Rimantadine warnings and precautions

# Warnings And Precautions
GENERAL: An increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine In clinical trials of Flumadine, the occurrence of seizure-like activity was observed in a small number of patients with a history of seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures develop, Flumadine should be discontinued.
The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency have only been evaluated after single dose administration. In a single dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower and the elimination half-life was 1.6-fold greater than that in healthy age-matched controls. In a study of 14 persons with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after the administration of a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, caution should be exercised when patients with renal or hepatic insufficiency are treated with rimantadine.
Transmission of rimantadine resistant virus should be considered when treating patients whose contacts are at high risk for influenza A illness. influenza A virus strains resistant to rimantadine can emerge during treatment and such resistant strains have been shown to be transmissible and to cause typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of the emergence of drug-resistant virus are not yet established, several small studies have demonstrated that 10% to 30% of patients with initially sensitive virus, upon treatment with rimantadine, shed rimantadine resistant virus. (Ref. 3, 4, 5, 6)
Clinical response to rimantadine, although slower in those patients who subsequently shed resistant virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are available in humans that address the activity or effectiveness of rimantadine therapy in subjects infected with resistant virus.
DRUG INTERACTIONS: cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of Flumadine was administered one hour after the initiation of cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine).
Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%.
Aspirin: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin.
Live Attenuated influenza Vaccine (LAIV): The concurrent use of Flumadine with live attenuated influenza vaccine has not been evaluated. However, because of potential interference between these products, the live attenuated intranasal influenza vaccine should not be administered until 48 hours after cessation of Flumadine and Flumadine should not be administered until two weeks after the administration of live attenuated intranasal influenza vaccine unless medically indicated. The concern about potential interference arises principally from the potential for antiviral drugs to inhibit replication of live vaccine virus.

## CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Carcinogenesis: Carcinogenicity studies in animals have not been performed.
Mutagenesis: No mutagenic effects were seen when rimantadine was evaluated in several standard assays for mutagenicity.
Impairment of Fertility: A reproduction study in male and female rats did not show detectable impairment of fertility at dosages up to 60 mg/kg/day (3 times the maximum human dose based on body surface area comparisons).
PREGNANCY: Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. rimantadine is reported to cross the placenta in mice. rimantadine has been shown to be embryotoxic in rats when given at a dose of 200 mg/kg/day (11 times the recommended human dose based on body surface area comparisons). At this dose the embryotoxic effect consisted of increased fetal resorption in rats; this dose also produced a variety of maternal effects including ataxia, tremors, convulsions and significantly reduced weight gain. No embryotoxicity was observed when rabbits were given doses up to 50 mg/kg/day (5 times the recommended human dose based on body surface area comparisons). However, there was evidence of a developmental abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs. This ratio is normally about 50:50 in a litter but was 80:20 after rimantadine treatment.
Nonteratogenic Effects: rimantadine was administered to pregnant rats in a peri- and postnatal reproduction toxicity study at doses of 30, 60 and 120 mg/kg/day (1.7, 3.4 and 6.8 times the recommended human dose based on body surface area comparisons). Maternal toxicity during gestation was noted at the two higher doses of rimantadine, and at the highest dose, 120 mg/kg/day, there was an increase in pup mortality during the first 2 to 4 days postpartum. Decreased fertility of the F1 generation was also noted for the two higher doses.
For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
NURSING MOTHERS: Flumadine should not be administered to nursing mothers because of the adverse effects noted in offspring of rats treated with rimantadine during the nursing period. rimantadine is concentrated in rat milk in a dose-related manner: 2 to 3 hours following administration of rimantadine, rat breast milk levels were approximately twice those observed in the serum.
PEDIATRIC USE: In children, Flumadine is recommended for the prophylaxis of influenza A. The safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection in children have not been established. Prophylaxis studies with Flumadine have not been performed in children below the age of 1 year.