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1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

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Amedeo Influenza


  

 

Rimantadine

Bernd Sebastian Kamps and Christian Hoffmann


(Green links: Free full-text articles)

Introduction

Rimantadine is an M2 ion channel inhibitor which specifically inhibits the replication of influenza A viruses by interfering with the uncoating process of the virus. M2 inhibitors block the ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991). The influenza virus enters its host cell by receptor-mediated endocytosis. Thereafter, acidification of the endocytotic vesicles is required for the dissociation of the M1 protein from the ribonucleoprotein complexes. Only then are the ribonucleoprotein particles imported into the nucleus via the nuclear pores. The hydrogen ions needed for acidification pass through the M2 channel. Rimantadine blocks the channel (Bui 1996).

The drug is effective against all influenza A subtypes that have previously caused disease in humans (H1N1, H2N2 and H3N2), but not against influenza B virus, because the M2 protein is unique to influenza A viruses. Rimantadine is not active against the avian flu subtype H5N1 strains that have recently caused disease in humans (Li 2004).

For both the prevention and treatment of influenza A, rimantadine has a comparable efficacy to amantadine but a lower potential for causing adverse effects (Stephenson 2001, Jefferson 2004).

The development of neutralising antibodies to influenza strains seems not to be affected by rimantadine. However, the presence of IgA in nasal secretions was significantly diminished in one study (Clover 1991).

A recently published study revealed an alarming increase in the incidence of amantadine-resistant and rimantadine-resistant H3N2 influenza A viruses over the past decade. In a recently published study, which assessed more than 7,000 influenza A viruses obtained worldwide from 1994 to 2005, drug resistance against amantadine and rimantadine increased from 0.4 % to 12.3 % (Bright 2005). Viruses collected in 2004 from South Korea, Taiwan, Hong Kong, and China show drug-resistance frequencies of 15 %, 23 %, 70 %, and 74 %, respectively. Some authors have suggested that the use of amantadine and rimantadine should be discouraged (Jefferson 2006). Recently, 109 out of 120 (91 %) of influenza A H3N2 viruses isolated from patients in the US contained an amino acid change at position 31 of the M2 protein, which confers resistance to amantadine and rimantadine. On the basis of these results, the Centre for Disease Control recommended that neither amantadine nor rimantadine be used for the treatment or prophylaxis of influenza A in the United States for the remainder of the 2005-06 influenza season (CDC 2006).

In most countries, rimantadine is not available.

Structure

Chemically, rimantadine hydrochloride is alpha-methyltricyclo-[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with a molecular weight of 215.77 and the following structural formula:

 

Pharmacokinetics

In healthy adults, peak plasma concentrations are reached 6 hours after oral administration. The single dose elimination half-life is about 30 hours in both adults (Hayden 1985) and children (Anderson 1987). Following oral administration, rimantadine is extensively metabolised in the liver and less than 25 % of the dose is excreted unchanged in the urine. In elderly people, the elimination is prolonged, with average AUC values and peak concentrations being 20 to 30 % higher than in healthy adults.

In chronic liver disease, rimantadine pharmacokinetics are not appreciably altered (Wills 1987); however, in patients with severe hepatic insufficiency, the AUC and the elimination half-life time are increased.

Renal insufficiency results in increased plasma concentrations of rimantadine metabolites. Haemodialysis does not remove rimantadine. Rimantadine dosage may therefore need to be reduced in patients with end-stage renal disease. Supplemental doses on dialysis days are not required (Capparelli 1988).

Toxicity

Gastrointestinal symptoms are the most frequent adverse events associated with rimantadine. Other side effects noted during clinical trials (all < 3 %) included nausea, vomiting, anorexia, and dry mouth, as well as CNS symptoms (insomnia, dizziness, nervousness). However, a study on the safety and efficacy of prophylactic long-term use in nursing homes showed no statistically significant differences in the frequencies of gastrointestinal or central nervous system symptoms between treatment and placebo groups (Monto 1995).

Less frequent adverse events (0.3 to 1 %) were diarrhoea, dyspepsia, impairment of concentration, ataxia, somnolence, agitation, depression, rash, tinnitus, and dyspnoea.

Rarely, seizures may develop in patients with a history of seizures, who are not receiving anticonvulsant medication. In these cases, rimantadine should be discontinued.

Generally, symptoms resolve rapidly after discontinuation of treatment.

The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency have only been evaluated after single-dose administration. Because of the potential for accumulation of rimantadine and its metabolites in plasma, caution should be exercised when treating patients with renal or hepatic insufficiency.

No well-controlled studies have been done in pregnant women to evaluate the safety of amantadine. We thus recommend that rimantadine is not prescribed for pregnant women. Likewise, rimantadine should not be administered to nursing mothers because of the adverse effects noted in the offspring of rats treated with rimantadine during the nursing period.

Comparative studies indicate that rimantadine is better tolerated than amantadine at equivalent doses (Jefferson 2004). In a direct comparison of prophylactic use of amantadine and rimantadine, more patients on amantadine (13 %) than recipients of rimantadine (6 %) withdrew from the study because of central nervous system side effects (Dolin 1982).

Efficacy

Rimantadine is not active against the avian flu subtype H5N1 strains that have recently caused disease in humans (Li 2004). Rimantadine may be effective for both the prevention and treatment of influenza A infection in "classic" human strains (H1N1, H2N2 and H3N2). The efficacy of rimantadine is comparable to amantadine. In a Cochrane review of 3 placebo-controlled trials on the prophylactic effect of rimantadine, however, rimantadine had only moderate effects on influenza cases and influenza-like illnesses (Jefferson 2006). In treatment, rimantadine significantly shortened the duration of fever but had no or at best moderate effect on nasal shedding of influenza A viruses. The low efficacy of rimantadine together with the relatively high rate of adverse events led the authors to conclude that the use of both M2 ion channel-blocking drugs, rimantadine and amantadine, should be discouraged in seasonal and pandemic influenza (Jefferson 2006) (see also the CDC recommendation in the Introduction).

Treatment

In early trials involving patients with uncomplicated influenza A H3N2 subtype virus infection, rimantadine treatment (200 mg/day for 5 days) was associated with significant reductions in nasal secretion viral titres, maximum temperature, time until defervescence (mean, 37 h shorter), and systemic symptoms compared with placebo (Hayden 1986). Rimantadine seems to be relatively safe even among vaccinated elderly individuals living in nursing homes (Monto 1995). In this population, a dosage reduction to 100 mg/day is recommended. In experimentally infected adults, rimantadine had no effect on nasal patency, mucociliary clearance, nasal signs, or on symptoms and signs of otologic complications (Doyle 1998).

Prophylaxis

Efficacy rates reported from prophylaxis trials vary widely. A review of clinical studies found that rimantadine was 64 % efficacious in prevention, and significantly shortened the duration of fever by 1.27 days (Demicheli 2000). Rimantadine may also be effective in children (Clover 1986, Crawford 1988).

Resistance

Point mutations in the M gene leading to amino acid changes in the M2 protein may lead to high-level resistance to rimantadine. The mutants are as virulent and have been shown to be as transmissible as wild-type virus and to cause a typical influenza illness. Such strains may develop in up to one third of treated patients, although in immunocompromised individuals, the percentage may be even higher (Englund 1998). Drug-resistant influenza A virus (H3N2) can be recovered from rimantadine-treated children and adults as early as 2 days after starting treatment (Hayden 1991).

Transmissibility is an important aspect when using rimantadine. An early study demonstrated failure of prevention of influenza infection due to apparent transmission of drug-resistant viral strains. The study concluded that rimantadine was ineffective in protecting household members from influenza A infection (Hayden 1989).

Avian influenza virus subtype H5N1, which has been associated with the human disease in East Asia between late 2003 and early 2004, is resistant to rimantadine (asparagine residue at position 31 of the M2 protein) (Li 2004).

Over the last decade, drug resistance to amantadine and rimantadine has increased from 0.4 % to 12.3 % (Bright 2005).

Drug Interactions

No clinically substantial interactions between rimantadine and other drugs have been identified. Cimetidine seems to reduce rimantadine clearance by 18 % (Holazo 1989). Acetaminophen reduces the peak concentration and AUC values of rimantadine by 11 %. Aspirin reduces the peak plasma concentrations and the AUC of rimantadine by approximately 10 %.

Recommendations for Use

In the EU, medicinal products containing rimantadine have been approved nationally (for additional information, please check the prescribing information).

In the US, rimantadine is licensed for prophylaxis in adults and children. For treatment, rimantadine is licensed for adults only. Rimantadine (Flumadine®) is available as 100 mg film-coated tablets and as syrup for oral administration.

Adults

In the US, the recommended dose for both prophylaxis and treatment is 100 mg bid.

A dose reduction to 100 mg daily is recommended in patients with

  • severe hepatic dysfunction
  • renal failure (CrCl ≤ 10 ml/min)
  • elderly nursing home patients (Patriarca 1984, Monto 1995).

Patients with any degree of renal insufficiency should be closely monitored, with dosage adjustments being made as necessary.

For treatment, rimantadine should be initiated within 48 hours after the onset of signs and symptoms of influenza A infection. Therapy should be continued for approximately seven days from the initial onset of symptoms.

Children

In the US, rimantadine is licensed for prophylactic use only. Children less than 10 years of age should receive 5 mg/kg but not exceeding 150 mg. Children 10 years of age or older receive the adult dose.

Warnings

Rimantadine should be used with caution in patients with epilepsy.

 

Summary

Trade name: Flumadine®

Drug class: M2 inhibitor

Indications: prophylaxis (adults and children) and treatment (adults only) of influenza A infection. Treatment must be initiated within 48 hours after the onset of symptoms.

Standard Dosage for Treatment: 100 mg bid.

A dose reduction to 100 mg daily is recommended in patients with severe hepatic dysfunction, renal failure (CrCl ≤ 10 ml/min) and in elderly nursing home patients.

Standard Dosage for Prophylaxis: 100 mg bid.

A dose reduction to 100 mg daily is recommended in patients with severe hepatic dysfunction, renal failure (CrCl ≤ 10 ml/min) and in elderly nursing home patients. Children less than 10 years of age should receive 5 mg/kg but not exceeding 150 mg. Children 10 years of age or older receive the adult dose.

Pharmacokinetics: peak plasma concentration is reached 6 hours after oral administration. The elimination half-life is 30 hours. Prolonged elimination in elderly people. Extensive metabolisation in the liver - less than 25 % is excreted unchanged in the urine. Increased plasma concentration in patients with severe hepatic and renal insufficiency.

Interactions: no significant interactions.

Side effects: gastrointestinal symptoms.

 

References

  1. Anderson EL, Van Voris LP, Bartram J, Hoffman HE, Belshe RB. Pharmacokinetics of a single dose of rimantadine in young adults and children. Antimicrob Agents Chemother 1987; 31: 1140-2. Abstract: http://amedeo.com/lit.php?id=3662473 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=3662473
  2. Belshe RB, Smith MH, Hall CB, Betts R, Hay AJ. Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection. J Virol 1988; 62: 1508-12. Abstract: http://amedeo.com/lit.php?id=3282079
  3. Belshe RB, Burk B, Newman F, Cerruti RL, Sim IS. Resistance of influenza A virus to amantadine and rimantadine: results of one decade of surveillance. J Infect Dis 1989; 159: 430-5. Abstract: http://amedeo.com/lit.php?id=2915166
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