Rimantadine Hydrochloride

Rimantadine hydrochloride tablet is indicated for the prophylaxis and treatment of illness caused by various strains of influenza A virus in adults (17 years and older). Rimantadine hydrochloride tablet is indicated for prophylaxis against influenza A virus in children (1 year to 16 years of age). Prophylaxis In controlled studies of children (1 year to 16 years of age), healthy adults (17 years and older), and elderly patients (65 years of age and older), rimantadine hydrochloride has been shown to be safe and effective in preventing signs and symptoms of infection caused by various strains of influenza A virus. Since rimantadine hydrochloride does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically-related viruses. Following vaccination during an influenza outbreak, rimantadine hydrochloride prophylaxis should be considered for the 2 to 4 week time period required to develop an antibody response. However, the safety and effectiveness of rimantadine hydrochloride prophylaxis have not been demonstrated for longer than 6 weeks. Treatment Rimantadine hydrochloride therapy should be considered for adults (17 years and older) who develop an influenza-like illness during known or suspected influenza A infection in the community. When administered within 48 hours after onset of signs and symptoms of infection caused by influenza A virus strains, rimantadine hydrochloride has been shown to reduce the duration of fever and systemic symptoms. The following points should be considered before initiating treatment or prophylaxis with rimantadine hydrochloride: Rimantadine hydrochloride is not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use rimantadine hydrochloride.

Rimantadine hydrochloride tablet is contraindicated in patients with known hypersensitivity to drugs of the adamantane class, including rimantadine and amantadine.

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 C max 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/m 2 ). Pregnancy Teratogenic Effects : 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/m 2 ). 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 mg/kg/d, 60 mg/kg/d and 120 mg/kg/d (1.7, 3.4 and 6.8 times the MRHD based on mg/m 2 ). 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.

In 1,027 patients treated with rimantadine hydrochloride in controlled clinical trials at the recommended dose of 200 mg daily, the most frequently reported adverse events involved the gastrointestinal and nervous systems. Incidence >1%: Adverse events reported most frequently (1 % to 3%) at the recommended dose in controlled clinical trials are shown in the table below. Rimantadine (n=1,027) Control (n=986) Nervous System Insomnia 2.1% 0.9% Dizziness 1.9% 1.1% Headache 1.4% 1.3% Nervousness 1.3% 0.6% Fatigue 1.0% 0.9% Gastrointestinal System Nausea 2.8% 1.6% Vomiting 1.7% 0.6% Anorexia 1.6% 0.8% Dry mouth 1.5% 0.6% Abdominal Pain 1.4% 0.8% Body as a Whole Asthenia 1.4% 0.5% Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were: Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia, somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus; Respiratory: dyspnea. Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination, confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation, hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia, syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia. Rates of adverse events, particularly those involving the gastrointestinal and nervous systems, increased significantly in controlled studies using higher than recommended doses of rimantadine hydrochloride. In most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse events reported above, the following were also reported at higher than recommended doses: increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation, diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain. Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436 healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions were reported with an incidence >1%. Rimantadine 200 mg/day (n=145) Placebo (n=143) Amantadine 200 mg/day (n=148) Nervous System Insomia 3.4% 0.7% 7.0% Nervousness 2.1% 0.7% 2.8% Impaired Concentration 2.1% 1.4% 2.1% Dizziness 0.7% 0.0% 2.1% Depression 0.7% 0.7% 3.5% Total % of subjects with adverse reactions 6.9% 4.1% 14.7% Total % of subjects withdrawn due to adverse reactions 6.9% 3.4% 14.0% Geriatric Use Approximately 200 patients over the age of 65 were evaluated for safety in controlled clinical trials with rimantadine hydrochloride. Geriatric subjects who received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably more central nervous system and gastrointestinal adverse events than comparable geriatric subjects receiving placebo. Central nervous system events including dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two times more often in subjects treated with rimantadine than in those treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain occurred at least twice as frequently in subjects receiving rimantadine than in those receiving placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 65, the recommended dose is 100 mg, daily (see CLINCAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 C max 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.

Teratogenic Effects : 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/m 2 ). 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 mg/kg/d, 60 mg/kg/d and 120 mg/kg/d (1.7, 3.4 and 6.8 times the MRHD based on mg/m 2 ). 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.

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.

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.

The mechanism of action of rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a virus protein specified by the virion M 2 gene plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine.