dosing Chart shows the total dosage for a range of birth weights.
SURVANTA DOSING CHART Weight (grams) Total Dose (mL) Weight (grams) Total Dose (mL) 600-650 2.6 1301-1350 5.4 651-700 2.8 1351-1400 5.6 701-750 3.0 1401-1450 5.8 751-800 3.2 1451-1500 6.0 801-850 3.4 1501-1550 6.2 851-900 3.6 1551-1600 6.4 901-950 3.8 1601-1650 6.6 951-1000 4.0 1651-1700 6.8 1001-1050 4.2 1701-1750 7.0 1051-1100 4.4 1751-1800 7.2 1101-1150 4.6 1801-1850 7.4 1151-1200 4.8 1851-1900 7.6 1201-1250 5.0 1901-1950 7.8 1251-1300 5.2 1951-2000 8.0
Four doses of SURVANTA can be administered in the first 48 hours of life. Doses should be given no more frequently than every 6 hours.

Directions for Use

SURVANTA should be inspected visually for discoloration prior to administration. The color of SURVANTA is off-white to light brown. If settling occurs during storage, swirl the vial gently (DO NOT SHAKE) to redisperse. Some foaming at the surface may occur during handling and is inherent in the nature of the product.

SURVANTA is stored refrigerated (2-8°C). Date and time need to be recorded in the box on front of the carton or vial, whenever SURVANTA is removed from the refrigerator. Before administration, SURVANTA should be warmed by standing at room temperature for at least 20 minutes or warmed in the hand for at least 8 minutes. Artificial warming methods should not be used. If a prevention dose is to be given, preparation of SURVANTA should begin before the infant’s birth.

Unopened, unused vials of SURVANTA that have been warmed to room temperature may be returned to the refrigerator within 24 hours of warming, and stored for future use. SURVANTA SHOULD NOT BE REMOVED FROM THE REFRIGERATOR FOR MORE THAN 24 HOURS. SURVANTA SHOULD NOT BE WARMED AND RETURNED TO THE REFRIGERATOR MORE THAN ONCE. Each single-use vial of SURVANTA should be entered only once. Used vials with residual drug should be discarded.

SURVANTA does not require reconstitution or sonication before use.
Tarka

Tarka

The recommended usual dosage range of trandolapril for hypertension is 1 to 4 mg per day administered in a single dose or two divided doses. The recommended usual dosage range of Isoptin-SR for hypertension is 120 to 480 mg per day administered in a single dose or two divided doses.

The hazards (see WARNINGS) of trandolapril are generally independent of dose; those of verapamil are a mixture of dose-dependent phenomena (primarily dizziness, AV block, constipation) and dose-independent phenomena, the former much more common than the latter. Therapy with any combination of trandolapril and verapamil will thus be associated with both sets of dose-independent hazards. The dose-dependent side effects of verapamil have not been shown to be decreased by the addition of trandolapril nor vice versa.

Rarely, the dose-independent hazards of trandolapril are serious. To minimize dose-independent hazards, it is usually appropriate to begin therapy with TARKA only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy at its respective maximally recommended dose and shortest dosing interval, or (b) the dose of one or the other monotherapy cannot be increased further because of dose-limiting side effects.

Clinical trials with TARKA have explored only once-a-day doses. The antihypertensive effect and or adverse effects of adding 4 mg of trandolapril once-a-day to a dose of 240 mg Isoptin-SR administered twice-a-day has not been studied, nor have the effects of adding as little of 180 mg Isoptin-SR to 2 mg trandolapril administered twice-a-day been evaluated. Over the dose range of Isoptin-SR 120 to 240 mg once-a-day and trandolapril 0.5 to 8 mg once-a-day, the effects of the combination increase with increasing doses of either component.

Replacement Therapy

For convenience, patients receiving trandolapril (up to 8 mg) and verapamil (up to 240 mg) in separate tablets, administered once-a-day, may instead wish to receive tablets of TARKA containing the same component doses.

TARKA should be administered with food.
Mavik

Mavik

Hypertension

The recommended initial dosage of MAVIK for patients not receiving a diuretic is 1 mg once daily in non-black patients and 2 mg in black patients. Dosage should be adjusted according to the blood pressure response. Generally, dosage adjustments should be made at intervals of at least 1 week. Most patients have required dosages of 2 to 4 mg once daily. There is little clinical experience with doses above 8 mg.

Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing. If blood pressure is not adequately controlled with MAVIK monotherapy, a diuretic may be added.

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of MAVIK. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with MAVIK. (see WARNINGS.) Then, if blood pressure is not controlled with MAVIK alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 0.5 mg MAVIK should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response. (see WARNINGS, PRECAUTIONS and DRUG INTERACTIONS.)

Concomitant administration of MAVIK with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium. (see PRECAUTIONS.)

Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction

The recommended starting dose is 1 mg, once daily. Following the initial dose, all patients should be titrated (as tolerated) toward a target dose of 4 mg, once daily. If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.

Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis

For patients with a creatinine clearance < 30 mL/min. or with hepatic cirrhosis, the recommended starting dose, based on clinical and pharmacokinetic data, is 0.5 mg daily. Patients should subsequently have their dosage titrated (as described above) to the optimal response.
Lupron Depot-ped

Lupron Depot-ped

2.1 Dose and Principles of Dosing 7.5 mg, 11.25 mg, or 15 mg for 1-month administration

LUPRON DEPOT-PED must be administered under the supervision of a physician.

LUPRON DEPOT-PED is administered as a single intramuscular injection once a month. The starting dose will be dictated by the child's weight, as indicated in the table below.
Table 1. Dosing Recommendations Based on Body Weight for LUPRON DEPOT-PED 1-month Formulations Body Weight Recommended Dose ≤ 25 kg 7.5 mg > 25-37.5 kg 11.25 mg > 37.5 kg 15 mg
The dose of LUPRON DEPOT-PED must be individualized for each child. If adequate hormonal and clinical suppression is not achieved with the starting dose, it should be increased to the next available higher dose (e.g. 11.25 mg or 15 mg at the next monthly injection). Similarly, the dose may be adjusted with changes in body weight. The injection site should be varied periodically.

The goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored after 1–2 months of initiating therapy and with each dose change to ensure adequate pituitary gonadotropin suppression. Once a dose that results in adequate hormonal suppression is found, it can often be maintained for the duration of therapy in most children. It is recommended, however, that adequate hormonal suppression be verified in such patients as weight can increase significantly while on therapy.

Each LUPRON DEPOT-PED strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.

LUPRON DEPOT-PED should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.3.

2.2 Dose and Principles of Dosing 11.25 mg or 30 mg for 3-month administration

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration must be administered under the supervision of a physician.

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be administered once every three months (12 weeks) as a single intramuscular injection. Regardless of the dose chosen, the goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, other available GnRH agonists indicated for the treatment of CPP should be considered.

Each LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.3.

2.3 Reconstitution and Administration Instructions
The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. Since LUPRON DEPOT-PED does not contain a preservative, the suspension should be injected immediately or discarded if not used within two hours. As with other drugs administered by injection, the injection site should be varied periodically. The LUPRON DEPOT-PED powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel. Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe.Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or shoulder; injection sites should be alternated.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc® safety device. If blood is present remove the needle immediately. Do not inject the medication.
Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT-PED should be mixed and used immediately.
AFTER INJECTION
Withdraw the needle. Once the syringe has been withdrawn, activate immediately the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device is fully extended over the needle and a CLICK is heard or felt.
2.2 Dose and Principles of Dosing 11.25 mg or 30 mg for 3-month administration

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration must be administered under the supervision of a physician.

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be administered once every three months (12 weeks) as a single intramuscular injection. Regardless of the dose chosen, the goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, other available GnRH agonists indicated for the treatment of CPP should be considered.

Each LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.3.

ADDITIONAL INFORMATION
Dispose of the syringe according to local regulations/procedures.
Advicor

Advicor

The patient should be placed on a standard cholesterol-lowering diet before receiving ADVICOR or its individual active components and should continue on this diet during treatment with lipid-altering therapy (see NCEP Treatment Guidelines for details on dietary therapy).

ADVICOR

ADVICOR should be taken at bedtime, with a low-fat snack. ADVICOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing. Patients not currently on NIASPAN must start ADVICOR at the lowest initial ADVICOR dose, a single 500 mg/20 mg tablet once daily at bedtime. The dose of ADVICOR should not be increased by more than 500 mg daily (based on the NIASPAN component) every 4 weeks. The dose of ADVICOR should be individualized based on targeted goals for cholesterol and triglycerides, and on patient response. Doses of ADVICOR greater than 2000 mg/40 mg daily are not recommended. If ADVICOR therapy is discontinued for an extended period (>7 days), reinstitution of therapy should begin with the lowest dose of ADVICOR.

Flushing of the skin (see ADVERSE REACTIONS) may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken up to approximately 30 minutes prior to ADVICOR dose). Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach.

Equivalent doses of ADVICOR may be substituted for equivalent doses of NIASPAN but should not be substituted for other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin preparations (see WARNINGS). Patients previously receiving niacin products other than NIASPAN should be started on NIASPAN with the recommended NIASPAN titration schedule, and the dose should subsequently be individualized based on patient response. A relative bioavailability study results indicated that ADVICOR tablet strengths (i.e. two tablets of 500 mg/20 mg and one tablet of 1000 mg/40 mg) are not interchangeable.

NIASPAN

NIASPAN should be taken at bedtime, after a low-fat snack, and doses should be individualized according to patient response. Therapy with NIASPAN must be initiated at 500mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy. NIASPAN must be titrated and the dose should not be increased by more than 500 mg every 4 weeks up to a maximum dose of 2000 mg a day. The recommended dose escalation is shown in Table 11 below. Patients already receiving a stable dose of NIASPAN may be switched directly to a niacin-equivalent dose of ADVICOR.

Table 11. Recommended Dosing

Maintenance Dose:

The daily dosage of NIASPAN should not be increased by more than 500 mg in any 4-week period. The recommended maintenance dose is 1000 mg (two 500 mg tablets) to 2000 mg (two 1000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2000 mg daily are not recommended. Women may respond at lower NIASPAN doses than men.

Flushing of the skin (see ADVERSE REACTIONS) may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken 30 minutes prior to NIASPAN dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of ADVICOR ingestion.

Equivalent doses of NIASPAN should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin (see WARNINGS). Patients previously receiving other niacin products should be started with the recommended NIASPAN titration schedule (see Table 11), and the dose should subsequently be individualized based on patient response. Single-dose bioavailability studies have demonstrated that NIASPAN tablet strengths are not interchangeable.

If NIASPAN therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 11).

NIASPAN tablets should be taken whole and should not be broken, crushed or chewed before swallowing.

Concomitant Therapy

Concomitant Therapy with Lovastatin

Patients already receiving a stable dose of lovastatin who require further TG-lowering or HDL-raising (e.g., to achieve NCEP non-HDL-C goals), may receive concomitant dosage titration with NIASPAN per NIASPAN recommended initial titration schedule (see Table 10, DOSAGE AND ADMINISTRATION section). For patients already receiving a stable dose of NIASPAN who require further LDL-lowering (e.g., to achieve NCEP LDL-C goals; Table 8), the usual recommended starting dose of lovastatin is 20 mg once a day. Dose adjustments should be made at intervals of 4 weeks or more. Combination therapy with NIASPAN and lovastatin should not exceed doses of 2000 mg and 40 mg daily, respectively.

Dosage in Patients with Renal or Hepatic Insufficiency

Use of NIASPAN in patients with renal or hepatic insufficiency has not been studied. NIASPAN is contraindicated in patients with significant or unexplained hepatic dysfunction (see WARNINGS, PRECAUTIONS. NIASPAN should be used with caution in patients with renal insufficiency (see CLINICAL PHARMACOLOGY).

Lovastatin

The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL cholesterol of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of lovastatin. A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin if cholesterol levels fall significantly below the targeted range.

Dosage in Patients taking Danazol, Diltiazem or Verapamil

In patients taking danazol, diltiazem, or verapamil concomitantly with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of lovastatin and should not exceed 20 mg/day.

Dosage in Patients taking Amiodarone

In patients taking amiodarone concomitantly with lovastatin, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug interactions).

Concomitant Lipid-Lowering Therapy

Use of lovastatin with gemfibrozil should be avoided.

Caution should be used when prescribing other fibrates with lovastatin, as fibrates can cause myopathy when given alone.

Dosage in Patients with Renal Insufficiency

In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).

Lovastatin

The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL cholesterol of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of lovastatin. A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin if cholesterol levels fall significantly below the targeted range.

Dosage in Patients taking Danazol, Diltiazem or Verapamil

In patients taking danazol, diltiazem, or verapamil concomitantly with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of lovastatin and should not exceed 20 mg/day.

Dosage in Patients taking Amiodarone

In patients taking amiodarone concomitantly with lovastatin, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug interactions).

Concomitant Lipid-Lowering Therapy

Use of lovastatin with gemfibrozil should be avoided.

Caution should be used when prescribing other fibrates with lovastatin, as fibrates can cause myopathy when given alone.

Dosage in Patients with Renal Insufficiency

In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
Prometrium

Prometrium

Prevention of Endometrial Hyperplasia

PROMETRIUM Capsules should be given as a single daily dose at bedtime, 200 mg orally for 12 days sequentially per 28-day cycle, to a postmenopausal woman with a uterus who is receiving daily conjugated estrogens tablets.

Treatment of Secondary Amenorrhea

PROMETRIUM Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.

Some women may experience difficulty swallowing PROMETRIUM Capsules. For these women, PROMETRIUM Capsules should be taken with a glass of water while in the standing position.
Synthroid

Synthroid

General Principles

The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of SYNTHROID that is adequate to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see WARNINGS and PRECAUTIONS). Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTIONS - Laboratory Tests).

SYNTHROID is administered as a single daily dose, preferably one-half to one-hour before breakfast. SYNTHROID should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS - Drug Interactions).

Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks.

Caution should be exercised when administering SYNTHROID to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS).

Specific Patient Populations

Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete

(see WARNINGS and PRECAUTIONS - Laboratory Tests)

Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., 100-125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than 200 mcg/day are seldom required. An inadequate response to daily doses ≥ 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions.

For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed. The recommended starting dose of levothyroxine sodium in elderly patients with cardiac disease is 12.5-25 mcg/day , with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized.

In patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized.

In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free- T4 level is restored to the upper half of the normal range.

Pediatric Dosage - Congenital or Acquired Hypothyroidism

(see PRECAUTIONS - Laboratory Tests)

General Principles

In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in diagnosis and institution of therapy may have deleterious effects on the child's intellectual and physical growth and development.

Undertreatment and overtreatment should be avoided (see PRECAUTIONS - Pediatric Use). SYNTHROID may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. This suspension can be administered by spoon or by dropper. DO NOT STORE THE SUSPENSION. Foods that decrease absorption of levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine sodium tablets (see PRECAUTIONS - Drug-Food Interactions).

Newborns

The recommended starting dose of levothyroxine sodium in newborn infants is 10-15 mcg/kg/day . A lower starting dose (e.g., 25 mcg/day) should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dL) or undetectable serum T4 concentrations, the recommended initial starting dose is 50 mcg/day of levothyroxine sodium.

Infants and Children

Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see Table 3). However, in children with chronic or severe hypothyroidism, an initial dose of 25 mcg/day of levothyroxine sodium is recommended with increments of 25 mcg every 2-4 weeks until the desired effect is achieved.

Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached.

Table 3. Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weighta 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day > 12 years but growth and puberty incomplete 2-3 mcg/kg/day Growth and puberty complete 1.7 mcg/kg/day a The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTIONS - Laboratory Tests and Pediatric Use).
Pregnancy

Pregnancy may increase levothyroxine requirements (see PREGNANCY).

Subclinical Hypothyroidism

If this condition is treated, a lower levothyroxine sodium dose (e.g., 1 mcg/kg/day) than that used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory parameters.

TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules

The target level for TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of SYNTHROID used for TSH suppression should be individualized based on the specific disease and the patient being treated.

In the treatment of well-differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH is suppressed to < 0.1 mU/L, and this usually requires a levothyroxine sodium dose of greater than 2 mcg/kg/day. However, in patients with high-risk tumors, the target level for TSH suppression may be < 0.01 mU/L.

In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e.g., 0.1 to either 0.5 or 1.0 mU/L) than that used for the treatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

Myxedema Coma

Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Therefore, oral thyroid hormone drug products are not recommended to treat this condition. Thyroid hormone products formulated for intravenous administration should be administered.
Marinol

Marinol

Appetite Stimulation: Initially, 2.5 mg MARINOL Capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of MARINOL Capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day MARINOL Capsules, administered in divided oral doses. Caution should be exercised in escalating the dosage of MARINOL Capsules because of the increased frequency of dose-related adverse experiences at higher dosages. (See PRECAUTIONS.)

Antiemetic: MARINOL Capsules is best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose. (See PRECAUTIONS.)

Storage Conditions

MARINOL Capsules should be packaged in a well-closed container and stored in a cool environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a refrigerator. Protect from freezing.
Exjade

Exjade

2.1 Testing Prior to Initiation of TECHNIVIE

Prior to initiation of TECHNIVIE, assess baseline hepatic laboratory and clinical parameters[see Contraindications (4) and Warnings and Precautions (5.1 and 5.2)].

2.2 Recommended Dosage in Adults

TECHNIVIE is ombitasvir, paritaprevir and ritonavir fixed dose combination tablets.

The recommended dosage of TECHNIVIE is two tablets taken orally once daily (in the morning). Take TECHNIVIE with a meal without regard to fat or calorie content [see Clinical Pharmacology (12.3)].

TECHNIVIE is used in combination with ribavirin (RBV). When administered with TECHNIVIE, the recommended dosage of RBV is based on weight: 1000 mg per day for subjects less than 75 kg and 1200 mg per day for those weighing at least 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.

Table 1 shows the recommended TECHNIVIE treatment regimen and duration for HCV genotype 4 patients without cirrhosis.
Table 1. Treatment Regimen and Duration for Patients with HCV Genotype 4 without Cirrhosis Patient Population Treatment Duration Genotype 4 without cirrhosis TECHNIVIE + ribavirin* 12 weeks *TECHNIVIE administered without RBV for 12 weeks may be considered for treatment-naïve patients who cannot take or tolerate ribavirin [see Microbiology (12.4) and Clinical Studies (14)].
2.3 Dosage in Patients with Hepatic Impairment

TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C)[see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.1 Testing Prior to Initiation of TECHNIVIE

Prior to initiation of TECHNIVIE, assess baseline hepatic laboratory and clinical parameters[see Contraindications (4) and Warnings and Precautions (5.1 and 5.2)].
Norvir

Norvir

NORVIR is administered orally in combination with other antiretroviral agents. It is recommended that NORVIR be taken with meals if possible.

General Dosing Guidelines Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued.

Dose modification for NORVIR Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings and Precautions (5), and Drug Interactions (7)].

2.1 Adult Patients

Recommended Dosage for treatment of HIV-1 The recommended dosage of ritonavir is 600 mg twice daily by mouth. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

2.2 Pediatric Patients

The recommended dosage of ritonavir in children greater than 1 month is 350 to 400 mg per m2 twice daily by mouth and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. The use of NORVIR oral solution is recommended for children greater than 1 month who cannot swallow capsules. Please refer to the NORVIR oral solution full prescribing information for pediatric dosage and administration.

2.1 Adult Patients

Recommended Dosage for treatment of HIV-1 The recommended dosage of ritonavir is 600 mg twice daily by mouth. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

2.2 Pediatric Patients

The recommended dosage of ritonavir in children greater than 1 month is 350 to 400 mg per m2 twice daily by mouth and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. The use of NORVIR oral solution is recommended for children greater than 1 month who cannot swallow capsules. Please refer to the NORVIR oral solution full prescribing information for pediatric dosage and administration.
Lupron Depot

Lupron Depot

LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.

Endometriosis

The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination with norethindrone acetate is six months. The choice of LUPRON DEPOT alone or LUPRON DEPOT plus norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be made by the health care professional in consultation with the patient and should take into consideration the risks and benefits of the addition of norethindrone to LUPRON DEPOT alone.

If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of LUPRON DEPOT administered monthly and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one six-month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. LUPRON DEPOT alone is not recommended for retreatment. If norethindrone acetate is contraindicated for the individual patient, then retreatment is not recommended.

An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.

Uterine Leiomyomata (Fibroids)

Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.

The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following instructions:

Reconstitution and Administration Instructions
The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. Since LUPRON DEPOT does not contain a preservative, the suspension should be injected immediately or discarded if not used within two hours. As with other drugs administered by injection, the injection site should be varied periodically. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel. Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc® safety device. If blood is present remove the needle immediately. Do not inject the medication.
Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately.AFTER INJECTION Withdraw the needle. Once the syringe has been withdrawn, activate immediately the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt.
ADDITIONAL INFORMATION
Dispose of the syringe according to local regulations/procedures.
Kaletra

Kaletra

Adult and children 2 years of age and older. Apply liberally to affected area not more than 5 times daily and 5-8 times per day for some severe cases or follow doctor's instruction.
Norvir

Norvir

NORVIR is administered orally. NORVIR tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure®, or Advera® within one hour of dosing.

General Dosing Guidelines

Patients who take the 600 mg twice daily soft gel capsule NORVIR dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (Cmax) achieved with the tablet formulation relative to the soft gel capsule [see Clinical Pharmacology (12.3)]. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.

Dose Modification for NORVIR

Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings and Precautions (5), and Drug Interactions (7)].

2.1 Adult Patients

Recommended Dosage for Treatment of HIV-1:

The recommended dosage of ritonavir is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

2.2 Pediatric Patients

Ritonavir should be used in combination with other antiretroviral agents [see Dosage and Administration (2)]. The recommended dosage of ritonavir in children greater than 1 month is 350 to 400 mg per m2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. When possible, dose should be administered using a calibrated dosing syringe.

NORVIR oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained [see Warnings and Precautions (5.2)].

NORVIR oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. Special attention should be given to accurate calculation of the dose of NORVIR, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for young children. Total amounts of alcohol and propylene glycol from all medicines that are to be given to pediatric patients 1 to 6 months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)].
Table 1. Pediatric Dosage Guidelines Body Surface Area (m2) Twice Daily Dose 250 mg per m2 Twice Daily Dose 300 mg per m2 Twice Daily Dose 350 mg per m2 Twice Daily Dose 400 mg per m2 0.20 0.6 mL (50 mg) 0.75 mL (60 mg) 0.9 mL (70 mg) 1.0 mL (80 mg) 0.25 0.8 mL (62.5 mg) 0.9 mL (75 mg) 1.1 mL (87.5 mg) 1.25 mL (100 mg) 0.50 1.6 mL (125 mg) 1.9 mL (150 mg) 2.2 mL (175 mg) 2.5 mL (200 mg) 0.75 2.3 mL (187.5 mg) 2.8 mL (225 mg) 3.3 mL (262.5 mg) 3.75 mL (300 mg) 1.00 3.1 mL (250 mg) 3.75 mL (300 mg) 4.4 mL (350 mg) 5 mL (400 mg) 1.25 3.9 mL (312.5 mg) 4.7 mL (375 mg) 5.5 mL (437.5 mg) 6.25 mL (500 mg) 1.50 4.7 mL (375 mg) 5.6 mL (450 mg) 6.6 mL (525 mg) 7.5 mL (600 mg)
Body surface area (BSA) can be calculated as follows1:
Lupron Depot

Lupron Depot

LUPRON DEPOT Must Be Administered Under the Supervision of a Physician.

Endometriosis

The recommended duration of treatment with LUPRON DEPOT–3 Month 11.25 mg alone or in combination with norethindrone acetate is six months. The choice of LUPRON DEPOT alone or LUPRON DEPOT plus norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be made by the health care professional in consultation with the patient and should take into consideration the risks and benefits of the addition of norethindrone to LUPRON DEPOT alone.

If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of LUPRON DEPOT-3 Month 11.25 mg administered every three months and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one six-month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. LUPRON DEPOT alone is not recommended for retreatment. If norethindrone acetate is contraindicated for the individual patient, then retreatment is not recommended.

An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.

Uterine Leiomyomata (Fibroids)

The recommended dose of LUPRON DEPOT–3 Month 11.25 mg is one injection. The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment with LUPRON DEPOT–3 Month 11.25 mg is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.

Due to different release characteristics, a fractional dose of the 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following instructions:

Reconstitution and Administration Instructions
The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. Since LUPRON DEPOT does not contain a preservative, the suspension should be injected immediately or discarded if not used within two hours. As with other drugs administered by injection, the injection site should be varied periodically. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel. Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc® safety device. If blood is present remove the needle immediately. Do not inject the medication.
Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately. AFTER INJECTION Withdraw the needle. Once the syringe has been withdrawn, activate immediately the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt.
ADDITIONAL INFORMATION
Dispose of the syringe according to local regulations/procedures.
Lupaneta Pack

Lupaneta Pack

2.1 Dosing Information

LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows:
3.75 mg of leuprolide acetate by intramuscular injection once a month for up to six injections (6 months of therapy); to be administered by a healthcare provider 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy
The initial course of treatment with leuprolide acetate for depot suspension 3.75 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months.

If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins [see Warnings and Precautions (5.1)].

Treatment beyond two six-month courses has not been studied and is not recommended due to concerns about adverse impact on bone mineral density.

2.2 Different Formulations of Leuprolide Acetate

Due to the specific release characteristics of the 1-month depot formulation, HCPs should not administer 3 doses of the 3.75 mg 1-month formulation simultaneously to mimic the pharmacological profile of the 11.25 mg 3-month formulation.

2.3 Reconstitution and Administration for Injection of Leuprolide Acetate
Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot suspension does not contain a preservative. Visually inspect the leuprolide acetate for depot suspension powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).
Figure 1:

Figure 2:
Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
Figure 3:
Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4:
Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid (see Figure 5). Alternate injection sites.
Figure 5:

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 6:
Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7:
10. Dispose of the syringe according to local regulations/procedures [see References (15)].
2.1 Dosing Information

LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows:
3.75 mg of leuprolide acetate by intramuscular injection once a month for up to six injections (6 months of therapy); to be administered by a healthcare provider 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy
The initial course of treatment with leuprolide acetate for depot suspension 3.75 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months.

If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins [see Warnings and Precautions (5.1)].

Treatment beyond two six-month courses has not been studied and is not recommended due to concerns about adverse impact on bone mineral density.

2.2 Different Formulations of Leuprolide Acetate

Due to the specific release characteristics of the 1-month depot formulation, HCPs should not administer 3 doses of the 3.75 mg 1-month formulation simultaneously to mimic the pharmacological profile of the 11.25 mg 3-month formulation.

2.3 Reconstitution and Administration for Injection of Leuprolide Acetate
Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot suspension does not contain a preservative. Visually inspect the leuprolide acetate for depot suspension powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).
Figure 1:

Figure 2:
Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
Figure 3:
Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4:
Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid (see Figure 5). Alternate injection sites.
Figure 5:

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 6:
Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7:
10. Dispose of the syringe according to local regulations/procedures [see References (15)].
Lupaneta Pack

Lupaneta Pack

2.1 Dosing Information

LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows:
11.25 mg of leuprolide acetate by intramuscular injection once every three months for up to two injections (6 months of therapy); to be administered by a healthcare provider 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy
The initial course of treatment with leuprolide acetate for depot suspension 11.25 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months.

If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins [see Warnings and Precautions (5.1)].

Treatment beyond two six-month courses has not been studied and is not recommended due to concerns about adverse impact on bone mineral density.

2.2 Different Formulations of Leuprolide Acetate

Due to different release characteristics, a fractional dose of the leuprolide acetate for depot suspension 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.

2.3 Reconstitution and Administration for Injection of Leuprolide Acetate
Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot suspension does not contain a preservative. Visually inspect the leuprolide acetate for depot suspension powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).
Figure 1:

Figure 2:
Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
Figure 3:
Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4:
Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid (see Figure 5).
Figure 5:

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 6:
Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7:
Dispose of the syringe according to local regulations/procedures [see References (15)].
2.1 Dosing Information

LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows:
11.25 mg of leuprolide acetate by intramuscular injection once every three months for up to two injections (6 months of therapy); to be administered by a healthcare provider 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy
The initial course of treatment with leuprolide acetate for depot suspension 11.25 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months.

If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins [see Warnings and Precautions (5.1)].

Treatment beyond two six-month courses has not been studied and is not recommended due to concerns about adverse impact on bone mineral density.

2.3 Reconstitution and Administration for Injection of Leuprolide Acetate
Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot suspension does not contain a preservative. Visually inspect the leuprolide acetate for depot suspension powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).
Figure 1:

Figure 2:
Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
Figure 3:
Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4:
Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid (see Figure 5).
Figure 5:

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 6:
Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7:
Dispose of the syringe according to local regulations/procedures [see References (15)].
Protonix Delayed-releas...

Protonix Delayed-release

MIVACRON SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY.

The dosage information provided below is intended as a guide only. Doses of MIVACRON should be individualized (see CLINICAL PHARMACOLOGY - Individualization of Dosages). Factors that may warrant dosage adjustment include but may not be limited to: the presence of significant kidney, liver, or cardiovascular disease, obesity (patients weighing greater than or equal to 30% more than ideal body weight for height), asthma, reduction in plasma cholinesterase activity, and the presence of inhalational anesthetic agents.

When using MIVACRON or other neuromuscular blocking agents to facilitate tracheal intubation, it is important to recognize that the most important factors affecting intubation are the depth of general anesthesia and the level of neuromuscular block. Satisfactory intubating conditions can usually be achieved before complete neuromuscular block is attained if there is adequate anesthesia.

The use of a peripheral nerve stimulator will permit the most advantageous use of MIVACRON, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery. When using a stimulator to monitor onset of neuromuscular block, clinical studies have shown that all four twitches of the train-of-four response may be present, with little or no fade, at the times recommended for intubation. Therefore, as with other neuromuscular blocking agents, it is important to use other criteria, such as clinical evaluation of the status of relaxation of jaw muscles and vocal cords, in conjunction with peripheral muscle twitch monitoring, to guide the appropriate time of intubation.

The onset of conditions suitable for tracheal intubation occurs earlier after a conventional intubating dose of succinylcholine than after recommended doses of MIVACRON.

Adults

Initial Doses

Doses of 0.15 mg/kg administered over 5 to 15 seconds, 0.2 mg/kg administered over 30 seconds, or 0.25 mg/kg administered in divided doses (0.15 mg/kg followed in 30 seconds by 0.1 mg/kg) are recommended for facilitation of tracheal intubation for most patients (see Table 7).
Table 7. Recommended Initial Dosing Regimens for Adults Dosing Paradigm* Anesthetic Induction Technique Studied Time to Generally Good-to- Excellent Intubating Conditions 0.15 mg/kg, intravenous (over 5 to 15 sec) Thiopental/opioid/N2O/O2 or propofol/opioid 2.5 to 3 min after completion of dose 0.2 mg/kg, intravenous (over 30 sec) Thiopental/opioid/N2O/O2 or propofol/opioid 2 to 2.5 min after completion of dose 0.25 mg/kg, intravenous (0.15 mg/kg followed in 30 sec by 0.1 mg/kg) Propofol/opioid 1.5 to 2 min after completion of 0.15 mg/kg dose * Dosing instituted after induction of adequate general anesthesia.
The purpose of slowed or divided dosing of MIVACRON at doses above 0.15 mg/kg is to minimize the transient decreases in blood pressure observed in some patients given these doses over 5 to 15 seconds (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and ADVERSE REACTIONS). The quality of intubation conditions does not significantly differ for the times and doses of MIVACRON recommended in Table 7, but the onset of suitable intubation conditions may be reached earlier with higher doses. The choice of a particular dose and regimen should be based on individual circumstances and patient requirements (see CLINICAL PHARMACOLOGY - Individualization of Dosages).

In patients with clinically significant cardiovascular disease and in patients with any history suggesting a greater sensitivity to the release of histamine or other mediators (e.g., asthma), the dose of MIVACRON should be 0.15 mg/kg or less, administered over 60 seconds (see PRECAUTIONS). No data are available on the use of doses of MIVACRON above 0.15 mg/kg in patients with clinically significant kidney or liver disease.

Clinically effective neuromuscular block may be expected to last for 15 to 20 minutes (range: 9 to 38 minutes) and spontaneous recovery may be expected to be 95% complete in 25 to 30 minutes (range: 16 to 41 minutes) following 0.15 mg/kg MIVACRON administered to patients receiving opioid/nitrous oxide/oxygen anesthesia. The expected duration of clinically effective block and time to 95% spontaneous recovery following 0.2 mg/kg MIVACRON are approximately 20 and 30 minutes, respectively, and following 0.25 mg/kg MIVACRON are approximately 25 and 35 minutes. Initiation of maintenance dosing during opioid/nitrous oxide/oxygen anesthesia is generally required approximately 15, 20 and 25 minutes following initial doses of 0.15 mg/kg, 0.2 mg/kg, and 0.25 mg/kg MIVACRON, respectively (see Table 1). Maintenance doses of 0.1 mg/kg each provide approximately 15 minutes of additional clinically effective block. For shorter or longer durations of action, smaller or larger maintenance doses may be administered.

The neuromuscular blocking action of MIVACRON is potentiated by isoflurane or enflurane anesthesia. Recommended initial doses of MIVACRON may be used to facilitate tracheal intubation prior to the administration of these agents; however, if MIVACRON is first administered after establishment of stable-state isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC), the initial dose of MIVACRON may be reduced by as much as 25%. Greater reductions in the dose of MIVACRON may be required with higher concentrations of enflurane or isoflurane. With halothane, which has only a minimal potentiating effect on MIVACRON, a smaller dosage reduction may be considered.

Continuous Infusion

Continuous infusion of MIVACRON may be used to maintain neuromuscular block. Upon early evidence of spontaneous recovery from an initial dose, an initial infusion rate of 9 to 10 mcg/kg/min is recommended. If continuous infusion is initiated simultaneously with the administration of an initial dose, a lower initial infusion rate should be used (e.g., 4 mcg/kg/min). In either case, the initial infusion rate should be adjusted according to the response to peripheral nerve stimulation and to clinical criteria. On average, an infusion rate of 5 to 7 mcg/kg/min (range: 1 to 15 mcg/kg/min) may be expected to maintain neuromuscular block within the range of 89% to 99% for extended periods in adults receiving opioid/nitrous oxide/oxygen anesthesia. In some patients, particularly those with higher infusion requirements (greater than 8 mcg/kg/min) during the first 30 minutes, the infusion rate required to maintain 89% to 99% T1 suppression may decrease gradually (by greater than or equal to 30%) with time over a 4- to 6-hour period of infusion (see CLINICAL PHARMACOLOGY - Pharmacodynamics). Reduction of the infusion rate by up to 35% to 40% should be considered when MIVACRON is administered during stable-state conditions of isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC). Greater reductions in the infusion rate of MIVACRON may be required with greater concentrations of enflurane or isoflurane. With halothane, smaller reductions in infusion rate may be required.

Children

Initial Doses

Dosage requirements for MIVACRON on a mg/kg basis are higher in children than in adults. Onset and recovery of neuromuscular block occur more rapidly in children than in adults (see CLINICAL PHARMACOLOGY).

The recommended dose of MIVACRON for facilitating tracheal intubation in children 2 to 12 years of age is 0.2 mg/kg administered over 5 to 15 seconds. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.2 mg/kg of MIVACRON produces maximum neuromuscular block in an average of 1.9 minutes (range: 1.3 to 3.3 minutes) and clinically effective block for 10 minutes (range: 6 to 15 minutes). Maintenance doses are generally required more frequently in children than in adults. Administration of doses of MIVACRON above the recommended range (greater than 0.2 mg/kg) is associated with transient decreases in MAP in some children (see CLINICAL PHARMACOLOGY - Hemodynamics). MIVACRON has not been studied in pediatric patients below the age of 2 years.

Continuous Infusion

Children require higher infusion rates of MIVACRON than adults. During opioid/nitrous oxide/oxygen anesthesia, the infusion rate required to maintain 89% to 99% neuromuscular block averages 14 mcg/kg/min (range: 5 to 31 mcg/kg/min). The principles for infusion of MIVACRON in adults are also applicable to children (see above).

Infusion Rate Tables

For adults and children the amount of infusion solution required per hour depends upon the clinical requirements of the patient, the concentration of MIVACRON in the infusion solution, and the patient's weight. The contribution of the infusion solution to the fluid requirements of the patient must be considered. Table 8 provides guidelines for delivery in mL/hr (equivalent to microdrops/min when 60 microdrops = 1 mL) of MIVACRON Injection (2 mg/mL).
Table 8. Infusion Rates for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia Using MIVACRON Injection (2 mg/mL) Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 10 14 16 18 20 Patient Weight (kg) Infusion Delivery Rate (mL/hr) 10 1.2 1.5 1.8 2.1 2.4 3 4.2 4.8 5.4 6 15 1.8 2.3 2.7 3.2 3.6 4.5 6.3 7.2 8.1 9 20 2.4 3 3.6 4.2 4.8 6 8.4 9.6 10.8 12 25 3 3.8 4.5 5.3 6 7.5 10.5 12 13.5 15 35 4.2 5.3 6.3 7.4 8.4 10.5 14.7 16.8 18.9 21 50 6 7.5 9 10.5 12 15 21 24 27 30 60 7.2 9 10.8 12.6 14.4 18 25.2 28.8 32.4 36 70 8.4 10.5 12.6 14.7 16.8 21 29.4 33.6 37.8 42 80 9.6 12 14.4 16.8 19.2 24 33.6 38.4 43.2 48 90 10.8 13.5 16.2 18.9 21.6 27 37.8 43.2 48.6 54 100 12 15 18 21 24 30 42 48 54 60
MIVACRON Injection Compatibility and Admixtures

Y-site Administration

MIVACRON Injection may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions).

Studies have shown that MIVACRON Injection is compatible with:
5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP Lactated Ringer's Injection, USP 5% Dextrose in Lactated Ringer's Injection Sufenta® (sufentanil citrate) Injection, diluted as directed Alfenta® (alfentanil hydrochloride) Injection, diluted as directed Sublimaze® (fentanyl citrate) Injection, diluted as directed Versed® (midazolam hydrochloride) Injection, diluted as directed Inapsine® (droperidol) Injection, diluted as directed
Compatibility studies with other parenteral products have not been conducted.

Dilution Stability

MIVACRON Injection diluted to 0.5 mg mivacurium per mL in 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, 0.9% Sodium Chloride Injection, USP, Lactated Ringer's Injection, USP, or 5% Dextrose in Lactated Ringer's Injection is physically and chemically stable when stored in PVC (polyvinylchloride) bags at 5° to 25°C (41° to 77°F) for up to 24 hours. Aseptic techniques should be used to prepare the diluted product. Admixtures of MIVACRON should be prepared for single patient use only and used within 24 hours of preparation. The unused portion of diluted MIVACRON should be discarded after each case.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear and colorless should not be used.
Vytorin

Vytorin

2.1 Testing Prior to Initiation of VIEKIRA PAK

Prior to initiation of VIEKIRA PAK, assess for laboratory and clinical evidence of hepatic decompensation [see Warnings and Precautions (5.1 and 5.2)].

2.2 Recommended Dosage in Adults

VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.

The recommended oral dosage of VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening). Take VIEKIRA PAK with a meal without regard to fat or calorie content [see Clinical Pharmacology (12.3)].

VIEKIRA PAK is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg/day for subjects <75 kg and 1200 mg/day for those ≥75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.

Table 1 shows the recommended VIEKIRA PAK treatment regimen and duration based on patient population.
Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced) Patient Population Treatment* Duration Genotype 1a, without cirrhosis VIEKIRA PAK + ribavirin 12 weeks Genotype 1a, with cirrhosis VIEKIRA PAK + ribavirin 24 weeks** Genotype 1b, without cirrhosis VIEKIRA PAK 12 weeks Genotype 1b, with cirrhosis VIEKIRA PAK + ribavirin 12 weeks *Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.**VIEKIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [see Clinical Studies (14.3)].
2.3 Use in Liver Transplant Recipients

In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA PAK with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype [see Clinical Studies (14.6)]. When VIEKIRA PAK is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed [see Drug Interactions (7)].

2.4 Hepatic Impairment

VIEKIRA PAK is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C)[see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Ultane

Ultane

The concentration of sevoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient's response.

Replacement of Desiccated CO2 Absorbents

When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters (see PRECAUTIONS).

Pre-anesthetic Medication

No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.

Induction

Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults.

Maintenance

Surgical levels of anesthesia can usually be achieved with concentrations of 0.5 - 3% sevoflurane with or without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anesthesia circuit.
Table 9. MAC Values for Adults and Pediatric Patients According to Age Age of Patient (years) Sevoflurane in Oxygen Sevoflurane in 65% N2O/35% O2 0 - 1 months # 3.3% 1 - < 6 months 3.0% 6 months - < 3 years 2.8% 2.0%@ 3 - 12 2.5% 25 2.6% 1.4% 40 2.1% 1.1% 60 1.7% 0.9% 80 1.4% 0.7% # Neonates are full-term gestational age. MAC in premature infants has not been determined.@ In 1 - < 3 year old pediatric patients, 60% N2O/40% O2 was used.
Ultane

Ultane

The concentration of sevoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient's response.

Replacement of Desiccated CO2 Absorbents

When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters (see PRECAUTIONS).

Pre-anesthetic Medication

No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.

Induction

Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults.

Maintenance

Surgical levels of anesthesia can usually be achieved with concentrations of 0.5 - 3% sevoflurane with or without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anesthesia circuit.
Table 9. MAC Values for Adults and Pediatric Patients According to Age Age of Patient (years) Sevoflurane in Oxygen Sevoflurane in 65% N2O/35% O2 0 - 1 months # 3.3% 1 - < 6 months 3.0% 6 months - < 3 years 2.8% 2.0%@ 3 - 12 2.5% 25 2.6% 1.4% 40 2.1% 1.1% 60 1.7% 0.9% 80 1.4% 0.7% # Neonates are full-term gestational age. MAC in premature infants has not been determined.@ In 1 - < 3 year old pediatric patients, 60% N2O/40% O2 was used.
Trilipix

Trilipix

2.1 General Considerations

Patients should be placed on an appropriate lipid-lowering diet before receiving Trilipix and should continue this diet during treatment. Trilipix delayed release capsules can be taken without regard to meals. Patients should be advised to swallow Trilipix capsules whole. Do not open, crush, dissolve, or chew capsules. Serum lipids should be monitored periodically.

2.2 Severe Hypertriglyceridemia

The initial dose of Trilipix is 45 to 135 mg once daily. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 135 mg once daily.

2.3 Primary Hypercholesterolemia or Mixed Dyslipidemia

The dose of Trilipix is 135 mg once daily.

2.4 Impaired Renal Function

Treatment with Trilipix should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment and should only be increased after evaluation of the effects on renal function and lipid levels at this dose. The use of Trilipix should be avoided in patients with severely impaired renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Geriatric Patients

Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5)].

2.1 General Considerations

Patients should be placed on an appropriate lipid-lowering diet before receiving Trilipix and should continue this diet during treatment. Trilipix delayed release capsules can be taken without regard to meals. Patients should be advised to swallow Trilipix capsules whole. Do not open, crush, dissolve, or chew capsules. Serum lipids should be monitored periodically.

2.2 Severe Hypertriglyceridemia

The initial dose of Trilipix is 45 to 135 mg once daily. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 135 mg once daily.

2.3 Primary Hypercholesterolemia or Mixed Dyslipidemia

The dose of Trilipix is 135 mg once daily.

2.4 Impaired Renal Function

Treatment with Trilipix should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment and should only be increased after evaluation of the effects on renal function and lipid levels at this dose. The use of Trilipix should be avoided in patients with severely impaired renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Geriatric Patients

Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5)].
Tridione

Tridione

TRIDIONE is administered orally.

Usual Adult Dosage

0.9-2.4 grams daily in 3 or 4 equally divided doses (i.e., 300−600 mg 3 or 4 times daily).

Initially, give 0.9 gram daily; increase this dose by 300 mg at weekly intervals until therapeutic results are seen or until toxic symptoms appear.

Maintenance dosage should be the least amount of drug required to maintain control.

Children's Dosage

Usually 0.3-0.9 gram daily in 3 or 4 equally divided doses.
Calcijex

Calcijex

Calcijex is for intravenous injection only.

The optimal dose of Calcijex (calcitriol injection) must be carefully determined for each patient.

The effectiveness of Calcijex therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The RDA for calcium in adults is 800 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

The recommended initial dose of Calcijex, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered intravenously three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcijex dose should be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels. The following is a suggested approach in dose titration:
PTH Levels Calcijex Dose the same or increasing increase decreasing by < 30% increase decreasing by > 30%, < 60% maintain decreasing by > 60% decrease one and one-half to three times the upper limit of normal maintain
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard unused portion.
Moderiba

Moderiba

Moderiba (ribavirin, USP) should be taken with food. Moderiba should be given in combination with peginterferon alfa-2a; it is important to note that Moderiba should never be given as monotherapy. See Peginterferon alfa-2a Package Insert for all instructions regarding peginterferon alfa-2a dosing and administration.

2.1 Chronic Hepatitis C Monoinfection

Adult Patients

The recommended dose of Moderiba tablets is provided in Table 1. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.

The daily dose of Moderiba is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 1).
Table 1 Peginterferon alfa-2a and Moderiba Dosing Recommendations Hepatitis C Virus (HCV) Genotype Peginterferon alfa-2a Dose* (once weekly) Moderiba Dose(daily) Duration Genotypes 1, 4 180 mcg <75 kg = 1000 mg≥75 kg = 1200 mg 48 weeks48 weeks Genotypes 2, 3 180 mcg 800 mg 24 weeks Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10).Data on genotypes 5 and 6 are insufficient for dosing recommendations.*See Peginterferon alfa-2a Package Insert for further details on peginterferon alfa-2a dosing and administration, including dose modification in patients with renal impairment.
Pediatric Patients

Peginterferon alfa-2a is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

Moderiba should be given in combination with peginterferon alfa-2a. Moderiba is available as a 200 mg, 400 mg and 600 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for Moderiba are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.
Table 2 Moderiba Dosing Recommendations for Pediatric Patients Body Weight in kilograms (kg) Moderiba Daily Dose* Moderiba Number of Tablets 23 – 33 400 mg/day 1 x 200 mg tablet A.M.1 x 200 mg tablet P.M. 34 – 46 600 mg/day 1 x 200 mg tablet A.M.2 x 200 mg tablets P.M.** 47 – 59 800 mg/day 2 x 200 mg tablets A.M.**2 x 200 mg tablets P.M.** 60 – 74 1000 mg/day 2 x 200 mg tablets A.M.**3 x 200 mg tablets P.M.*** ≥75 1200 mg/day 3 x 200 mg tablets A.M.***3 x 200 mg tablets P.M.*** *approximately 15 mg/kg/day**or 1 x 400 mg tablet***or 1 x 600 mg tablet
2.2 Chronic Hepatitis C with HIV Coinfection

Adult Patients

The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is peginterferon alfa-2a 180 mcg subcutaneous once weekly and Moderiba 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

2.3 Dose Modifications

Adult and Pediatric Patients

If severe adverse reactions or laboratory abnormalities develop during combination Moderiba/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, Moderiba/peginterferon alfa-2a therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status.

Moderiba should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2)].
Table 3 Moderiba Dose Modification Guidelines in Adults and Pediatrics Body weight in kilograms (kg) Laboratory Values Hemoglobin <10 g/dL in patients with no cardiac disease, orDecrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease Hemoglobin <8.5 g/dL in patients with no cardiac disease, orHemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease Adult Patients older than 18 years of age Any weight 1 x 200 mg tablet A.M. 2 x 200 mg tablets or 1 x 400 mg tablet P.M. Discontinue Moderiba Pediatric Patients 5 to 18 years of age 23 – 33 kg 1 x 200 mg tablet A.M. Discontinue Moderiba 34 – 46 kg 1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M. 47 – 59 kg 1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M. 60 – 74 kg 1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M. or 1 x 400 mg tablet P.M. ≥75 kg 1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M. or1 x 400 mg tablet P.M.
The guidelines for Moderiba dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once Moderiba has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Moderiba at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that Moderiba be increased to the original assigned dose (1000 mg to 1200 mg).

Pediatric Patients

Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in Moderiba dose to the original dose may be attempted depending upon the physician’s judgment. If Moderiba has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Moderiba at one-half the full dose.

2.4 Renal Impairment

The total daily dose of Moderiba should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of peginterferon alfa-2a should be reduced for creatinine clearance less than 30 mL/min as follows in Table 4[see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and Peginterferon alfa-2a Package Insert].
Table 4 Dosage Modification for Renal Impairment Creatinine Clearance Peginterferon alfa-2a Dose (once weekly) Moderiba Dose(daily) 30 to 50 mL/min 180 mcg Alternating doses, 200 mg and 400 mg every other day Less than 30 mL/min 135 mcg 200 mg daily Hemodialysis 135 mcg 200 mg daily
The dose of Moderiba should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, Moderiba should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Moderiba, Moderiba/peginterferon alfa-2a therapy should be discontinued.

No data are available for pediatric subjects with renal impairment.

2.5 Discontinuation of Dosing

Discontinuation of peginterferon alfa-2a/Moderiba therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

Peginterferon alfa-2a/Moderiba therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].
Androgel

Androgel

Dosage and Administration for AndroGel 1.62% differs from AndroGel 1%. For dosage and administration of AndroGel 1% refer to its full prescribing information. (2)
Prior to initiating AndroGel 1.62%, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.
2.1 Dosing and Dose Adjustment

The recommended starting dose of AndroGel 1.62% is 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet) applied topically once daily in the morning to the shoulders and upper arms.

The dose can be adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20.25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets). To ensure proper dosing, the dose should be titrated based on the pre-dose morning serum testosterone concentration from a single blood draw at approximately 14 days and 28 days after starting treatment or following dose adjustment. In addition, serum testosterone concentration should be assessed periodically thereafter. Table 1 describes the dose adjustments required at each titration step.
Table 1: Dose Adjustment Criteria Pre-Dose Morning Total Serum Testosterone Concentration Dose Titration Greater than 750 ng/dL Decrease daily dose by 20.25 mg (1 pump actuation or the equivalent of one 20.25 mg packet) Equal to or greater than 350 and equal to or less than 750 ng/dL No change: continue on current dose Less than 350 ng/dL Increase daily dose by 20.25 mg (1 pump actuation or the equivalent of one 20.25 mg packet)
The application site and dose of AndroGel 1.62% are not interchangeable with other topical testosterone products.

2.2 Administration Instructions

AndroGel 1.62% should be applied to clean, dry, intact skin of the upper arms and shoulders. Do not apply AndroGel 1.62% to any other parts of the body, including the abdomen, genitals, chest, armpits (axillae), or knees [see Clinical Pharmacology (12.3)]. Area of application should be limited to the area that will be covered by the patient's short sleeve t-shirt. Patients should be instructed to use the palm of the hand to apply AndroGel 1.62% and spread across the maximum surface area as directed in Table 2 (for pump) and Table 3 (for packets) and in Figure 1.
Table 2: Application Sites for AndroGel 1.62%, Pump Total Dose of Testosterone Total Pump Actuations Pump Actuations Per Upper Arm and Shoulder Upper Arm and Shoulder #1 Upper Arm and Shoulder #2 20.25 mg 1 1 0 40.5 mg 2 1 1 60.75 mg 3 2 1 81 mg 4 2 2
Table 3: Application Sites for AndroGel 1.62%, Packets
Total Dose of Testosterone Total packets Gel Applications Per Upper Arm and Shoulder Upper Arm and Shoulder #1 Upper Arm and Shoulder #2 20.25 mg One 20.25 mg packet One 20.25 mg packet 0 40.5 mg One 40.5 mg packet Half of contents of One 40.5 mg packet Half of contents of One 40.5 mg packet 60.75 mg One 20.25 mg packet AND One 40.5 mg packet One 40.5 mg packet One 20.25 mg packet 81 mg Two 40.5 mg packets One 40.5 mg packet One 40.5 mg packet
The prescribed daily dose of AndroGel 1.62% should be applied to the right and left upper arms and shoulders as shown in the shaded areas in Figure 1.

Figure 1. Application Sites for AndroGel 1.62%

Once the application site is dry, the site should be covered with clothing [see Clinical Pharmacology (12.3)]. Wash hands thoroughly with soap and water. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel 1.62%, are flammable.

The patient should avoid swimming or showering or washing the administration site for a minimum of 2 hours after application [see Clinical Pharmacology (12.3)].

To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose.

After the priming procedure, fully depress the actuator once for every 20.25 mg of AndroGel 1.62%. AndroGel 1.62% should be delivered directly into the palm of the hand and then applied to the application sites.

When using packets, the entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. When 40.5 mg packets need to be split between the left and right shoulder, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied. Alternatively, AndroGel 1.62% can be applied directly to the application sites from the pump or packets.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AndroGel 1.62%-treated skin:
Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%. AndroGel 1.62% should only be applied to the upper arms and shoulders. The area of application should be limited to the area that will be covered by a short sleeve t-shirt. Patients should wash their hands with soap and water immediately after applying AndroGel 1.62%. Patients should cover the application site(s) with clothing (e.g., a t-shirt) after the gel has dried. Prior to situations in which direct skin-to-skin contact is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible.
2.1 Dosing and Dose Adjustment

The recommended starting dose of AndroGel 1.62% is 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet) applied topically once daily in the morning to the shoulders and upper arms.

The dose can be adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20.25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets). To ensure proper dosing, the dose should be titrated based on the pre-dose morning serum testosterone concentration from a single blood draw at approximately 14 days and 28 days after starting treatment or following dose adjustment. In addition, serum testosterone concentration should be assessed periodically thereafter. Table 1 describes the dose adjustments required at each titration step.
Table 1: Dose Adjustment Criteria Pre-Dose Morning Total Serum Testosterone Concentration Dose Titration Greater than 750 ng/dL Decrease daily dose by 20.25 mg (1 pump actuation or the equivalent of one 20.25 mg packet) Equal to or greater than 350 and equal to or less than 750 ng/dL No change: continue on current dose Less than 350 ng/dL Increase daily dose by 20.25 mg (1 pump actuation or the equivalent of one 20.25 mg packet)
The application site and dose of AndroGel 1.62% are not interchangeable with other topical testosterone products.

2.2 Administration Instructions

AndroGel 1.62% should be applied to clean, dry, intact skin of the upper arms and shoulders. Do not apply AndroGel 1.62% to any other parts of the body, including the abdomen, genitals, chest, armpits (axillae), or knees [see Clinical Pharmacology (12.3)]. Area of application should be limited to the area that will be covered by the patient's short sleeve t-shirt. Patients should be instructed to use the palm of the hand to apply AndroGel 1.62% and spread across the maximum surface area as directed in Table 2 (for pump) and Table 3 (for packets) and in Figure 1.
Table 2: Application Sites for AndroGel 1.62%, Pump Total Dose of Testosterone Total Pump Actuations Pump Actuations Per Upper Arm and Shoulder Upper Arm and Shoulder #1 Upper Arm and Shoulder #2 20.25 mg 1 1 0 40.5 mg 2 1 1 60.75 mg 3 2 1 81 mg 4 2 2
Table 3: Application Sites for AndroGel 1.62%, Packets
Total Dose of Testosterone Total packets Gel Applications Per Upper Arm and Shoulder Upper Arm and Shoulder #1 Upper Arm and Shoulder #2 20.25 mg One 20.25 mg packet One 20.25 mg packet 0 40.5 mg One 40.5 mg packet Half of contents of One 40.5 mg packet Half of contents of One 40.5 mg packet 60.75 mg One 20.25 mg packet AND One 40.5 mg packet One 40.5 mg packet One 20.25 mg packet 81 mg Two 40.5 mg packets One 40.5 mg packet One 40.5 mg packet
The prescribed daily dose of AndroGel 1.62% should be applied to the right and left upper arms and shoulders as shown in the shaded areas in Figure 1.

Figure 1. Application Sites for AndroGel 1.62%

Once the application site is dry, the site should be covered with clothing [see Clinical Pharmacology (12.3)]. Wash hands thoroughly with soap and water. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel 1.62%, are flammable.

The patient should avoid swimming or showering or washing the administration site for a minimum of 2 hours after application [see Clinical Pharmacology (12.3)].

To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose.

After the priming procedure, fully depress the actuator once for every 20.25 mg of AndroGel 1.62%. AndroGel 1.62% should be delivered directly into the palm of the hand and then applied to the application sites.

When using packets, the entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. When 40.5 mg packets need to be split between the left and right shoulder, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied. Alternatively, AndroGel 1.62% can be applied directly to the application sites from the pump or packets.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AndroGel 1.62%-treated skin:
Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%. AndroGel 1.62% should only be applied to the upper arms and shoulders. The area of application should be limited to the area that will be covered by a short sleeve t-shirt. Patients should wash their hands with soap and water immediately after applying AndroGel 1.62%. Patients should cover the application site(s) with clothing (e.g., a t-shirt) after the gel has dried. Prior to situations in which direct skin-to-skin contact is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible.
K-tab

K-tab

The usual dietary potassium intake by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

K-TAB tablets provide 8 mEq, 10 mEq and 20 mEq of potassium chloride.

K-TAB tablets should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS).

NOTE: K-TAB tablets are to be swallowed whole without crushing, chewing or sucking the tablets.
Vyvanse

Vyvanse

2.1 General Administration Recommendations

KALETRA tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed. KALETRA oral solution must be taken with food.

2.2 Dosage Recommendations in Adults

Considerations in Determining KALETRA Once Daily vs. Twice Daily Dosing Regimen:
KALETRA can be given as once daily or twice daily dosing regimen in patients with less than three lopinavir resistance-associated substitutions. KALETRA must be given as twice daily dosing regimen in patients with three or more resistance-associated substitutions. Table 1 includes the recommended once daily dosing regimen and Tables 2 and 3 include the recommended twice daily dosing regimen.
KALETRA once daily dosing regimen is not recommended in:
Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V [see Microbiology (12.4)]. In combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions (7.3)]. In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)]. In pregnant women [see Dosage and Administration (2.4), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
The dose of KALETRA must be increased when administered in combination with efavirenz, nevirapine or nelfinavir.

Table 3 outlines the dosage recommendations for twice daily dosing when KALETRA is taken in combination with efavirenz, nevirapine or nelfinavir.
Table 1. Recommended Dosage in Adults- KALETRA Once Daily Regimen KALETRA Dosage Form Recommended Dosage Total KALETRA Dosage per Day 200/50 mg Tablet 4 tablets orally once daily 800/200 mg 400/100 mg Oral Solution 10 mL orally once daily 800/200 mg Table 2. Recommended Dosage in Adults - KALETRA Twice Daily Regimen KALETRA Dosage Form Recommended Dosage Total KALETRA Dosage per Day 200/50 mg Tablet 2 tablets orally twice daily 800/200 mg 400/100 mg Oral Solution 5 mL orally twice daily 800/200 mg Table 3. Recommended Dosage in Adults - KALETRA Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir KALETRA Dosage Form Recommended Dosage Total KALETRA Dosage per Day 200/50 mg Tablet and 100/25 mg Tablet 2 KALETRA 200/50 mg tablets and 1 KALETRA 100/25 mg tablet orally twice daily 1000/250 mg 400/100 mg Oral Solution 6.5 mL orally twice daily 1000/250 mg
2.3 Dosage Recommendations in Pediatric Patients

KALETRA tablets and oral solution should not be administered once daily in pediatric patients < 18 years of age. The dose of the oral solution should be administered using a calibrated dosing syringe.

Before prescribing KALETRA 100/25 mg tablets, children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a KALETRA tablet, the KALETRA oral solution formulation should be prescribed.

KALETRA oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained [see Warnings and Precautions (5.2)].

KALETRA oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol. Special attention should be given to accurate calculation of the dosage of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for infants and young children. Total amounts of alcohol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)].

Pediatric Dosage Calculations

Calculate the appropriate dose of KALETRA for each individual pediatric patient based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.

Body surface area (BSA) can be calculated as follows:

The KALETRA dose can be calculated based on weight or BSA:

Based on Weight:

Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg)

Based on BSA:

Patient BSA (m2) × Prescribed lopinavir dose (mg/m2) = Administered lopinavir dose (mg)

If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:

Volume of KALETRA solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)

Dosage Recommendation in Pediatric Patients 14 Days to 6 Months:

In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution is 16/4 mg/kg or 300/75 mg/m2 twice daily. Prescribers should calculate the appropriate dose based on body weight or body surface area. Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to 6 months.

It is recommended that KALETRA not be administered in combination with efavirenz, nevirapine, or nelfinavir in patients < 6 months of age.
Table 4. Recommended KALETRA Oral Daily Dosage in Pediatric Patients 14 days to 6 months Patient Age Based on Weight (mg/kg) Based on BSA (mg/m2) Frequency 14 days to 6 months 16/4 300/75 Given twice daily
Dosage Recommendation in Pediatric Patients 6 Months to 18 Years:

Without Concomitant Efavirenz, Nevirapine, or Nelfinavir

Dosing recommendations using oral solution

In children 6 months to 18 years of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution without concomitant efavirenz, nevirapine, or nelfinavir is 230/57.5 mg/m2 given twice daily, not to exceed the recommended adult dose (400/100 mg [5 mL] twice daily). If weight-based dosing is preferred, the recommended dosage of lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for patients ≥ 15 kg to 40 kg is 10/2.5 mg/kg given twice daily. Table 5 summarizes the recommended daily dosing regimen for pediatric patients 6 months to 18 years.
Table 5. Recommended KALETRA Oral Daily Dosage in Pediatric Patients 6 months to 18 years Patient Age Based on Weight (mg/kg) Based on BSA (mg/m2) Frequency 6 months to 18 years <15 kg 12/3 230/57.5 Given twice daily ≥15 kg to 40 kg 10/2.5
Dosing recommendations using tablets

Table 6 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets.
Table 6. Pediatric Dosing Recommendations for Patients 6 Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets Without Concomitant Efavirenz, Nevirapine, or Nelfinavir Body Weight (kg) Body Surface Area (m2)* Recommended number of 100/25 mg Tablets Twice Daily 15 to 25 ≥0.6 to < 0.9 2 >25 to 35 ≥0.9 to < 1.4 3 >35 ≥1.4 4 (or two 200/50 mg tablets) * KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet.
Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir

Dosing recommendations using oral solution

A dose increase of KALETRA to 300/75 mg/m2 using KALETRA oral solution is needed when co-administered with efavirenz, nevirapine, or nelfinavir in children (both treatment-naïve and treatment-experienced) 6 months to 18 years of age, not to exceed the recommended adult dose (533/133 mg [6.5 mL] twice daily). If weight-based dosing is preferred, the recommended dosage for patients <15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients >15 kg to 45 kg is 11/2.75 mg/kg given twice daily.

Dosing recommendations using tablets

Table 7 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir.
Table 7. Pediatric Dosing Recommendations for Patients 6 Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets With Concomitant Efavirenz†, Nevirapine, or Nelfinavir† Body Weight (kg) Body Surface Area (m2)* Recommended number of 100/25 mg Tablets Twice Daily 15 to 20 ≥0.6 to < 0.8 2 >20 to 30 ≥0.8 to < 1.2 3 >30 to 45 ≥1.2 to <1.7 4 (or two 200/50 mg tablets) >45 ≥1.7 5 [see Dosage and Administration (2.2)] * KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet.† Please refer to the individual product labels for appropriate dosing in children.
2.4 Dosage Recommendations in Pregnancy

Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. Once daily KALETRA dosing is not recommended in pregnancy [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions. No dosage adjustment of KALETRA is required for patients during the postpartum period. Avoid use of KALETRA oral solution in pregnant women [see Use in Specific Populations (8.1)].
2.1 General Administration Recommendations

KALETRA tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed. KALETRA oral solution must be taken with food.

2.2 Dosage Recommendations in Adults

Considerations in Determining KALETRA Once Daily vs. Twice Daily Dosing Regimen:
KALETRA can be given as once daily or twice daily dosing regimen in patients with less than three lopinavir resistance-associated substitutions. KALETRA must be given as twice daily dosing regimen in patients with three or more resistance-associated substitutions. Table 1 includes the recommended once daily dosing regimen and Tables 2 and 3 include the recommended twice daily dosing regimen.
KALETRA once daily dosing regimen is not recommended in:
Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V [see Microbiology (12.4)]. In combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions (7.3)]. In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)]. In pregnant women [see Dosage and Administration (2.4), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
The dose of KALETRA must be increased when administered in combination with efavirenz, nevirapine or nelfinavir.

Table 3 outlines the dosage recommendations for twice daily dosing when KALETRA is taken in combination with efavirenz, nevirapine or nelfinavir.
Table 1. Recommended Dosage in Adults- KALETRA Once Daily Regimen KALETRA Dosage Form Recommended Dosage Total KALETRA Dosage per Day 200/50 mg Tablet 4 tablets orally once daily 800/200 mg 400/100 mg Oral Solution 10 mL orally once daily 800/200 mg Table 2. Recommended Dosage in Adults - KALETRA Twice Daily Regimen KALETRA Dosage Form Recommended Dosage Total KALETRA Dosage per Day 200/50 mg Tablet 2 tablets orally twice daily 800/200 mg 400/100 mg Oral Solution 5 mL orally twice daily 800/200 mg Table 3. Recommended Dosage in Adults - KALETRA Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir KALETRA Dosage Form Recommended Dosage Total KALETRA Dosage per Day 200/50 mg Tablet and 100/25 mg Tablet 2 KALETRA 200/50 mg tablets and 1 KALETRA 100/25 mg tablet orally twice daily 1000/250 mg 400/100 mg Oral Solution 6.5 mL orally twice daily 1000/250 mg
2.4 Dosage Recommendations in Pregnancy

Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. Once daily KALETRA dosing is not recommended in pregnancy [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions. No dosage adjustment of KALETRA is required for patients during the postpartum period. Avoid use of KALETRA oral solution in pregnant women [see Use in Specific Populations (8.1)].
Teveten

Teveten

The usual recommended starting dose of TEVETEN® is 600 mg once daily when used as monotherapy in patients who are not volume-depleted (see WARNINGS, Hypotension in Volume- and/or Salt-Depleted Patients). TEVETEN® can be administered once or twice daily with total daily doses ranging from 400 mg to 800 mg. There is limited experience with doses beyond 800 mg/day.

If the antihypertensive effect measured at trough using once-daily dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks.

TEVETEN® may be used in combination with other antihypertensive agents such as thiazide diuretics or calcium channel blockers if additional blood-pressure-lowering effect is required. Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.

Elderly, Hepatically Impaired or Renally Impaired Patients

No initial dosing adjustment is generally necessary for elderly or hepatically impaired patients or those with renal impairment. No initial dosing adjustment is generally necessary in patients with moderate and severe renal impairment, with maximum dose not exceeding 600 mg daily.

TEVETEN® may be taken with or without food.
Teveten Hct

Teveten Hct

The usual recommended starting dose of eprosartan is 600 mg once daily when used as monotherapy in patients who are not volume-depleted (see WARNINGS, Hypotension in Volume- and/or Salt-Depleted Patients). Eprosartan can be administered once or twice daily and total daily doses ranging from 400 mg to 800 mg. There is limited experience with doses beyond 800 mg/day. If the antihypertensive effect measured at trough using once-daily monotherapy dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks. Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. The side effects (see WARNINGS) of eprosartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent (e.g., pancreatitis) phenomena, the former much more common than the latter. Therapy with any combination of eprosartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

Replacement Therapy

TEVETEN® HCT may be substituted for the individual components. The usual recommended dose of TEVETEN® HCT is 600 mg/12.5 mg once daily when used as combination therapy in patients who are not volume-depleted (see WARNINGS, Hypotension in Volume-and/or Salt-Depleted Patients). If the antihypertensive effect measured at trough using TEVETEN® HCT 600/12.5 mg is inadequate, patients may be titrated to TEVETEN® HCT 600/25 mg once daily. Higher doses have not been studied in combination. Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks. If the patient under treatment with TEVETEN® HCT requires additional blood pressure control at trough, or to maintain a twice a day dosing schedule of monotherapy, 300 mg TEVETEN® may be added as evening dose. TEVETEN® HCT may be used in combination with other antihypertensive agents such as calcium channel blockers if additional blood-pressure-lowering effect is required. Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.

Elderly, Hepatically Impaired or Renally Impaired Patients: No initial dosing adjustment is generally necessary for elderly or hepatically impaired patients or those with renal impairment. No initial dosing adjustment is generally necessary in patients with moderate and severe renal impairment with maximum dose not exceeding 600 mg daily. TEVETEN® HCT may be taken with or without food.
Lupron Depot

Lupron Depot

LUPRON DEPOT must be administered under the supervision of a physician.
Table 1. LUPRON DEPOT Recommended Dosing Dosage 7.5 mg for 1-Month Administration 22.5 mg for 3-Month Administration 30 mg for 4-Month Administration 45 mg for 6-Month Administration Recommended dose 1 injection every 4 weeks 1 injection every 12 weeks 1 injection every 16 weeks 1 injection every 24 weeks
2.1 LUPRON DEPOT 7.5 mg for 1-Month Administration

The recommended dose of LUPRON DEPOT 7.5 mg for 1-month administration is one injection every 4 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 4 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.2 LUPRON DEPOT 22.5 mg for 3-Month Administration

The recommended dose of LUPRON DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 12 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.3 LUPRON DEPOT 30 mg for 4-Month Administration

The recommended dose of LUPRON DEPOT 30 mg for 4-month administration is one injection every 16 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 16 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.4 LUPRON DEPOT 45 mg for 6-Month Administration

The recommended dose of LUPRON DEPOT 45 mg for 6-month administration is one injection every 24 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 24 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.5 Reconstitution and Administration for Injection of LUPRON DEPOT
Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because LUPRON DEPOT does not contain a preservative. Visually inspect the LUPRON DEPOT powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear and colorless. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).
Figure 1

Figure 2
Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
Figure 3
Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4
Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see Figure 5).
Figure 5

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc® safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 6
Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7

10. Dispose of the syringe according to local regulations/procedures.

2.1 LUPRON DEPOT 7.5 mg for 1-Month Administration

The recommended dose of LUPRON DEPOT 7.5 mg for 1-month administration is one injection every 4 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 4 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.2 LUPRON DEPOT 22.5 mg for 3-Month Administration

The recommended dose of LUPRON DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 12 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.3 LUPRON DEPOT 30 mg for 4-Month Administration

The recommended dose of LUPRON DEPOT 30 mg for 4-month administration is one injection every 16 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 16 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.4 LUPRON DEPOT 45 mg for 6-Month Administration

The recommended dose of LUPRON DEPOT 45 mg for 6-month administration is one injection every 24 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and should be administered every 24 weeks as a single intramuscular injection.

For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.5.

2.5 Reconstitution and Administration for Injection of LUPRON DEPOT
Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. Inject the suspension immediately or discard if not used within two hours, because LUPRON DEPOT does not contain a preservative. Visually inspect the LUPRON DEPOT powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear and colorless. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).
Figure 1

Figure 2
Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).
Figure 3
Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).
Figure 4
Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see Figure 5).
Figure 5

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc® safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 6
Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).
Figure 7

10. Dispose of the syringe according to local regulations/procedures.
Niaspan

Niaspan

NIASPAN should be taken at bedtime, after a low-fat snack, and doses should be individualized according to patient response. Therapy with NIASPAN must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy. The recommended dose escalation is shown in Table 1 below.
Table 1. Recommended Dosing Week(s) Daily dose NIASPAN Dosage INITIALTITRATION 1 to 4 500 mg 1 NIASPAN 500 mg tablet at bedtime SCHEDULE 5 to 8 1000 mg 1 NIASPAN 1000 mg tablet or 2 NIASPAN 500 mg tablets at bedtime * 1500 mg 2 NIASPAN 750 mg tablets or 3 NIASPAN 500 mg tablets at bedtime * 2000 mg 2 NIASPAN 1000 mg tablets or 4 NIASPAN 500 mg tablets at bedtime * After Week 8, titrate to patient response and tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 mg daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended. Women may respond at lower doses than men.
Maintenance Dose

The daily dosage of NIASPAN should not be increased by more than 500 mg in any 4-week period. The recommended maintenance dose is 1000 mg (two 500 mg tablets or one 1000 mg tablet) to 2000 mg (two 1000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2000 mg daily are not recommended. Women may respond at lower NIASPAN doses than men [see Clinical Studies (14.2)].

Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable.

Flushing of the skin [see Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to NIASPAN dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of NIASPAN ingestion.

Equivalent doses of NIASPAN should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin [see Warnings and Precautions (5)]. Patients previously receiving other niacin products should be started with the recommended NIASPAN titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response.

If NIASPAN therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1).

NIASPAN tablets should be taken whole and should not be broken, crushed or chewed before swallowing.

Dosage in Patients with Renal or Hepatic Impairment

Use of NIASPAN in patients with renal or hepatic impairment has not been studied. NIASPAN is contraindicated in patients with significant or unexplained hepatic dysfunction. NIASPAN should be used with caution in patients with renal impairment [see Warnings and Precautions (5)].
Biaxin

Biaxin

BIAXIN Filmtab (clarithromycin tablets, USP) and BIAXIN Granules (clarithromycin for oral suspension, USP) may be given with or without food. BIAXIN XL Filmtab (clarithromycin extended-release tablets) should be taken with food. BIAXIN XL tablets should be swallowed whole and not chewed, broken or crushed.

Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. In patients with severe renal impairment (CLCR < 30 mL/min), the dose of clarithromycin should be reduced by 50%. However, when patients with moderate or severe renal impairment are taking clarithromycin concomitantly with atazanavir or ritonavir, the dose of clarithromycin should be reduced by 50% or 75% for patients with CLCR of 30 to 60 mL/min or < 30 mL/min, respectively.
ADULT DOSAGE GUIDELINES BIAXIN Tablets BIAXIN XL Tablets Infection Dosage(q12h) Duration(days) Dosage(q24h) Duration(days) Pharyngitis/Tonsillitis due to S. pyogenes 250 mg 10 - - Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14 H. influenzae M. catarrhalis S. pneumoniae Acute exacerbation of chronic bronchitis due to H. influenzae 500 mg 7-14 2 x 500 mg 7 H. parainfluenzae 500 mg 7 2 x 500 mg 7 M. catarrhalis 250 mg 7-14 2 x 500 mg 7 S. pneumoniae 250 mg 7-14 2 x 500 mg 7 Community-Acquired Pneumonia due to H. influenzae 250 mg 7 2 x 500 mg 7 H. parainfluenzae - - 2 x 500 mg 7 M. catarrhalis - - 2 x 500 mg 7 S. pneumoniae 250 mg 7-14 2 x 500 mg 7 C. pneumoniae 250 mg 7-14 2 x 500 mg 7 M. pneumoniae 250 mg 7-14 2 x 500 mg 7 Uncomplicated skin and skin structure 250 mg 7-14 - - S. aureus S. pyogenes
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple therapy: BIAXIN/lansoprazole/amoxicillin

The recommended adult dose is 500 mg BIAXIN, 30 mg lansoprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 or 14 days (see INDICATIONS AND USAGEandCLINICAL STUDIES sections).

Triple therapy: BIAXIN/omeprazole/amoxicillin

The recommended adult dose is 500 mg BIAXIN, 20 mg omeprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 days (see INDICATIONS AND USAGE and CLINICAL STUDIES sections). In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual therapy: BIAXIN/omeprazole

The recommended adult dose is 500 mg BIAXIN given three times daily (q8h) and 40 mg omeprazole given once daily (qAM) for 14 days (see INDICATIONS AND USAGE and CLINICAL STUDIES sections). An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual therapy: BIAXIN/ranitidine bismuth citrate

The recommended adult dose is 500 mg BIAXIN given twice daily (q12h) or three times daily (q8h) and 400 mg ranitidine bismuth citrate given twice daily (q12h) for 14 days. An additional 14 days of 400 mg twice daily is recommended for ulcer healing and symptom relief. BIAXIN and ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min (see INDICATIONS AND USAGE and CLINICAL STUDIES sections).

Children

The usual recommended daily dosage is 15 mg/kg/day divided q12h for 10 days.
PEDIATRIC DOSAGE GUIDELINES Based on Body Weight Dosing Calculated on 7.5 mg/kg q12h Weight Dose Kg lbs (q12h) 125 mg/5 mL 250 mg/5 mL 9172533 20375573 62.5 mg125 mg187.5 mg250 mg 2.5 mL q12h 5 mL q12h7.5 mL q12h 10 mL q12h 1.25 mL q12h2.5 mL q12h3.75 mL q12h5 mL q12h
Mycobacterial Infections

Prophylaxis

The recommended dose of BIAXIN for the prevention of disseminated Mycobacterium avium disease is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. No studies of clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC treatment studies in children. Dosing recommendations for children are in the table above.

Treatment

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to Mycobacterium avium complex. Clarithromycin should be used in combination with other antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (see CLINICAL STUDIES). The recommended dose for mycobacterial infections in adults is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. Dosing recommendations for children are in the table above.

Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be discontinued when the patient is considered at low risk of disseminated infection.

Constituting Instructions

The table below indicates the volume of water to be added when constituting:
Total Volume After Constitution Clarithromycin Concentration After Constitution Amount of Water to be Added* 50 mL 125 mg/5 mL 27 mL 100 mL 125 mg/5 mL 55 mL 50 mL 250 mg/5 mL 27 mL 100 mL 250 mg/5 mL 55 mL * see instructions below.
Add half the volume of water to the bottle and shake vigorously. Add the remainder of water to the bottle and shake.

Shake well before each use. Oversize bottle provides shake space. Keep tightly closed. Do not refrigerate. After mixing, store below 25ºC (77ºF) and use within 14 days.
Depakene

Depakene

2.1 Epilepsy

Depakene is intended for oral administration. Depakene capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat.

Patients should be informed to take Depakene every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.

Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depakene has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15 mg/kg/day):
Table 1. Initial Daily Dose Weight Total Daily Dose (mg) Number of Capsules or Teaspoonfuls of Syrup (Kg) (Lb) Dose 1 Dose 2 Dose 3 10 - 24.9 22 - 54.9 250 0 0 1 25 - 39.9 55 - 87.9 500 1 0 1 40 - 59.9 88 - 131.9 750 1 1 1 60 - 74.9 132 - 164.9 1,000 1 1 2 75 - 89.9 165 - 197.9 1,250 2 1 2
2.2 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Depakote Er

Depakote Er

Depakote ER is an extended-release product intended for once-a-day oral administration. Depakote ER tablets should be swallowed whole and should not be crushed or chewed.

2.1 Mania

Depakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.

There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote ER treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment (i.e., beyond 3 weeks).

2.2 Epilepsy

Depakote ER (divalproex sodium) extended release tablets are administered orally, and must be swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depakote ER has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

2.3 Migraine

Depakote ER is indicated for prophylaxis of migraine headaches in adults.

The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products, doses of Depakote ER should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER, Depakote should be used instead.

2.4 Conversion from Depakote to Depakote ER

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s discretion to increase the patient’s Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion Depakote Depakote ER Total Daily Dose (mg) (mg) 500* - 625 750 750* - 875 1000 1000*-1125 1250 1250-1375 1500 1500-1625 1750 1750 2000 1875-2000 2250 2125-2250 2500 2375 2750 2500-2750 3000 2875 3250 3000-3125 3500 * These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
There is insufficient data to allow a conversion factor recommendation for patients with DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see Clinical Pharmacology (12.2)].

2.5 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250 mg can only be achieved by the use of Depakote. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

Compliance

Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.

2.1 Mania

Depakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.

There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote ER treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment (i.e., beyond 3 weeks).

2.2 Epilepsy

Depakote ER (divalproex sodium) extended release tablets are administered orally, and must be swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depakote ER has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

2.3 Migraine

Depakote ER is indicated for prophylaxis of migraine headaches in adults.

The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products, doses of Depakote ER should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER, Depakote should be used instead.

2.4 Conversion from Depakote to Depakote ER

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s discretion to increase the patient’s Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion Depakote Depakote ER Total Daily Dose (mg) (mg) 500* - 625 750 750* - 875 1000 1000*-1125 1250 1250-1375 1500 1500-1625 1750 1750 2000 1875-2000 2250 2125-2250 2500 2375 2750 2500-2750 3000 2875 3250 3000-3125 3500 * These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
There is insufficient data to allow a conversion factor recommendation for patients with DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see Clinical Pharmacology (12.2)].

2.5 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250 mg can only be achieved by the use of Depakote. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

Compliance

Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
Depacon

Depacon

2.1 Epilepsy

Depacon is for intravenous use only.

Use of Depacon for periods of more than 14 days has not been studied. Patients should be switched to oral valproate products as soon as it is clinically feasible.

Depacon should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.

In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma levels of valproate were given single infusions of Depacon (up to 15 mg/kg and mean dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min). Patients generally tolerated the more rapid infusions well [see Adverse Reactions (6.1)]. This study was not designed to assess the effectiveness of these regimens. For pharmacokinetics with rapid infusions, see Clinical Pharmacology (12.3).

Initial Exposure to Valproate

The following dosage recommendations were obtained from studies utilizing oral divalproex sodium products.

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depacon has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depacon therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depacon may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

As the Depacon dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Replacement Therapy

When switching from oral valproate products, the total daily dose of Depacon should be equivalent to the total daily dose of the oral valproate product [see Clinical Pharmacology (12)], and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary. Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be monitored more closely. If the total daily dose exceeds 250 mg, it should be given in a divided regimen. There is no experience with more rapid infusions in patients receiving Depacon as replacement therapy. However, the equivalence shown between Depacon and oral valproate products (Depakote) at steady state was only evaluated in an every 6 hour regimen. Whether, when Depacon is given less frequently (i.e., twice or three times a day), trough levels fall below those that result from an oral dosage form given via the same regimen, is unknown. For this reason, when Depacon is given twice or three times a day, close monitoring of trough plasma levels may be needed.

2.2 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Administration

Rapid infusion of Depacon has been associated with an increase in adverse reactions. There is limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min in patients with epilepsy [see Adverse Reactions (6)].

Depacon should be administered intravenously as a 60 minute infusion, as noted above. It should be diluted with at least 50 mL of a compatible diluent. Any unused portion of the vial contents should be discarded.

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

Compatibility and Stability

Depacon was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature 15-30°C (59-86°F).
dextrose (5%) injection, USP sodium chloride (0.9%) injection, USP lactated ringer's injection, USP
Depakote Sprinkles

Depakote Sprinkles

2.1 Epilepsy

Depakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depakote Sprinkle Capsules has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depakote Sprinkle Capsules may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

As the Depakote Sprinkle Capsules dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote Sprinkle Capsules should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote Sprinkle Capsules, a dosing schedule of two or three times a day may be elected in selected patients.

2.2 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

Administration of Sprinkle Capsules

Depakote Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft food such as applesauce or pudding. The drug/food mixture should be swallowed immediately (avoid chewing) and not stored for future use. Each capsule is oversized to allow ease of opening.
Depakote

Depakote

Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed.

Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.

2.1 Mania

Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.

There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months.

2.2 Epilepsy

Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients.

2.3 Migraine

Depakote is indicated for prophylaxis of migraine headaches in adults.

Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.

2.4 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Avastin

Avastin

Dosage and Administration for AndroGel 1% differs from AndroGel 1.62%. For dosage and administration of AndroGel 1.62% refer to its full prescribing information. (2)
Prior to initiating AndroGel 1%, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.
2.1 Dosing and Dose Adjustment

The recommended starting dose of AndroGel 1% is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day).

Dose Adjustment To ensure proper dosing, serum testosterone concentrations should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily AndroGel 1% dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician (see Table 1, Dosing Information for AndroGel 1%). If the serum testosterone concentration exceeds the normal range, the daily AndroGel 1% dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 50 mg, AndroGel 1% therapy should be discontinued. In addition, serum testosterone concentrations should be assessed periodically.

The application site and dose of AndroGel 1% are not interchangeable with other topical testosterone products.

2.2 Administration Instructions

AndroGel 1% should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient’s short sleeve T-shirt. Do not apply AndroGel 1% to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. AndroGel 1% should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen.

The prescribed daily dose of AndroGel 1% should be applied to the right and left upper arms/shoulders and/or right/left abdomen as shown in the shaded areas in the figure below.

After applying the gel, the application site should be allowed to dry prior to dressing. Hands should be washed thoroughly with soap and water after application. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel 1%, are flammable.

The patient should be advised to avoid swimming or showering for at least 5 hours after the application of AndroGel 1%.

Multi-Dose Pump

To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, patients should completely depress the pump one time actuation for every 12.5 mg of testosterone required to achieve the daily prescribed dosage. The product should be delivered directly into the palm of the hand and then applied to the desired application sites. Alternatively, AndroGel 1% can be applied directly to the application sites. Table 1 provides dosing information for adult males.
Table 1: Dosing Information for AndroGel 1% Amount of Testosterone Number of Pump Actuations 50 mg 4 (once daily) 75 mg 6 (once daily) 100 mg 8 (once daily)
Packets

The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AndroGel 1%-treated skin:
Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1%. Patients should wash hands with soap and water immediately after application of AndroGel 1%. Patients should cover the application site(s) with clothing (e.g., a T-shirt) after the gel has dried. Prior to situation in which direct skin-to-skin contact is anticipated, patients should wash the application site thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which AndroGel 1% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible.
Zemplar

Zemplar

2.1 Chronic Kidney Disease Stages 3 and 4

Zemplar Capsules may be administered daily or three times a week. When dosing three times weekly, the dose should be administered not more frequently than every other day. The total weekly doses for both daily and three times a week dosage regimens are similar [see Clinical Studies (14.1)].

Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.

Initial Dose

The initial dose of Zemplar Capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.
Baseline iPTH Level Daily Dose Three Times a Week Dose* ≤ 500 pg/mL 1 mcg 2 mcg > 500 pg/mL 2 mcg 4 mcg * To be administered not more often than every other day
Dose Titration

Dosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is a suggested approach to dose titration.
Dose Adjustment at 2 to 4 Week Intervals iPTH Level Relative to Baseline Zemplar Capsule Dose Daily Dosage Three Times a Week Dosage* The same, increased ordecreased by < 30% Increase dose by 1 mcg 2 mcg Decreased by ≥ 30% and ≤ 60% Maintain dose - - Decreased by > 60% oriPTH < 60 pg/mL Decrease dose by 1 mcg 2 mcg * To be administered not more often than every other day
If a patient is taking the lowest dose, 1 mcg, on the daily regimen and a dose reduction is needed, the dose can be decreased to 1 mcg three times a week. If a further dose reduction is required, the drug should be withheld as needed and restarted at a lower dosing frequency. If a patient is on a calcium-based phosphate binder, the phosphate-binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hypercalcemia is observed, the dose of Zemplar should be reduced or withheld until these parameters are normalized.

Serum calcium and phosphorus levels should be closely monitored after initiation of Zemplar Capsules, during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions (5.3), Drug Interactions (7) and Clinical Pharmacology (12.3)].

2.2 Chronic Kidney Disease Stage 5

Zemplar Capsules are to be administered three times a week, not more frequently than every other day.

Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.

Initial Dose

The initial dose of Zemplar Capsules in micrograms is based on a baseline iPTH level (pg/mL)/80. To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower [see Clinical Pharmacology (12.2) and Clinical Studies (14.2)].

Dose Titration

Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of Zemplar Capsules is based on the following formula:

Titration dose (micrograms) = most recent iPTH level (pg/ml)/80

Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If serum calcium is elevated, the dose should be decreased by 2 to 4 micrograms lower than that calculated by the most recent iPTH/80. If further adjustment is required, the dose of paricalcitol capsules should be reduced or withheld until these parameters are normalized.

As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio (e.g., iPTH/100) may be warranted.
Vicodin Hp

Vicodin Hp

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

VICODIN® (Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/300 mg): The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dosage should not exceed 8 tablets.

VICODIN ES® (Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/300 mg): The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets.

VICODIN HP® (Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/300 mg): The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets.
Vicoprofen

Vicoprofen

Carefully consider the potential benefits and risks of VICOPROFEN and other treatment options before deciding to use VICOPROFEN. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with VICOPROFEN, the dose and frequency should be adjusted to suit an individual patient's needs.

For the short-term (generally less than 10 days) management of acute pain, the recommended dose of VICOPROFEN is one tablet every 4 to 6 hours, as necessary. Dosage should not exceed 5 tablets in a 24-hour period. It should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The lowest effective dose or the longest dosing interval should be sought for each patient (see WARNINGS), especially in the elderly. After observing the initial response to therapy with VICOPROFEN, the dose and frequency of dosing should be adjusted to suit the individual patient's need, without exceeding the total daily dose recommended.
Humira

Humira

HUMIRA is administered by subcutaneous injection.

2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis

The recommended dose of HUMIRA for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with HUMIRA. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of HUMIRA to 40 mg every week.

2.2 Juvenile Idiopathic Arthritis

The recommended dose of HUMIRA for patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with HUMIRA.
Patients (2 years of age and older) Dose 10 kg (22 lbs) to <15 kg (33 lbs) 10 mg every other week (10 mg Prefilled Syringe) 15 kg (33 lbs) to <30 kg (66 lbs) 20 mg every other week(20 mg Prefilled Syringe) ≥30 kg (66 lbs) 40 mg every other week(HUMIRA Pen or 40 mg Prefilled Syringe)
HUMIRA has not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

2.3 Adult Crohn’s Disease

The recommended HUMIRA dose regimen for adult patients with Crohn’s disease (CD) is 160 mg initially on Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a maintenance dose of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with HUMIRA. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] or MTX may be continued during treatment with HUMIRA if necessary. The use of HUMIRA in CD beyond one year has not been evaluated in controlled clinical studies.

2.4 Pediatric Crohn’s Disease

The recommended HUMIRA dose regimen for pediatric patients 6 years of age and older with Crohn’s disease (CD) is based on body weight as shown below:
Pediatric Patients Induction Dose Maintenance Dose Starting at Week 4 (Day 29) 17 kg (37 lbs) to < 40 kg (88 lbs) 80 mg on Day 1 (administered as two 40 mg injections in one day); and 40 mg two weeks later (on Day 15) 20 mg every other week ≥ 40 kg (88 lbs) 160 mg on Day 1 (administered as four injections in one day or as two 40 mg injections per day for two consecutive days); and 80 mg two weeks later (on Day 15) (administered as two 40 mg injections in one day) 40 mg every other week
2.5 Ulcerative Colitis

The recommended HUMIRA dose regimen for adult patients with ulcerative colitis (UC) is 160 mg initially on Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dose of 40 mg every other week.

Only continue HUMIRA in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with HUMIRA. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] may be continued during treatment with HUMIRA if necessary.

2.6 Plaque Psoriasis

The recommended dose of HUMIRA for adult patients with plaque psoriasis (Ps) is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of HUMIRA in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.

2.7 Hidradenitis Suppurativa

The recommended dose of HUMIRA for adult patients with hidradenitis suppurativa (HS) is 160 mg (given as four 40 mg injections on Day 1 or as two 40 mg injections per day on Days 1 and 2), followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly dosing two weeks later (Day 29).

2.8 Monitoring to Assess Safety

Prior to initiating HUMIRA and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)].

2.9 General Considerations for Administration

HUMIRA is intended for use under the guidance and supervision of a physician. A patient may self-inject HUMIRA or a caregiver may inject HUMIRA using either the HUMIRA Pen or prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

You may leave HUMIRA at room temperature for about 15 to 30 minutes before injecting. Do not remove the cap or cover while allowing it to reach room temperature. Carefully inspect the solution in the HUMIRA Pen, prefilled syringe, or single-use institutional use vial for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. HUMIRA does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the needle cover of the syringe because it contains dry rubber (latex).

Instruct patients using the HUMIRA Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use].

Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard.

The HUMIRA single-use institutional use vial is for administration within an institutional setting only, such as a hospital, physician’s office or clinic. Withdraw the dose using a sterile needle and syringe and administer promptly by a healthcare provider within an institutional setting. Only administer one dose per vial. The vial does not contain preservatives; therefore, discard unused portions.

2.4 Pediatric Crohn’s Disease

The recommended HUMIRA dose regimen for pediatric patients 6 years of age and older with Crohn’s disease (CD) is based on body weight as shown below:
Pediatric Patients Induction Dose Maintenance Dose Starting at Week 4 (Day 29) 17 kg (37 lbs) to < 40 kg (88 lbs) 80 mg on Day 1 (administered as two 40 mg injections in one day); and 40 mg two weeks later (on Day 15) 20 mg every other week ≥ 40 kg (88 lbs) 160 mg on Day 1 (administered as four injections in one day or as two 40 mg injections per day for two consecutive days); and 80 mg two weeks later (on Day 15) (administered as two 40 mg injections in one day) 40 mg every other week

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