Rapivab (Page 3 of 5)

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% 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.

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 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.

8.4 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)].

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 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)].

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), Clinical Studies (14.2)].

10 OVERDOSAGE

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.

11 DESCRIPTION

RAPIVAB (peramivir) is an inhibitor of influenza virus neuraminidase. The chemical name is (1S,2S,3R,4R)-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4-(carbamimidoylamino)-2-hydroxycyclopentanecarboxylic acid, trihydrate. The chemical formula is C₁₅ H₂₈ N₄ O₄ ∙ 3H₂ O_, representing a molecular weight of 382.45. The molecular structure is as follows:

RAPIVAB injection is a clear, colorless, sterile, isotonic solution (200 mg per 20 mL) in glass vials fitted with rubber stoppers and royal blue flip-off seals. Each mL contains 10 mg peramivir (on an anhydrous basis) in 0.9% sodium chloride solution. The pH may have been adjusted with sodium hydroxide, USP and/or hydrochloric acid, USP. The pH is 5.5 to 8.5.