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 rimantadine hydrochloride, 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 rimantadine hydrochloride. If seizures develop, rimantadine hydrochloride should be discontinued. The safety and pharmacokinetics of rimantadine in hepatic insufficiency have only been evaluated after single dose administration. In a study of 14 subjects 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 hepatic insufficiency are treated with rimantadine. Following multiple-dose administration of rimantadine, there were no clinically relevant differences in rimantadine systemic exposure between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine systemic exposure increased by 81%, compared with healthy subjects. Because of the potential for increased accumulation of rimantadine metabolites in renally impaired subjects, caution should be exercised when these patients 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. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Rimantadine hydrochloride has not been shown to prevent such complications. Drug Interactions Acetaminophen: Rimantadine hydrochloride, 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. Co-administration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine hydrochloride, 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. Cimetidine: When a single 100 mg dose of rimantadine hydrochloride was administered with steady-state cimetidine (300 mg four times a day), there were no statistically significant differences in rimantadine Cmax or AUC between rimantadine hydrochloride alone and rimantadine hydrochloride in the presence of cimetdine. Live Attenuated Influenza Vaccine (LAIV): The concurrent use of rimantadine hydrochloride with live attenuated intranasal 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 rimantadine hydrochloride and rimantadine hydrochloride 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: Oral administration of rimantadine to rats for 2 years at doses up to 100 mg/kg/d [approximately 11 to 14 times the maximum recommended human dose (MRHD) based on AUC] showed no evidence of increased tumor incidence. 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 MRHD based on mg/m2). 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/d (11 times the MRHD based on mg/m2). 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/d (approximately 0.1 times the MRHD based on AUC), but evidence of a developmental abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs were noted. This ratio is normally about 50:50 in a litter but was 80:20 after rimantadine treatment. However, in a repeat embryofetal toxicity study in rabbits at doses up to 50 mg/kg/d (approximately 0.1 times the MRHD based on AUC), this abnormality was not observed. 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/d (1.7, 3.4 and 6.8 times the MRHD based on mg/m2). 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, rimantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Nursing Mothers Rimantadine hydrochloride 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 (1 year to 16 years of age), rimantadine hydrochloride is recommended for the prophylaxis of influenza A. The safety and effectiveness of rimantadine hydrochloride in the treatment of symptomatic influenza infection in children (1 year to 16 years of age) have not been established. Prophylaxis studies with rimantadine hydrochloride have not been performed in children below the age of 1 year.