Data from FDA - Curated by Marshall Pearce - Last updated 06 November 2017

Indication(s)

1 INDICATIONS AND USAGE RAPIVAB is indicated for the treatment of acute uncomplicated influenza in patients 2 years 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)]. RAPIVAB is an influenza virus neuraminidase inhibitor indicated for the treatment of acute uncomplicated influenza in patients 2 years and older who have been symptomatic for no more than two days. (1) Limitations of Use: Efficacy based on clinical trials in which the predominant influenza virus type was influenza A; a limited number of subjects infected with influenza B virus were enrolled. (1) Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use. (1) Efficacy could not be established in patients with serious influenza requiring hospitalization. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS 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)]. Patients with known serious hypersensitivity or anaphylaxis to peramivir or any component of RAPIVAB (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)] Neuropsychiatric Events [see Warnings and Precautions (5.2)] Most common adverse reaction (incidence >2%) is diarrhea (6) To report SUSPECTED ADVERSE REACTIONS, contact BioCryst Pharmaceuticals, Inc. at 1-844-273-2327 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults (18 years of age and older) In five randomized, double-blind, controlled trials, 1,399 subjects with acute uncomplicated influenza received a single dose of RAPIVAB, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 subjects receiving RAPIVAB 600 mg (intravenous or intramuscular), the most commonly observed adverse reaction was diarrhea, occurring at a rate of 8% versus 7% in subjects receiving placebo. No subject receiving RAPIVAB 600 mg experienced a serious adverse event and less than 1% discontinued study because of an adverse reaction. Clinically significant laboratory abnormalities (DAIDS Grade 2-4) listed in Table 3 occurred more frequently in subjects treated with RAPIVAB 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included. Table 3: Laboratory Abnormalities Occurring in ≥2% of Subjects Treated with RAPIVAB 600 mg Laboratory Parameter AbnormalityFrequencies based on treatment-emergent laboratory abnormalities RAPIVAB 600 mg Placebo Alanine Aminotransferase (>2.5 × ULN) (N=654) 3% (N=430) 2% Serum Glucose (>160 mg/dL) (N=660) 5% (N=433) 3% Creatine Phosphokinase (≥6.0 × ULN) (N=654) 4% (N=431) 2% Neutrophils (<1.000 ×109/L) (N=654) 8% (N=430) 6% In a subset of subjects with serious influenza requiring hospitalization treated with RAPIVAB 600 mg as monotherapy (N=101), the following adverse reactions were also reported more frequently with RAPIVAB as compared to placebo: constipation (4% versus 2%), insomnia (3% versus 0%), AST increased (3% versus 2%), and hypertension (2% versus 0%). Adverse Reactions in Adolescent and Pediatric Subjects (2 to 17 years of age) Assessment of adverse reactions is based on a randomized, active-controlled study in which 110 adolescent and pediatric subjects ages 2 to 17 years of age with acute uncomplicated influenza received open-label treatment with a single dose of RAPIVAB (N=88), or 5 days of treatment with oseltamivir (N=22) [see Use In Specific Populations (8.4) and Clinical Studies (14.2)]. The safety profile of RAPIVAB in subjects 2 to 17 years of age was generally similar to that observed in adults. Specific adverse reactions reported in pediatric subjects treated with RAPIVAB (occurring in ≥2% of subjects) and not reported in adults included vomiting (3% versus 9% for oseltamivir), fever and tympanic membrane erythema (2% versus 0%, respectively, for each of these events). The only clinically significant laboratory abnormality (DAIDS Grade 2) occurring in ≥2% of pediatric subjects treated with RAPIVAB was proteinuria by dipstick analysis (3% versus 0% for oseltamivir). 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of RAPIVAB in Japan. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: Stevens-Johnson Syndrome, exfoliative dermatitis, rash [see Warnings and Precautions (5.1)] General disorders and administration site conditions: anaphylactic/anaphylactoid reactions [see Warnings and Precautions (5.1)] Psychiatric: abnormal behavior, hallucination [see Warnings and Precautions (5.2)]

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Administer RAPIVAB as a single dose within 2 days of onset of influenza symptoms (2.1) Administer RAPIVAB by intravenous infusion for a minimum of 15 minutes (2.1) Recommended Usual Dose Single Dose Adults and adolescents (13 years and older) 600 mg Pediatric patients (2 to 12 years of age) 12 mg/kg (up to 600 mg) Recommended Dose Adjustments in Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) ≥ 50 30-49 10-29 Adults and adolescents (13 years and older) 600 mg 200 mg 100 mg Pediatric patients Up to maximum dose of 600 mg (2 to 12 years of age) 12 mg/kg 4 mg/kg 2 mg/kg Hemodialysis: Administer after dialysis (2.2) RAPIVAB must be diluted prior to administration (2.3) See the Full Prescribing Information for drug compatibility information (2.4) 2.1 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 dose of RAPIVAB in adult and adolescent patients 13 years of age or older with acute uncomplicated influenza is a single 600 mg dose, administered via intravenous infusion for 15 to 30 minutes. Pediatric Patients (2 to 12 years of age) The recommended dose of RAPIVAB in pediatric patients 2 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. 2.2 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 dose should be reduced for patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 1 and Table 2. No dose 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)]. Table 1. Dosage Adjustment for Adults and Adolescents (13 years and older) with Altered Creatinine Clearance Creatinine ClearanceCalculated using the Cockcroft and Gault equation. (mL/min) ≥50 30-49 10-29 Recommended Dose (mg) 600 mg 200 mg 100 mg Table 2. Dosage Adjustment for Pediatric Patients (2 to 12 years of age) with Altered Creatinine Clearance Creatinine ClearanceCalculated using the Cockcroft and Gault equation. (mL/min) ≥50 30-49 10-29 Recommended Dose (mg/kg)Up to maximum dose of 600 mg 12 mg/kg 4 mg/kg 2 mg/kg 2.3 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)] in 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer's to a maximum volume of 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. 2.4 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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 2-4% and 15-20%, 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 6-17. 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 6-17. 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 7-19. 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. 8.2 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 11-13. 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. 8.4 Pediatric Use The safety and effectiveness of RAPIVAB for the treatment of influenza has been established in pediatric patients 2 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 110 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), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. Study 305 included: 13 to 17 years of age: 21 subjects treated with RAPIVAB 600 mg 2 to 12 years of age: 67 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 2 years of age have not been established. 8.5 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)]. 8.6 Patients with Impaired Renal Function A reduced dose of RAPIVAB is recommended for patients with creatinine clearance below 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 or higher [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)]. 8.7 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) and Clinical Studies (14.2)].

Interactions

7 DRUG INTERACTIONS This section describes clinically relevant drug interactions with RAPIVAB. Drug-drug interaction studies are described elsewhere in the labeling [see Clinical Pharmacology (12.3)]. Live attenuated influenza vaccine (LAIV), intranasal: Avoid use of LAIV within 2 weeks before or 48 hours after administration of RAPIVAB, unless medically indicated (7.1) 7.1 Influenza Vaccines Inactivated influenza vaccine can be administered at any time relative to use of RAPIVAB. For live attenuated influenza vaccine (LAIV), antiviral drugs may inhibit viral replication and thus may reduce vaccine efficacy. The concurrent use of RAPIVAB with LAIV intranasal has not been evaluated. Because of the potential for interference between these two products, avoid use of LAIV within 2 weeks before or 48 hours after administration of RAPIVAB unless medically indicated.

More information

Category Value
Authorisation number NDA206426
Agency product number QW7Y7ZR15U
Orphan designation No
Product NDC 61364-181
Date Last Revised 25-09-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1598082
Storage and handling Store vials of RAPIVAB injection in original cartons at 20° to 25°C (68° to 77°F). Excursions are permitted to 15° to 30°C (59° to 86°F). Do not use if seal over bottle opening is broken or missing.
Marketing authorisation holder bioCSL Inc.