Rapivab
(peramivir)Dosage & Administration
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Rapivab Prescribing Information
RAPIVAB is indicated for the treatment of acute uncomplicated influenza in patients 6 months and older who have been symptomatic for no more than 2 days.
Limitations of Use:
- Efficacy of RAPIVAB is based on clinical trials of naturally occurring influenza in which the predominant influenza infections were influenza A virus; a limited number of subjects infected with influenza B virus were enrolled.
- Influenza viruses change over time. Emergence of resistance substitutions could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use RAPIVAB [see Microbiology (12.4)].
- The efficacy of RAPIVAB could not be established in patients with serious influenza requiring hospitalization [see Clinical Studies (14.3)].
Dosage in Acute Uncomplicated Influenza
Administer RAPIVAB within 2 days of onset of symptoms of influenza.
Adults and Adolescents (13 years of age and older)
The recommended dosage of RAPIVAB in adult and adolescent patients 13 years of age and older with acute uncomplicated influenza is a single 600 mg dose, administered via intravenous infusion for 15 to 30 minutes.
Pediatric Patients (6 months to 12 years of age)
The recommended dosage of RAPIVAB in pediatric patients 6 months to 12 years of age with acute uncomplicated influenza is a single 12 mg/kg dose (up to a maximum dose of 600 mg), administered via intravenous infusion for 15 to 30 minutes.
Dosing in Patients with Renal Impairment
Significantly increased drug exposures were observed when RAPIVAB was administered to adult subjects with renal dysfunction [see Clinical Pharmacology (12.3)]. Therefore, the RAPIVAB dosage should be reduced for patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 1 and Table 2. No dosage adjustment is required for single administration of RAPIVAB in patients with creatinine clearance of 50 mL/min or higher [see Clinical Pharmacology (12.3)].
In patients with chronic renal impairment maintained on hemodialysis, RAPIVAB should be administered after dialysis at a dose adjusted based on renal function (Table 1 and Table 2) [see Clinical Pharmacology (12.3)].
| Creatinine Clearancea (mL/min) | |||
|---|---|---|---|
| ≥50 | 30 to 49 | 10 to 29 | |
| a Calculated using the Cockcroft and Gault equation. | |||
| Recommended Dose (mg) | 600 mg | 200 mg | 100 mg |
| Creatinine Clearancea (mL/min) | |||
|---|---|---|---|
| ≥50 | 30 to 49 | 10 to 29 | |
| a Calculated using the Cockcroft and Gault equation. | |||
| b Up to maximum dose of 600 mg. | |||
| Recommended Dose (mg/kg)b | 12 mg/kg | 4 mg/kg | 2 mg/kg |
No data are available to inform a recommendation for dosage adjustment with RAPIVAB in pediatric patients 6 months to less than 2 years of age with creatinine clearance less than 50 mL/min [see Use in Specific Populations (8.4, 8.6), Clinical Pharmacology (12.3)].
Preparation of RAPIVAB for Intravenous Infusion
Use aseptic technique during the preparation of RAPIVAB to prevent inadvertent microbial contamination. There is no preservative or bacteriostatic agent present in the solution.
Follow the steps below to prepare a diluted solution of RAPIVAB:
- (a)
- Do not use if seal over bottle opening is broken or missing.
- (b)
- Visually inspect RAPIVAB for particulate matter and discoloration prior to administration.
- (c)
- Dilute an appropriate dose of RAPIVAB 10 mg/mL solution [see Dosage and Administration (2.1, 2.2)] in 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer's. The maximum infusion volume is provided in Table 3. The final concentration of diluted RAPIVAB for administration should be between 1 mg/mL and 6 mg/mL.
Table 3. Maximum Infusion Volume by Age and Weight Age Weight (kg) Maximum Infusion Volumea (mL) aInfusion volume is the total volume of RAPIVAB 10 mg/mL solution and diluent. The final concentration of diluted RAPIVAB for administration should be between 1 mg/mL and 6 mg/mL. Infants 6 months to 1 year of age Any 25 mL Adults and pediatric patients 1 year and older 5 kg to less than 10 kg 25 mL 10 kg to less than 15 kg 50 mL 15 kg to less than 20 kg 75 mL At least 20 kg 100 mL - (d)
- Administer the diluted solution via intravenous infusion for 15 to 30 minutes.
- (e)
- Discard any unused diluted solution of RAPIVAB after 24 hours.
Once a diluted solution of RAPIVAB has been prepared, administer immediately or store under refrigerated conditions (2° to 8°C or 36° to 46°F) for up to 24 hours. If refrigerated, allow the diluted solution of RAPIVAB to reach room temperature then administer immediately.
Drug Compatibility
RAPIVAB injection is compatible with 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer's. Do not mix or co-infuse RAPIVAB with other intravenous medications.
RAPIVAB injection is compatible with materials commonly used for administration such as polyvinylchloride (PVC) bags and PVC-free bags, polypropylene syringes, and polyethylene tubing.
Each vial of RAPIVAB injection contains 200 mg per 20 mL (10 mg per mL) as a clear, colorless solution [see How Supplied/Storage and Handling (16)].
Pregnancy
Risk Summary
Limited available data with RAPIVAB use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza in pregnancy [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed in rats when peramivir was administered by intravenous bolus injection during organogenesis at the maximum feasible dose, resulting in systemic drug exposures (AUC) approximately 8 times those in humans at the recommended dose. However, when peramivir was administered to rats by continuous intravenous infusion during the same gestation period, fetal abnormalities of reduced renal papilla and dilated ureters were observed. In rabbits, administration of peramivir during organogenesis at exposures 8 times those in humans at the recommended dose resulted in developmental toxicity (abortion or premature delivery) at a maternally toxic dose [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small for gestational age.
Data
Animal Data
Reproductive toxicity studies have been performed in rats and rabbits. In rats, peramivir was administered once daily by intravenous bolus injection at doses of 200, 400, and 600 mg/kg/day on Gestational Days 6 to 17. No treatment-related fetal toxicities were observed when peramivir was administered by intravenous bolus injection at the maximum feasible dose of 600 mg/kg, resulting in exposures approximately 8 times those in humans at the recommended dose.
Peramivir was also administered by continuous intravenous infusion to rats at daily doses of 50, 400, and 1000 mg/kg/day on Gestational Days 6 to 17. Dose related increases in the incidence of fetal abnormalities of reduced renal papilla and dilated ureters were observed at 400 and 1000 mg/kg/day. The systemic drug exposure in rats at a dose without fetal effects was less than the exposures in humans at the recommended dose.
In rabbits, peramivir was administered once daily by intravenous bolus injection at doses of 25, 50, 100, and 200 mg/kg/day on Gestational Days 7 to 19. Developmental toxicity (abortion or premature delivery) was observed at maternally toxic dose levels (100 and 200 mg/kg/day) resulting in exposures approximately 8 times those in humans at the recommended dose. The exposure in rabbits at doses without developmental toxicity was less than the exposure in humans at the recommended dose.
A pre/post-natal developmental toxicity study was performed in pregnant rats administered peramivir once daily by intravenous infusion at doses of 50, 200, 400, and 600 mg/kg/day on Gestational Day 6 through Lactation Day 20. No significant effects of peramivir on developmental outcomes were observed in nursing pups at up to the highest dose tested.
Lactation
Risk Summary
There are no data on the presence of RAPIVAB in human milk, the effects on the breastfed infant, or the effects on milk production. Peramivir is present in rat milk [see Data]. Limited clinical data during lactation preclude a clear determination of the risk of RAPIVAB to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RAPIVAB and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Data
A pharmacokinetic study was performed in lactating rats administered a single intravenous dose of peramivir (10 mg/kg) on Lactation/Postpartum Days 11 to 13. The maximum concentration of peramivir in milk was reached at 0.75 hours post-dose. The milk to plasma AUC ratio of peramivir was approximately 0.5.
Pediatric Use
The safety and effectiveness of RAPIVAB for the treatment of influenza has been established in pediatric patients 6 months to 17 years of age. Use of RAPIVAB for this indication is supported by evidence from adequate and well-controlled trials of RAPIVAB in adults with additional data from Study 305, a randomized, active-controlled trial of 130 adolescent and pediatric subjects with acute uncomplicated influenza who received open-label treatment with a single dose of RAPIVAB or 5 days of treatment with oseltamivir administered within 48 hours of onset of symptoms of influenza [see Dosage and Administration (2.1, 2.2, 2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Study 305 included:
- 13 to 17 years of age: 21 subjects treated with RAPIVAB 600 mg
- 6 months to 12 years of age: 86 subjects treated with RAPIVAB 12 mg/kg (up to a maximum dose of 600 mg)
Safety and effectiveness of RAPIVAB in pediatric patients less than 6 months of age have not been established. No data are available for RAPIVAB use in pediatric patients 6 months to less than 2 years with creatinine clearance <50 mL/min to inform a recommendation for dosage adjustment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Geriatric Use
Clinical trials of RAPIVAB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in exposures between the elderly and younger subjects [see Clinical Pharmacology (12.3)].
Patients with Impaired Renal Function
A reduced dose of RAPIVAB is recommended for patients 2 years and older with creatinine clearance <50 mL/min [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Dose adjustment is not required for a single administration of RAPIVAB for patients with creatinine clearance ≥50 mL/min [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
In patients with chronic renal impairment maintained on hemodialysis, RAPIVAB should be administered after dialysis at a dose adjusted based on renal function [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
No data are available for RAPIVAB use in pediatric patients 6 months to less than 2 years with creatinine clearance <50 mL/min to inform a recommendation for dosage adjustment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Patients with Serious Influenza Requiring Hospitalization
The use of RAPIVAB was not shown to provide benefit in patients with serious influenza requiring hospitalization [see Indications and Usage (1), Clinical Studies (14.2)].
RAPIVAB is contraindicated in patients with known serious hypersensitivity or anaphylaxis to peramivir or any component of the product. Severe allergic reactions have included anaphylaxis, erythema multiforme, and Stevens-Johnson syndrome [see Warnings and Precautions (5.1)].
Serious Skin/Hypersensitivity Reactions
Rare cases of serious skin reactions, including erythema multiforme, have been reported with RAPIVAB in clinical studies and in postmarketing experience. Cases of anaphylaxis and Stevens-Johnson syndrome have been reported in postmarketing experience with RAPIVAB. Discontinue RAPIVAB and institute appropriate treatment if anaphylaxis or a serious skin reaction occurs or is suspected. The use of RAPIVAB is contraindicated in patients with known serious hypersensitivity or anaphylaxis to RAPIVAB [see Contraindications (4), Adverse Reactions (6.2)].
Neuropsychiatric Events
Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur in uncomplicated influenza as well.
There have been postmarketing reports of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including RAPIVAB. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RAPIVAB to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior.
Risk of Bacterial Infections
There is no evidence for efficacy of RAPIVAB in any illness caused by agents other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RAPIVAB has not been shown to prevent such complications.
Prescribers should be alert to the potential for secondary bacterial infections and treat with antibiotics as appropriate.