As with any overdose, supportive therapy should be administered as indicated. Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children (Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported anecdotally to be beneficial in patients with central nervous system effects from overdoses of amantadine.
Орвирем (rimantadine) is contraindicated in patients with known hypersensitivity to drugs of the adamantane class, including rimantadine and amantadine.
REFERENCES
7. Casey DE. N Engl J Med. 1978;298(9):516.
In 1,027 patients treated with Орвирем (rimantadine) 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 (1-3%) at the recommended dose in controlled clinical trials are shown in the table below.
| Rimantadine (n=1027) | 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 Орвирем (rimantadine). 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 | |||
| Insomnia | 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% |
Approximately 200 subjects over the age of 65 were evaluated for safety in controlled clinical trials with Орвирем (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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Орвирем (rimantadine) is indicated for the prophylaxis and treatment of illness caused by various strains of influenza A virus in adults (17 years and older).
Орвирем (rimantadine) is indicated for prophylaxis against influenza A virus in children (1 year to 16 years of age).
ProphylaxisIn 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), Орвирем (rimantadine) has been shown to be safe and effective in preventing signs and symptoms of infection caused by various strains of influenza A virus. Since Орвирем (rimantadine) 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, Орвирем (rimantadine) prophylaxis should be considered for the 2 to 4 week time period required to develop an antibody response. However, the safety and effectiveness of Орвирем (rimantadine) prophylaxis have not been demonstrated for longer than 6 weeks.
TreatmentОрвирем (rimantadine) 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, Орвирем (rimantadine) has been shown to reduce the duration of fever and systemic symptoms.
The following points should be considered before initiating treatment or prophylaxis with Орвирем (rimantadine) :
No information provided.
PRECAUTIONS GeneralAn increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine. In clinical trials of Орвирем (rimantadine) , 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 Орвирем (rimantadine). If seizures develop, Орвирем (rimantadine) 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. Орвирем (rimantadine) has not been shown to prevent such complications.
REFERENCES
3. Hayden FG, Belshe RB, Clover RD, et al. N Engl J Med. 1989;321(25):1696-1702.
4. Hall CB, Dolin R, Gala CL, et al. Pediatrics. 1987;80(2):275-282.
5. Thompson J, Fleet W, Lawrence E, et al. J Med Virol. 1987;21(3):249-255.
6. Belshe RB, Smith MH, Hall CB, et al. J Virol. 1988;62(5):1508-1512.
Carcinogenesis, Mutagenesis, And Impairment Of Fertility CarcinogenesisOral administration of rimantadine to rats for 2 years at doses up to 100 mg/kg/d [approximately 11- 14 times the maximum recommended human dose (MRHD) based on AUC] showed no evidence of increased tumor incidence.
MutagenesisNo mutagenic effects were seen when rimantadine was evaluated in several standard assays for mutagenicity.
Impairment of FertilityA reproduction study in male and female rats did not show detectable impairment of fertility at dosages up to 60 mg/kg/d (3 times the MRHD based on mg/m²).
PregnancyTeratogenic Effects: Pregnancy Category C. There are no adequate and wellcontrolled 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 was 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 EffectsRimantadine 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, Орвирем (rimantadine) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
Nursing MothersОрвирем (rimantadine) 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 UseIn children (1 year to 16 years of age), Орвирем (rimantadine) is recommended for the prophylaxis of influenza A. The safety and effectiveness of Орвирем (rimantadine) in the treatment of symptomatic influenza infection in children (1 year to 16 years of age) have not been established. Prophylaxis studies with Орвирем (rimantadine) have not been performed in children below the age of 1 year.
The recommended adult dose of Орвирем (rimantadine) is 100 mg twice a day. Study durations ranged from 11 days to 6 weeks in adult and elderly patients. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/min) and in elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects.
Children (1 year to 16 years of age)(see Directions for Compounding of an Oral Suspension from Орвирем (rimantadine) Tablets to prepare an oral suspension for administration to children and patients with difficulty swallowing tablets).
Children (Birth to 11 months)The safety and efficacy of Орвирем (rimantadine) for prophylaxis of influenza in pediatric patients younger than 1 year of age have not been established.
For Treatment In Adults Adults(17 years and older)The recommended adult dose of Орвирем (rimantadine) is 100 mg twice a day for 7 days. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects. Орвирем (rimantadine) therapy should be initiated as soon as possible, preferably within 48 hours after onset of signs and symptoms of influenza A infection. Therapy should be continued for approximately seven days from the initial onset of symptoms.
Children (16 years of age and younger)Орвирем (rimantadine) is not indicated for treatment of influenza in pediatric patients 16 years or younger.
Directions for the Compounding of an Oral Suspension from Орвирем (rimantadine) Tablets (Final Concentration = 10 mg/mL)1
These directions are provided for use only during emergency situations, for patients who have difficulty swallowing tablets or where lower doses are needed. The pharmacist may compound a suspension (10 mg/mL) from Орвирем (rimantadine HCl) Tablets, 100 mg using Ora-Sweet®.† Other vehicles have not been studied.
To make an oral suspension (10 mg/mL) from 100 mg Орвирем (rimantadine) tablets, you will need the following:
Compounding Procedures
A 100 mg tablet of Орвирем (rimantadine) is required for each 10 mL of compounded oral suspension to make a concentration of 10 mg/mL
A compounded oral suspension is stable for 14 days. Therefore, the maximum amount of oral suspension that can be dispensed to a patient should not exceed a 14 day supply.
Step A: Guidance for how to determine the Number of Tablets and Total Volume needed to compound a 10 mg/mL oral suspension for each patient
Step B: Once the total Number of Tablets and Volume are determined then follow the procedures below for compounding the oral suspension (10 mg/mL) from Орвирем (rimantadine) Tablets 100 mg
Verify your calculations before you begin to compound an oral suspension.
A 100 mg tablet of Орвирем (rimantadine) is required for each 10 mL's of compounded oral suspension to make a concentration of 10 mg/mL.
Labeling and Dispensing Information for the Compounded Oral Suspension
