Peramivir

Risk Summary

Limited available data with peramivir 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 [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.

Risk Summary

There are no data on the presence of peramivir 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 peramivir to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for peramivir 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.

Carcinogenesis

Carcinogenicity studies by intravenous injection of peramivir were not performed. However, in an oral carcinogenicity study in Sprague-Dawley rats no drug-related neoplasms were observed at drug exposures 0.2- to 0.5-fold that of humans at the clinically recommended dose of 600 mg/day.

Mutagenesis

Peramivir was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the Chinese hamster ovary chromosomal aberration test, and the in vivo mouse micronucleus test with intravenous administration.

Impairment of Fertility

Peramivir had no effects on mating or fertility in rats up to 600 mg/kg/day, at which exposures were approximately 8-fold of those in humans at the clinically recommended dose.

• Serious skin and hypersensitivity reactions
• Neuropsychiatric Events

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 peramivir, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 subjects receiving peramivir 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 peramivir 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 the table below occurred more frequently in subjects treated with peramivir 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included.

Laboratory Abnormalities Occurring in ≥2% of Subjects Treated with Peramivir 600 mg:

==*= Frequencies based on treatment-emergent laboratory abnormalities

In a subset of subjects with serious influenza requiring hospitalization treated with peramivir 600 mg as monotherapy (N=101), the following adverse reactions were also reported more frequently with peramivir 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 peramivir (N=88), or 5 days of treatment with oseltamivir (N=22).

The safety profile of peramivir 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 peramivir (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 peramivir was proteinuria by dipstick analysis (3% versus 0% for oseltamivir).

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of peramivir. 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