VA Class:AM800
Rimantadine hydrochloride, an adamantane derivative, is a synthetic antiviral agent1, 3, 10, 13, 15, 16, 40, 42 that is structurally related to amantadine and active against influenza A virus.2, 3, 4, 5, 8, 10, 15, 16, 17, 40, 42
Rimantadine hydrochloride has been used for the treatment and prophylaxis of infections caused by susceptible influenza A viruses.1, 2, 3, 4, 5, 7, 11, 15, 37, 39, 47, 59, 61
Treatment of Seasonal Influenza A Virus Infections
Rimantadine has been used for the treatment of influenza infections caused by susceptible influenza A viruses in adults 17 years of age or older.1, 2, 3, 4, 5, 7, 11, 13, 15, 37, 39, 47, 59, 61 Although safety and efficacy have not been established for the treatment of influenza in children 16 years of age or younger,1, 13 the drug has been used for the treatment of susceptible influenza A virus infections in some children†.6, 15, 37, 59
Beginning in the 2005-2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to adamantanes (amantadine, rimantadine),105, 116, 121 and resistance to amantadine and rimantadine among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.105, 112, 117, 144, 162, 551, 552 In addition, the influenza A (H1N1)pdm09 virus, previously referred to as the novel 2009 influenza A (H1N1) virus or swine-origin influenza A (H1N1) virus, that has circulated during recent influenza seasons is resistant to amantadine and rimantadine.52, 105, 112, 117, 144, 151, 162, 551, 552 Amantadine and rimantadine have little or no activity against influenza B.1, 11, 13, 15, 16, 35, 42, 551
The US Centers for Disease Control and Prevention (CDC) and other experts recommend that adamantanes (amantadine, rimantadine) not be used for the treatment of seasonal influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112, 144, 488
Viral surveillance data available from local and state health departments and the CDC should be considered when selecting an antiviral for treatment of seasonal influenza.112, 137, 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve.137, 144
The CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season.137, 144 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from the CDC at [Web].
When rimantadine has been used in otherwise healthy adults and children† for symptomatic treatment of uncomplicated seasonal influenza caused by susceptible influenza A virus and administered within 48 hours after the onset of symptoms, the drug has decreased viral shedding and reduced the degree and duration of fever, headache, and respiratory symptoms with a more rapid return to routine daily activities.1, 2, 3, 5, 11, 13, 15, 16, 33, 37, 61 The drug does not appear to be effective in preventing otologic manifestations of influenza A infection in adults.33, 63 It is not known whether rimantadine is effective for the symptomatic treatment of this infection in patients whose symptoms have been present for more than 48 hours since most controlled studies evaluating efficacy of the drug only included patients whose symptoms had been present for 48 hours or less.2, 3, 5 Some evidence suggests that symptomatic improvement during the initial 24 hours of therapy with usual dosages of rimantadine may be somewhat slower than that with amantadine, probably because of pharmacokinetic differences between the drugs.2, 5, 16, 42
There have been no well-controlled studies to date to determine the efficacy of rimantadine treatment in preventing serious complications of influenza A virus infection (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases).15, 39 Most studies evaluating efficacy of rimantadine for the treatment of influenza A infections have been performed in otherwise healthy adults and children with uncomplicated influenza; data are limited and inconclusive concerning efficacy of rimantadine for treatment of influenza in individuals at high risk for serious influenza-related complications.1, 2, 5, 6, 11, 13, 15, 16, 37
Rimantadine- and amantadine-resistant strains of influenza A virus may appear in up to approximately 33% of patients receiving the drugs for treatment of influenza A infection.15, 16, 39, 41, 42 Individuals with influenza A infection who are receiving rimantadine or amantadine antiviral treatment may shed strains of the virus that are susceptible to the drugs early in the course of treatment; however, they may shed resistant strains after 2-7 days of therapy.63 Although most patients recover uneventfully even after resistant strains emerge (because of host immune responses), resistant strains are pathogenic and transmissible and can result in failures of drug prophylaxis in close contacts (e.g., family members, nursing home contacts).9, 11, 39, 40, 41, 42, 63 Immunocompromised patients may shed resistant strains for prolonged periods.44, 63 Individuals with influenza-like illness should be separated from and avoid contact with uninfected individuals as much as possible, regardless of whether they are receiving antiviral therapy.8, 40
Prevention of Seasonal Influenza A Virus Infections
Rimantadine has been used for prophylaxis of influenza infection caused by susceptible influenza A viruses in adults, adolescents, and children 1 year of age or older.1, 2, 3, 4, 5, 7, 11, 13, 15, 37, 39, 47, 59, 61
Annual vaccination with seasonal influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.1, 13, 100, 105, 112, 116, 144, 488 Prophylaxis with an appropriate antiviral agent active against circulating influenza strains is considered an adjunct to vaccination for the control and prevention of influenza in certain individuals.1, 13, 105, 112, 116, 144, 488
The CDC and other experts recommend that adamantanes (amantadine, rimantadine) not be used for prevention of seasonal influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112, 144, 488
Viral surveillance data available from local and state health departments and the CDC should be considered when selecting an antiviral for the prophylaxis of influenza.112, 137, 488 The most appropriate antiviral for prevention of influenza is selected based on information regarding the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.137, 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve.137, 144
The CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.137, 144 Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from the CDC at [Web].
Controlled studies in children (1-16 years of age),1, 4, 7, 13, 16 adults (17 years of age or older),1, 3, 16 and geriatric individuals (65 years of age or older)1, 8, 13, 16, 47 have shown rimantadine to be effective in preventing influenza caused by susceptible influenza A;1, 11, 13, 16 limited evidence indicates that a protective effect is achieved in up to 90% of individuals who receive the drug throughout an influenza A outbreak.3, 7, 16
Clinical studies indicate that rimantadine is as effective as amantadine3, 7, 11, 13, 16 or influenza vaccination11 in preventing seasonal influenza A illness. The protective effect of rimantadine or amantadine and influenza vaccination may be additive.39, 40, 47 In contrast to results of studies evaluating efficacy when antiviral prophylaxis is given for a season or part of a season, results of studies evaluating antiviral prophylaxis with amantadine or rimantadine after known exposure have not been consistent.9, 11, 41, 42 While postexposure prophylaxis with rimantadine or amantadine provided protection in families when the index case did not receive antiviral therapy, the drugs did not provide protection from influenza A infection in household contacts when rimantadine or amantadine was used to treat the index case, presumably because of spread of resistant virus within the household.9, 11, 39, 40, 41, 42
Avian Influenza A Virus Infections
Adamantane derivatives (amantadine, rimantadine) have been recommended as alternatives for the treatment or prophylaxis of avian influenza A virus infections† in certain situations.94
The CDC and World Health Organization (WHO) recommend use of a neuraminidase inhibitor (oseltamivir, zanamivir) for the treatment or prophylaxis of avian influenza A infections.50, 94, 104 If neuraminidase inhibitors are unavailable, use of amantadine or rimantadine might be considered an alternative if local surveillance data indicate that the strain is known or likely to be susceptible.94 Avian influenza A (H5N1) and avian influenza A (H7N9) generally have been resistant to the adamantane derivatives.50, 94, 104
For information on treatment or prevention of avian influenza A virus infection, see Uses: Avian Influenza A Virus Infections in Oseltamivir 8:18.28.
Rimantadine hydrochloride is administered orally.1, 13
Rimantadine hydrochloride is commercially available as tablets containing 100 mg of the drug.1, 13
For use only during emergency situations for patients who cannot swallow tablets or when lower dosage is needed, rimantadine hydrochloride oral suspensions containing 10 mg/mL can be prepared extemporaneously using the 100-mg tablets of the drug.1, 13 The manufacturer's information should be consulted for specific directions on how to prepare extemporaneous oral suspensions of the drug.1, 13
Treatment of Seasonal Influenza A Virus Infections
For the treatment of influenza caused by susceptible influenza A viruses, the usual dosage of rimantadine hydrochloride in adults 17-64 years of age is 100 mg twice daily for 7 days.1, 13 The drug should be initiated as soon as possible, preferably within 48 hours after the onset of symptoms.1, 13
Prevention of Seasonal Influenza A Virus Infections
For prophylaxis of influenza caused by susceptible influenza A viruses, the usual dosage of rimantadine hydrochloride in adults 17-64 years of age is 100 mg twice daily.1, 13
The duration of rimantadine prophylaxis in clinical studies ranged from 11 days to 6 weeks.1, 13 The safety and efficacy of rimantadine prophylaxis given for longer than 6 weeks have not been determined.1, 13
Treatment of Seasonal Influenza A Virus Infections
For the treatment of influenza caused by susceptible influenza A viruses in geriatric adults 65 years of age or older, including those residing in nursing homes, rimantadine hydrochloride should be given in a dosage of 100 mg daily for 7 days.1, 13 Some clinicians suggest that a dosage of 100 mg twice daily can be considered for adults 65 years of age or older who reside in the community, but should be reduced to 100 mg daily if adverse effects occur with the higher dosage.144 The drug should be initiated as soon as possible, preferably within 48 hours after the onset of symptoms.1, 13
Prevention of Seasonal Influenza A Virus Infections
For prophylaxis of influenza caused by susceptible influenza A viruses in adults 65 years of age or older, the usual dosage of rimantadine hydrochloride is 100 mg daily.1, 13, 144
The duration of rimantadine prophylaxis in clinical studies ranged from 11 days to 6 weeks.1, 13 The safety and efficacy of rimantadine prophylaxis given for longer than 6 weeks have not been determined.1, 13
Treatment of Seasonal Influenza A Virus Infections
For the treatment of influenza caused by susceptible influenza A viruses in children 13 years of age or older†, the American Academy of Pediatrics (AAP) recommends that rimantadine hydrochloride be given in a dosage of 100 mg twice daily.105 The manufacturers state that rimantadine is not indicated for the treatment of influenza in pediatric patients 16 years of age or younger.1, 13
Prevention of Seasonal Influenza A Virus Infections
For prophylaxis of influenza caused by susceptible influenza A viruses, the usual dosage of rimantadine hydrochloride in children 1-9 years of age is 5 mg/kg (up to 150 mg) once daily.1, 13, 105 Children 10 years of age or older should receive a dosage of 100 mg twice daily for prophylaxis of influenza;1, 13, 105 however, the AAP suggests that a dosage of 5 mg/kg (up to 150 mg) daily be used in those who weigh less than 40 kg.105
The duration of rimantadine prophylaxis in children in clinical studies ranged from 5-6 weeks.1, 13 The safety and efficacy of rimantadine prophylaxis given for longer than 6 weeks have not been determined.1, 13
Dosage in Renal and Hepatic Impairment
Unlike amantadine, which is eliminated unchanged, rimantadine is extensively metabolized in the liver.1, 11, 13, 15, 16, 40, 55 Because of potential accumulation of rimantadine and/or its metabolites in plasma, the drug should be used with caution in patients with hepatic impairment and such patients should be monitored for adverse effects.1, 13 If rimantadine hydrochloride is used in patients with severe hepatic impairment, dosage should be reduced to 100 mg daily.1, 13, 144
Because of potential accumulation of rimantadine and/or its metabolites in plasma, the drug should be used with caution in patients with renal impairment and such patients should be monitored for adverse effects.1, 13 If rimantadine hydrochloride is used in patients with severe renal impairment (creatinine clearance 5-29 mL/minute) or renal failure (creatinine clearance 10 mL/minute or less), dosage should be reduced to 100 mg daily.1, 13, 144
Rimantadine generally is well tolerated, although serious adverse effects have been reported rarely.1, 2, 3, 4, 5, 6, 7, 9, 13, 17, 18, 37, 40, 42, 47, 53 The most frequently reported adverse effects with rimantadine are similar to those observed with amantadine and include adverse CNS and GI effects; however, rimantadine is associated with less frequent and/or severe nervous system effects than amantadine, including in geriatric adults.1, 2, 3, 8, 11, 13, 16, 17, 18, 19, 40, 47, 63
Adverse effects associated with rimantadine usually are mild and are reversible upon discontinuance of the drug.3, 17 In some patients, adverse effects may subside or disappear after the first week despite continued therapy with the drug.17 The incidence of adverse effects (e.g., CNS and GI effects) reported in geriatric patients receiving rimantadine or placebo in clinical studies has been higher than the incidence in younger adults or children.47, 53, 144
Insomnia,1, 3, 13, 40, 47, 53 nervousness/jitteriness,1, 3, 9, 13, 40, 47, 53 dizziness/lightheadedness,1, 3, 19, 40, 47, 53 or impaired concentration1, 3, 13, 47 has been reported in 2.1-3.4, 1.3-2.1, 0.7-1.9, or 2.1% of patients, respectively, receiving the recommended dosage of rimantadine hydrochloride (200 mg daily) in clinical studies.1, 13 Such CNS effects generally resolve within 48 hours after discontinuance of the drug.3 Headache,1, 13, 19, 40, 47 asthenia,1, 47 fatigue,1, 13, 19, 47, 53 or depression1, 9, 13, 47, 53 occurred in 1.4, 1.4, 1, or 0.7% of patients, respectively, in these studies.1, 13 Ataxia,1, 13 somnolence,1, 13 or agitation1, 13 has occurred in 0.3-1% of patients receiving rimantadine in clinical studies.1 Adverse nervous system effects reported in less than 0.3% of patients in clinical studies include gait abnormalities,1 euphoria,1 hyperkinesia,1, 13 tremor,1, 13 hallucinations,1, 13 or confusion.1, 13, 47, 53 Agitation1, 13 and hypesthesia1, 13 have occurred in patients receiving rimantadine dosages exceeding the recommended dosage.1, 13
Seizures or seizure-like activity has been reported in a few patients with a history of seizure disorder who were receiving rimantadine but whose anticonvulsant therapy had been withdrawn.1, 13, 40, 61 Seizures have occurred rarely in nursing home residents receiving rimantadine.40, 47 (See Cautions: Precautions and Contraindications.)
Adverse CNS effects (e.g., nervousness, anxiety, impaired concentration, lightheadedness) are less common with usual dosages of rimantadine than amantadine, probably in part because of differences in the pharmacokinetics of the drugs.2, 3, 8, 11, 16, 17, 18, 19, 40 In a 6-week study of daily 200-mg prophylactic doses of rimantadine hydrochloride or amantadine hydrochloride in healthy adults, about 6 or 13% of patients receiving the respective drug discontinued therapy because of adverse CNS effects versus about 4% of those receiving placebo.3, 63 While neuropsychiatric (e.g., delirium, marked behavioral changes) or psychomotor dysfunction has occurred in patients receiving amantadine, these effects have not been reported in patients receiving rimantadine.17, 18, 19, 40
While the type of adverse CNS effects reported in rimantadine-treated geriatric individuals is similar to that in younger adults, these adverse effects occur more frequently in geriatric individuals.47 In controlled studies in patients 65 years of age or older receiving rimantadine hydrochloride 200 or 400 mg daily or placebo for 1-50 days, CNS effects including dizziness, headache, anxiety, asthenia, and fatigue, occurred up to 2 times more often in geriatric individuals receiving rimantadine than in those receiving placebo.1, 13 Nursing home residents, a group with many underlying medical problems, may be particularly susceptible to adverse CNS effects.47, 63
Nausea1, 3, 9, 13, 37, 47, 53 is one of the most frequent adverse GI effects of rimantadine and has been reported in about 3% of patients receiving the usual dosage (200 mg daily) of the drug.1, 13 Vomiting,1, 9, 13, 37, 47, 53 anorexia,1, 13, 47, 53 dry mouth,1, 13, 19, 47 or abdominal pain1, 9, 13, 47 has occurred in 1-2% of patients receiving the drug in the recommended dosage.1, 13 Adverse GI effects reported in 0.3-1% of patients include diarrhea1, 13 or dyspepsia.1, 13 Dysphagia1, 13 or stomatitis1, 13 has occurred in patients receiving rimantadine dosages exceeding the recommended dosage.1, 13 The incidence of adverse GI effects is comparable for rimantadine and amantadine.3, 40, 42
Nursing home residents may be particularly susceptible to adverse GI effects of rimantadine or amantadine.47, 63 In controlled studies in patients 65 years of age or older receiving rimantadine 200 or 400 mg daily or placebo for 1-50 days, adverse GI effects (nausea, vomiting, abdominal pain) occurred at least twice as frequently in geriatric individuals receiving rimantadine compared with the incidence in those receiving placebo.1, 13 The GI effects appeared to be dose related.1, 13
Rash,1, 3, 9, 13, 47 tinnitus,1, 13 or dyspnea1, 13 has occurred in 0.3-1% of patients receiving rimantadine.1, 13
Adverse effects reported in less than 0.3% of patients include bronchospasm,1, 13 cough,1, 13 pallor,1, 13 palpitation,1, 13 hypertension,1, 13 cerebrovascular disorder,1, 13 cardiac failure,1, 13 pedal edema,1, 13 heart block,1, 13 tachycardia,1, 13 syncope,1, 13 nonpuerperal lactation,1, 13 alteration in taste,1, 13 or parosmia.1, 13
Increased lacrimation,1, 13 increased micturition frequency,1, 13 fever,1, 13 rigor,1, 13 diaphoresis,1, 13 or ocular pain1, 13 has been reported in patients receiving rimantadine dosages exceeding the recommended dosage.1, 13
Precautions and Contraindications
Rimantadine is contraindicated in patients with known hypersensitivity to adamantane derivatives (i.e., amantadine, rimantadine).1, 13
Rimantadine should be discontinued if seizures develop.1, 13 The effect of rimantadine therapy on the incidence of seizures in patients with seizure disorders has not been fully evaluated.144 Seizure-like activity has been reported rarely when rimantadine was used in patients with a history of seizures who were not receiving anticonvulsants.1, 13 In addition, an increased incidence of seizures has been reported when amantadine was used in patients with a history of epilepsy.1, 13
Because viral surveillance data indicate that the majority of seasonal influenza A (H3N2) and influenza A (H1N1)pdm09 viruses circulating during recent influenza seasons have been resistant to adamantanes (amantadine, rimantadine),105, 112, 144, 488, 551, 552 the US Centers for Disease Control and Prevention (CDC) and other experts state that amantadine and rimantadine should not be used for the treatment or prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112, 144, 488
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.1, 13 There is no evidence that rimantadine prevents such complications.1, 13
Unlike amantadine, which is eliminated unchanged, rimantadine is extensively metabolized in the liver.1, 11, 13, 15, 16, 42 Because of potential accumulation of rimantadine and/or its metabolites in plasma, the drug should be used with caution in patients with hepatic impairment and such patients should be monitored for adverse effects.1, 13 In addition, reduced dosage should be used in those with severe hepatic impairment.1, 13 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Rimantadine should be used with caution in patients with renal impairment and such patients should be monitored for adverse effects.1, 13 In addition, reduced dosage should be used in those with severe renal impairment (creatinine clearance 5-29 mL/minute) or renal failure (creatinine clearance 10 mL/minute or less).1, 13 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
The manufacturers state that safety and efficacy of rimantadine hydrochloride for the treatment of influenza A virus infection have not been established in children 16 years of age or younger.1, 13 The drug has been used for the treatment of influenza A infection in a limited number of children 1-15 years of age†; results of these studies suggest that safety and efficacy of rimantadine in this age group are similar to those in adults.37, 59, 61
Safety and efficacy of rimantadine hydrochloride for prophylaxis of influenza A virus infection have not been established in children younger than 1 year of age.1, 13
Safety and efficacy of rimantadine have been evaluated in controlled clinical studies in approximately 200 individuals 65 years of age or older.1, 13, 47, 53 When rimantadine hydrochloride is given in a dosage of 200 mg daily, the incidence of CNS and GI effects reported in elderly chronically ill adults is higher than that reported in younger healthy adults.144 Among older patients, the incidence and severity of CNS effects appear to be lower in those receiving rimantadine hydrochloride in a dosage of 100 mg daily than in those receiving amantadine at dosages adjusted for estimated renal clearance.144
Because geriatric patients may have decreased renal function and may be at increased risk of rimantadine-induced toxicity, reduced rimantadine hydrochloride dosage usually is recommended for this age group, especially for elderly nursing home patients.1, 13, 144 (See Dosage: Geriatric Dosage.)
Mutagenicity and Carcinogenicity
Rimantadine was not mutagenic in several standard assays for mutagenicity.1, 13
There was no evidence of increased tumor incidence in a 2-year study in rats using oral rimantadine doses up to 100 mg/kg daily (approximately 11-14 times the maximum recommended human dose [MRHD] based on area under the plasma concentration-time curve [AUC]).1, 13
Pregnancy, Fertility, and Lactation
There are no adequate and well-controlled studies using rimantadine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1, 13
Rimantadine hydrochloride has been reported to be embryotoxic (i.e., increased fetal resorption) in rats when administered in a dosage of 200 mg/kg daily (11 times the MRHD based on mg/m2); this dose also was associated with several maternal effects including ataxia, tremor, seizures, and substantially reduced weight gain.1, 13 In rabbits, developmental abnormality (i.e., change in the ratio of fetuses with 12 or 13 ribs) was observed with rimantadine hydrochloride dosages of 50 mg/kg daily (approximately 0.1 times the MRHD based on AUC), but embryotoxicity was not observed and this abnormality did not occur when a repeat embryofetal toxicity study was performed using the same dosage.1, 13 Reproductive studies in rats given rimantadine hydrochloride dosages of 30, 60, or 120 mg/kg daily (1.7, 3.4, or 6.8 times the MRHD based on mg/m2) during the perinatal and postnatal period have shown an increase in pup mortality during the first 2-4 days postpartum in rats given the 120-mg/kg daily dosage, and maternal toxicity during gestation in rats given the 60- or 120-mg/kg daily dosage.1, 13
There was no evidence of impaired fertility in a reproduction study in male and female rats using rimantadine hydrochloride dosages up to 60 mg/kg daily (3 times the MRHD based on mg/m2).1, 13 Decreased fertility in the F1 generation was reported when female rats received 60 or 120 mg/kg daily during the perinatal and postnatal period.1, 13
Rimantadine hydrochloride should not be used in nursing women.1, 13 Studies in rats indicate that rimantadine is distributed into milk and adverse effects have been noted in offspring of rats given the drug during the nursing period.1, 13
Concomitant use of rimantadine hydrochloride (100 mg twice daily) and acetaminophen (650 mg 4 times daily) in healthy adults reduced the peak plasma concentration and area under the plasma concentration-time curve (AUC) of rimantadine by approximately 11%.1, 13
Concomitant use of rimantadine hydrochloride (100 mg twice daily) and aspirin (650 mg 4 times daily for 8 days) reduced the peak plasma concentration and AUC of rimantadine by approximately 10%.1, 13
Concomitant use of rimantadine hydrochloride (single 100-mg dose) and cimetidine (300 mg 4 times daily) in healthy adults did not have a clinically important effect on peak plasma concentrations or AUC of rimantadine.1, 13, 62
Rimantadine hydrochloride does not interfere with the antibody response to influenza virus vaccine inactivated (IIV),1, 13 and the vaccine may be administered concomitantly with or at any time before or after rimantadine.1, 13, 100
Safety and efficacy of concomitant use of influenza vaccine live intranasal (LAIV) and rimantadine have not been studied.1, 13, 100 Because influenza antiviral agents reduce replication of influenza viruses and may inhibit the vaccine virus, LAIV should not be administered until at least 48 hours after rimantadine is discontinued and rimantadine should not be administered until at least 2 weeks after administration of LAIV, unless medically indicated.1, 13, 100 If rimantadine is administered within 2 weeks after LAIV, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) recommends that the LAIV dose be repeated 48 hours or more after the last dose of the antiviral agent.100 Alternatively, individuals who received rimantadine 2 days before to 14 days after LAIV may be revaccinated with either IIV or influenza vaccine recombinant (RIV).100
Limited information is available on the acute toxicity of rimantadine.1, 13
Acute overdosage of a related drug, amantadine, has resulted in agitation, hallucinations, cardiac arrhythmia, and death.1, 13, 64 The possibility that similar effects might occur with rimantadine overdosage should be considered.1, 13, 64
If acute overdosage of rimantadine occurs, supportive and symptomatic treatment should be initiated and the patient closely observed.1 The patient should be observed for seizures.1, 13, 40, 61, 64 Rimantadine is not removed by hemodialysis.1, 13, 20
The manufacturers1, 13 of rimantadine state that IV administration of physostigmine salicylate has been effective in the management of CNS toxicity caused by amantadine.1, 13, 64 However, the risks of physostigmine therapy as an antidote should be considered. (See Physostigmine Salicylate 12:04.)
The exact mechanism of the antiviral activity of rimantadine has not been fully elucidated.1, 13, 16, 40, 46, 57
Rimantadine, like amantadine, inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein.1, 13, 11, 15, 16, 41, 42, 46 The M2 protein of influenza A functions as an ion channel and is important in at least 2 aspects of virus replication, disassembly of the infecting virus particle and regulation of the ionic environment of the transport pathway.15, 16, 41, 42, 46 By interfering with the ion channel function of the M2 protein, rimantadine inhibits 2 stages in the replicative cycle of influenza A.11, 15, 16, 41, 42, 46 Early in the virus reproductive cycle, rimantadine inhibits uncoating of the virus particle, presumably by inhibiting the acid-mediated dissociation of the virion nucleic acid and proteins, which prevents nuclear transport of viral genome material.11, 15, 16, 41, 42, 43, 63 Rimantadine also prevents viral maturation in some strains of influenza A (e.g., H7 strains) by promoting pH-induced conformational changes in influenza A hemagglutinin during its intracellular transport late in the replicative cycle.15, 16, 41, 42, 43, 46, 63 Adsorption of the virus to and penetration into cells do not appear to be affected by rimantadine.42, 43, 45, 46 In addition, rimantadine does not interfere with the synthesis of viral components (e.g., RNA-directed RNA polymerase activity).43, 45
Rimantadine treatment of established influenza A infection does not appear to interfere with antibody response to the infection; however, some reduction in local immune responses has been observed in some patients.16, 33, 40, 42, 58 Because prophylactic use of rimantadine can prevent influenza illness and to a lesser extent subclinical infection, some individuals who take rimantadine can still develop immune responses that may protect them when they are exposed to the same or antigenically related viruses following discontinuance of rimantadine prophylaxis.1, 63 Rimantadine does not interfere with the immunogenicity of influenza A virus vaccine inactivated.1, 13 (See Influenza Virus Vaccines under Drug Interactions.)
Rimantadine-mediated increases in lysosomal pH may inhibit virus-induced membrane fusion in enveloped RNA viruses that are susceptible to higher concentrations of rimantadine than those required to inhibit influenza A.16
Unlike amantadine, rimantadine does not exhibit antiparkinsonian activity.17
Rimantadine shares the antiviral spectrum of activity of amantadine.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 42, 43, 45 Cell culture studies have shown that low concentrations of rimantadine (i.e., less than 1 mcg/mL) produce an inhibitory action against susceptible influenza A, including susceptible strains of H1N1, H2N2, and H3N2.1, 4, 5, 11, 12, 13, 16, 42, 45
Prior to the 2005-2006 influenza season, most influenza A (H3N2) strains circulating in the US were susceptible to adamantanes (amantadine, rimantadine).105, 116, 121 In addition, amantadine and rimantadine were active against most seasonal influenza A (H1N1) viruses circulating in the US during the 2008-2009 and 2009-2010 influenza seasons.117, 139, 162 However, seasonal influenza A (H3N2) and influenza A (H1N1)pdm09 viruses circulating during recent influenza seasons have been resistant to these drugs.52, 117, 139, 144, 151, 162, 551, 552 (See Resistance.)
Although some strains of avian influenza A H5N1 may be susceptible to rimantadine in vitro,38, 39 most avian influenza A virus strains tested (including H5N1 and H7N9) have been resistant to amantadine and rimantadine.50, 76, 104
The precise relationship between in vitro susceptibility of influenza A virus to rimantadine and clinical response to therapy with the drug has not been determined.1, 13 Results of several in vitro studies indicate that rimantadine is more active on a weight basis than amantadine.10, 15, 16, 42
Genetic studies indicate that the amino acid sequence in the transmembrane portion of the M2 protein of influenza A virus influences susceptibility of the virus to rimantadine and amantadine.1, 10, 13, 15, 16, 42, 43, 46 Single amino acid changes in a critical transmembrane region of the M2 protein are associated with antiviral resistance to the drugs, providing further evidence of the importance of this domain in the protein as a target site for antiviral activity.1, 10, 11, 13, 15, 16, 40, 41, 42, 43, 46 There is some evidence that susceptibility of certain strains (e.g., H7) may be influenced by gene coding for the viral hemagglutinin.46
Rimantadine generally is inactive against influenza B at concentrations that inhibit influenza A.1, 11, 13, 15, 16, 35, 42 At very high concentrations (10-50 mcg/mL), the drug exhibits some in vitro activity against influenza B and other enveloped viruses (e.g., parainfluenzae, respiratory syncytial virus), but this activity is not considered clinically relevant because of the relatively high, potentially toxic doses that would be required.11, 16, 42
Strains of influenza A resistant to rimantadine have been produced in vitro, and rimantadine-resistant strains have emerged during treatment with the drug.1, 6, 8, 9, 10, 11, 12, 13, 41, 42, 43, 46
Resistance to adamantane-derivative antivirals can result from point mutations in the viral RNA segment 7 encoding the M2 protein that leads to amino acid alterations at residue 31 or nearby positions in the transmembrane portion of the M2 protein of the virus.6, 8, 9, 10, 11, 12, 16, 41, 42, 43, 46, 48 However, substitutions at any one of 5 amino acid positions in the transmembrane domain of influenza A M2 confer resistance to rimantadine.1, 13 The most common substitution causing resistance among influenza A (H1N1) and A (H3N2) is S31N.1, 13 Other less common substitutions causing resistance include substitutions A30F, V27A, V30A, and L26F.1, 13
Although the frequency with which resistant strains emerge and the extent of their transmission have not been elucidated fully,1, 6, 8, 10, 13, 41, 42, 43 limited evidence suggests that following treatment with rimantadine in immunocompetent patients infected with initially susceptible strains of influenza A, 10-30% will shed rimantadine-resistant virus.1, 6, 9, 11, 13, 41, 42, 43 Limited information is available on the emergence of drug-resistant influenza A virus in immunocompromised patients receiving rimantadine or amantadine; isolates recovered from immunocompromised patients (adult bone marrow transplant recipients, adults with leukemia) who shed virus for longer than 3 days have been screened for antiviral susceptibility.44 While initial viral isolates were susceptible to rimantadine or amantadine, subsequent isolates from almost all of the patients were resistant.44 Rimantadine resistance also has been reported in clinical isolates of circulating seasonal influenza strains obtained from individuals who have not received rimantadine.1, 13
Results of a study that screened circulating influenza A viruses obtained from various countries between 1994 and 2005 indicated a substantial increase in the percentage of amantadine- and rimantadine-resistant influenza A H3N2 isolates in the US and Asia (China, Hong Kong, Taiwan, South Korea).84 In Asia, the incidence of such resistance was 1.1% in both 1995 and 2000 and increased to 24.3% in 2003 and 27% in 2004.84 In the US, the incidence of such resistance was 0.3% in 1995, 1.6% in 2000, and 1.9% in 2004; however, about 15% of influenza A H3N2 strains obtained in the US from October 2004 to March 2005 were resistant to amantadine and rimantadine.84 Most strains of seasonal influenza A (H3N2) circulating in the US during the 2005-2006 influenza season contained the amino acid alteration associated with resistance to amantadine and rimantadine.121 Data from subsequent influenza seasons indicate that the incidence of resistance to adamantanes among influenza A (H3N2) isolates remains high.93, 117, 162, 551, 552
Although amantadine and rimantadine were active against most seasonal influenza A (H1N1) viruses circulating in the US during the 2008-2009 and 2009-2010 influenza seasons,117, 139, 162 the influenza A (H1N1)pdm09 virus circulating during recent influenza seasons is resistant to amantadine and rimantadine.52, 105, 117, 144, 151, 162, 551, 552
Complete cross-resistance occurs between the adamantanes; influenza A viruses resistant to rimantadine are resistant to amantadine and vice versa.1, 9, 10, 13, 16, 41, 42, 43, 46, 48
The pharmacokinetics of rimantadine hydrochloride have been studied in children, healthy adults, and geriatric adults.1, 13, 14, 18, 21, 40, 49, 51, 53, 54, 55, 56, 60 The pharmacokinetics of the drug also have been evaluated in a limited number of patients with renal or hepatic impairment.1, 13, 20, 22, 40
The pharmacokinetic profile of rimantadine is characterized by relatively low plasma drug concentrations but high and persistent rimantadine concentrations in respiratory secretions (e.g., nasal secretions), and extensive metabolism in the liver.1, 13, 40, 49, 51, 54 A correlation between plasma rimantadine concentrations and antiviral activity has not been established,1, 13 although there is some evidence of a relationship between plasma concentrations and adverse effects, albeit exhibiting considerable interindividual variation.18
Rimantadine hydrochloride is well absorbed following oral administration with peak plasma concentrations generally occurring within 6 hours in healthy adults.1, 13, 14, 40, 49, 51 Presence of food in the GI tract does not affect the rate or extent of absorption.1, 13, 14
Following oral administration of a single 100-mg dose of rimantadine hydrochloride in healthy adults, peak plasma concentrations averaged 74 ng/mL (range: 45-138 ng/mL).1, 13, 49 Following oral administration of rimantadine hydrochloride 100 mg twice daily for 10 days in healthy adults 18-43 years of age, peak plasma concentrations averaged 416 ng/mL on day 10 and trough concentrations ranged from 175-422 ng/mL on day 5.49 Following oral administration of rimantadine hydrochloride 100 mg twice daily for 9.5 days in healthy adults 50-60 years of age (mean creatinine clearance 95 mL/minute), 61-70 years of age (mean creatinine clearance 88 mL/minute), or 71-79 years of age (mean creatinine clearance 79 mL/minute), peak plasma concentrations averaged 417, 401, or 538 ng/mL, respectively, after the last dose on day 10.54 Trough concentrations averaged 292, 275, or 368 ng/mL, respectively, on day 5 when they had reached relatively constant values.54 With multiple dosing, peak plasma concentrations after the last dose were almost 5 times those after the first dose.54 Results of this study did not reveal substantial age-related differences in the pharmacokinetics of rimantadine; however, geriatric patients frequently have decreased renal function, and peak plasma rimantadine concentration and area under the concentration-time curve (AUC) in individuals 50-79 years of age appear to be related to creatinine clearance.1, 13, 54 Substantial increases in peak plasma concentrations (i.e., 2- to 4-fold) have been reported in nursing home residents receiving rimantadine.1, 13, 53 In one study, steady-state plasma concentrations in nursing home residents (68-102 years of age) receiving rimantadine hydrochloride 100 mg twice daily averaged 1159 ng/mL.53
Following oral administration of rimantadine hydrochloride 100 mg twice daily in healthy adults, steady-state plasma concentrations are achieved by day 5.40, 49, 54 AUC values following administration of rimantadine hydrochloride 100 mg twice daily for 10 days in individuals 18-70 years of age are about 30% greater than values predicted from single-dose studies.1, 13
Following oral administration of a single 6.6-mg/kg dose of rimantadine hydrochloride in a limited number of children 4-8 years of age, plasma concentrations averaged 657 ng/mL (range: 446-988 ng/mL) at 5-6 hours, and 300 ng/mL (range: 170-424 ng/mL) at 24 hours.1, 13, 60
In a pharmacokinetic study in healthy geriatric adults, steady-state peak plasma concentrations, average AUC, and elimination half-life were 20-30% higher in those 71-79 years of age compared with adults 50-71 years of age.1, 13 In addition, steady-state concentrations in geriatric nursing home patients 68-102 years of age were twofold to fourfold higher than those reported in healthy young and geriatric adults.1, 13
In a limited number of adults with chronic liver disease (e.g., stabilized cirrhosis) receiving a single 200-mg dose of rimantadine hydrochloride, peak plasma concentrations and AUCs were essentially the same as those in healthy adults.1, 13, 22, 40 However, AUCs were increased threefold in adults with severe hepatic dysfunction compared with those in healthy adults.1, 13
In individuals with renal impairment who received 100 mg of rimantadine hydrochloride twice daily for 14 days, the peak plasma concentrations and AUC were not appreciably affected in those with mild or moderate renal impairment (creatinine clearance 30-80 mL/minute), but peak plasma concentrations were 75% higher and the AUC was 81% higher in those with severe renal impairment (creatinine clearance 5-29 mL/minute) compared with healthy adults.1, 13
Distribution of rimantadine hydrochloride into body tissues and fluids has not been fully characterized.40, 63 Following oral administration, rimantadine is distributed into nasal secretions in concentrations 50% higher than plasma concentrations.40, 51, 54 In one study in adults 51-79 years of age receiving rimantadine hydrochloride 100 mg twice daily for 9.5 days, steady-state trough rimantadine concentration in nasal secretions or plasma averaged 465 or 310 ng/mL, respectively.40, 54 Rimantadine has been detected in CSF in animals.40 Rimantadine is about 40% bound to plasma proteins, mainly albumin.1, 13, 40
It is not known whether rimantadine crosses the placenta in humans; placental transfer of the drug has been demonstrated in mice.1, 13 While it is not known whether rimantadine is distributed into human milk, the drug is distributed into milk in rats.1, 13
Rimantadine hydrochloride is metabolized extensively in the liver to at least 3 hydroxylated metabolites.1, 13, 40, 55 These have been designated as conjugated and unconjugated 3-, 4α-, and 4β-hydroxylated metabolites.40, 55 A glucuronide conjugate of rimantadine also has been identified.40, 55 In healthy adults, about 74% of a single 200-mg oral dose was excreted in urine within 72 hours as metabolites and unchanged drug.1, 13, 40, 55 Less than 25% of an oral dose is excreted in urine unchanged.1, 13, 40
The plasma elimination half-life of rimantadine following oral administration averages 25-38 hours in adults and children with normal renal and hepatic function.1, 13, 40, 49, 51, 54, 60
While the plasma elimination half-life following a single 200-mg dose of rimantadine hydrochloride in individuals with chronic liver disease (e.g., stabilized cirrhosis) is not appreciably affected compared with healthy individuals, the plasma elimination half-life in those with severe liver disease is prolonged approximately twofold and the apparent clearance is about 50% lower compared with healthy individuals.1, 13
In individuals with renal impairment who received 100 mg of rimantadine hydrochloride twice daily for 14 days, the plasma elimination half-life was only slightly prolonged (18% or less) in those with mild or moderate renal impairment (creatinine clearance 30-80 mL/minute), but was increased by 49% in those with severe renal impairment (creatinine clearance 5-29 mL/minute).1, 13
Following a single 200-mg dose of rimantadine hydrochloride in 8 hemodialysis patients (creatinine clearance 0-10 mL/minute), the plasma elimination half-life was increased 1.6-fold (44 versus 28 hours) and apparent clearance decreased 40% compared with healthy individuals.1, 13, 20, 40
Rimantadine is not removed by hemodialysis.1, 13, 20
Rimantadine hydrochloride is a synthetic adamantane-derivative (a symmetric tricyclic amine) antiviral agent.1, 3, 10, 13, 15, 16, 40, 42 Rimantadine is structurally related to amantadine, differing only in the side chain of the 10 carbon ring.2, 3, 4, 5, 8, 10, 13, 15, 16, 17, 40, 42 While the structure-activity relationship of the adamantanes remains to be determined, the octanol/water coefficient for rimantadine is substantially higher than that for amantadine.10, 40, 43
Rimantadine hydrochloride occurs as a white to off-white crystalline powder and has solubilities of 50 mg/mL in water at 20°C.1, 13
Depending on the manufacturer, commercially available rimantadine hydrochloride tablets should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.1, 13
Oral suspensions of rimantadine hydrochloride containing 10 mg/mL prepared extemporaneously using 100-mg tablets of the drug (see Dosage and Administration: Administration) may be stored at room temperature for up to 14 days.1, 13
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 100 mg* | ||
Rimantadine Hydrochloride Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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