Rapivab Drug Information

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 5 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 <1% discontinued study because of an adverse reaction. Clinically significant laboratory abnormalities (DAIDS Grades 2 to 4) listed in Table 4 occurred more frequently in subjects treated with RAPIVAB 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included.

Table 4: Laboratory Abnormalities Occurring in ≥2% of Subjects Treated with RAPIVAB 600 mg Laboratory Parameter Abnormality a RAPIVAB 600 mg Placebo a Frequencies based on treatment-emergent laboratory abnormalities. 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 ×10 9 /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 (6 months to 17 years of age) Assessment of adverse reactions is based on a randomized, active-controlled study in which 130 adolescent and pediatric subjects ages 6 months to 17 years of age with acute uncomplicated influenza received open-label treatment with a single dose of RAPIVAB (n = 107), or 5 days of treatment with oseltamivir (n = 23) . The safety profile of RAPIVAB in subjects 6 months to 17 years of age was generally similar to that observed in adults. The only adverse reaction reported in pediatric subjects treated with RAPIVAB (occurring in ≥2% of subjects) and not reported in adults was vomiting (3% versus 9% for oseltamivir). The only clinically significant laboratory abnormality (DAIDS Grade 2) occurring in ≥2% of pediatric subjects treated with RAPIVAB (and not previously reported in adults) was proteinuria by dipstick analysis (3% versus 0% for oseltamivir).

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of RAPIVAB. 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 . General Disorders and Administration Site Conditions: Anaphylactic/anaphylactoid reactions . Psychiatric: Abnormal behavior, hallucination .

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.

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 . 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 . 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.

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. 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 .

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 . Patients with known serious hypersensitivity or anaphylaxis to peramivir or any component of RAPIVAB

There is no human experience of acute overdosage with RAPIVAB. Treatment of overdosage with RAPIVAB should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with RAPIVAB. RAPIVAB is cleared by renal excretion and can be cleared by hemodialysis.