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Bernd Sebastian Kamps and Christian Hoffmann Amantadine inhibits the replication of influenza A viruses by interfering with the uncoating of the virus inside the cell. Like rimantadine, it is an M2 inhibitor which blocks 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. Amantadine blocks the channel (Bui 1996). Amantadine 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 protein M2 is unique to influenza A viruses. For both the prevention and treatment of influenza A, amantadine has a similar efficacy to rimantadine (Stephenson 2001, Jefferson 2004). Comparative studies indicate that adverse effects were significantly more common with amantadine than rimantadine (Jefferson 2004). Amantadine is not active against the avian influenza subtype H5N1 strains which have recently caused disease in humans (Li 2004). Besides influenza, amantadine may also be indicated in the treatment of Parkinson induced extrapyramidal reactions. Moreover, it may be effective as an adjunct to interferon-based combination therapy in patients with chronic hepatitis C who have failed prior hepatitis C therapy (Lim 2005). per day in some European countries, amantadine is by far the cheapest treatment for influenza A, compared to daily costs of 5 The use of amantadine is associated with the rapid emergence of drug-resistant variants. Resistant isolates of influenza A are genetically stable and fully transmissible, and the pathogenic potential is comparable to that of wild-type virus isolates. In immunocompromised patients, resistant virus can be shed for prolonged periods (Boivin 2002). According to a study which assessed more than 7,000 influenza A virus samples obtained from 1994 to 2005, drug resistance against amantadine and rimantadine has increased worldwide from 0.4 % to 12.3 % (Bright 2005). Virus samples collected in 2004 from South Korea, Taiwan, Hong Kong, and China showed drug-resistance frequencies of 15 %, 23 %, 70 %, and 74 %, respectively. Some authors have suggested that the use of amantadine and rimantadine should be frankly discouraged (Jefferson 2006). Recently, 109 out of 120 (91 %) 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). http://www.influenzareport.com/ir/drugs/amanta.htm Amantadine is well absorbed orally and maximum drug concentrations (Cmax) are directly dose-related for doses of up to 200 mg/day. Doses above 200 mg/day may result in disproportional increases in Cmax. In healthy volunteers, peak concentration were reached after 3 hours and the half-life was 17 hours (range: 10 to 25 hours). Amantadine is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. In individuals older than 60 years, the plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased. The clearance is also reduced in patients with renal insufficiency: the elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 ml/min and averages eight days in patients on chronic haemodialysis. Amantadine is not removed by haemodialysis. As the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. Gastrointestinal symptoms - mainly nausea but also vomiting, diarrhoea, constipation, and loss of appetite - are the major side effects. In addition, amantadine has a wide range of toxicities which may be in part attributable to the anticholinergic effects of the drug, and some reversible CNS side effects may occur during a 5-day-treatment in a substantial number of patients (van Voris 1981). As the occurrence of adverse effects is dose-related, adverse events are particularly common in the elderly and those with impaired renal function. Side effects begin within two days of the start of the drug, and usually disappear rapidly after cessation of treatment. CNS toxicity may manifest as dizziness, nervousness, and insomnia. In a four-week prophylaxis trial, these symptoms occurred in up to 33 % of young individuals (Bryson 1980). Decreased performance on sustained attention tasks was also observed. Other CNS adverse effects include agitation, difficulty concentrating, insomnia, and lowered seizure threshold. In a direct comparison of the prophylactic use of amantadine and rimantadine, more patients receiving amantadine (13 % vs. 6% on rimantidine) withdrew from the study because of CNS side effects (Dolin 1982). Less frequently (1-5 %) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral oedema, orthostatic hypotension, headache, somnolence, dream abnormality, agitation, dry nose, diarrhoea and fatigue (Symmetrel 2003). Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram. In the past, some patients attempted suicide by overdosing with amantadine. As a result, it is recommended that the minimum quantity of drug is prescribed (Symmetrel 2003). http://www.influenzareport.com/ir/drugs/amanta.htm Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has therefore resulted in cardiac, respiratory, renal or central nervous system toxicity. There is no specific antidote. For more information, please check the prescribing information (Symmetrel 2003). In a Cochrane review of 15 placebo-controlled trials on the prophylactic effect of amantadine, amantadine prevented 61 % of influenza cases and 25 % of cases of influenza-like illness but had no effect on asymptomatic cases (Jefferson 2006). In treatment, amantadine significantly shortened the duration of fever (by 0.99 days) but had no effect on nasal shedding of influenza A virus. The low efficacy of amantadine together with the relatively high rate of adverse events led the authors to conclude that the use of amantadine should be discouraged in seasonal and pandemic influenza (Jefferson 2006) (see also the CDC recommendation in the Introduction). Point mutations in the M gene lead to amino acid changes in the transmembrane region of the M2 protein and may confer high-level resistance to amantadine. The five amino acid sites known to be involved are 26, 27, 30, 31, and 34 (Holsinger 1994). The use of amantadine for treatment has been associated with the rapid emergence of resistant viruses capable of transmission, compromising its potential as a prophylaxis as well its efficacy as a treatment (Fleming 2003). The mutants are as virulent and transmissible as the wild-type virus. In an avian model, they were also genetically stable, showing no reversion to the wild-type after several passages in birds (Bean 1989). These results suggest that resistant mutants may have the potential to threaten the effective use of amantadine for the control of epidemic influenza. Amantadine adds to the sedating effects of alcohol and other sedating drugs such as benzodiazepines, tricyclic antidepressants, dicyclomine, certain antihistamines, opiate agonists and certain antihypertensive medications. Such combinations can cause dizziness, confusion, light headedness, or fainting. Co-administration of quinine or quinidine with amantadine has been shown to reduce the renal clearance of amantadine by about 30 % (Gaudry 1993). Co-administration of thioridazine can worsen the tremor in elderly patients with Parkinson Amantadine does not completely prevent the host immune response to influenza A infection (Sears 1987) - individuals who take the drug may still develop immune responses to the natural disease or vaccination and may be protected when exposed at a later date to antigenically related viruses. http://www.influenzareport.com/ir/drugs/amanta.htm In the EU, indications for influenza A treatment vary between the member states (i.e., indicated for treatment and/or prophylaxis of adults; or adults and children; or only adults and adolescents). Please check the prescribing information. In the US, amantadine is indicated for the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains. Treatment should be started as soon as possible, preferably within 24 to 48 hours after the onset of symptoms, and should be continued for 24 to 48 hours after the disappearance of clinical signs. Amantadine is also indicated for prophylaxis against the signs and symptoms of influenza A virus infection when early vaccination is not feasible or when the vaccine is contraindicated or not available. Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness. Amantadine should be continued for at least 10 days following known exposure. When prophylaxis is started with inactivated influenza A virus vaccine, it should be administered for 2 to 4 weeks after the vaccine has been given (i.e., until protective antibody responses develop). When inactivated influenza A virus vaccine is unavailable or contraindicated, amantadine should be administered for the duration of known influenza A infection in the community because of repeated and unknown exposure. The daily dosage of amantadine for adults is 200 mg; two 100 mg tablets (or four teaspoonfuls of syrup) as a once daily dose. The daily dosage may be split into one tablet of 100 mg twice a day. If central nervous system effects develop on a once daily dosage, a split dosage schedule may reduce such complaints. In persons of 65 years of age or older, the daily dosage of amantadine is 100 mg. Low-dose amantadine (100 mg/day) can reduce toxicity and may maintain the prophylactic efficacy seen with 200 mg/day (Sears 1987). In an experimental challenge study on 78 subjects, using doses of 50 mg, 100 mg or 200 mg/day, there was no significant difference between the groups in influenza illness or viral shedding (Reuman 1989). In elderly institutionalised patients, individualised dosing of amantadine, based upon a patient s creatinine clearance, seems to be effective while reducing adverse reactions (Kolbe 2003). In paediatric patients, lower total daily doses should be calculated on the basis of 4.4 to 8.8 mg/kg/day (2 to 4 mg/lb/day). However, given the relatively low efficacy of amantadine and the high risk of occurrence of gastrointestinal and CNS adverse effects, the authors do not recommend the administration of amantadine in children. Amantadine is contraindicated in severe renal impairment and patients with http://www.influenzareport.com/ir/drugs/amanta.htm epilepsy. In addition, it should be used cautiously in elderly patients (impaired renal function?). Amantadine may cause mydriasis and should therefore not be given to patients with untreated closed-angle glaucoma. The safety of amantadine in pregnant women has not been established. The dose of amantadine may need careful adjustment in patients with congestive heart failure, peripheral oedema, or orthostatic hypotension. Care should be exercised when administering amantadine to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents (Symmetrel 2003). Amantadine is available as 100 mg tablets or capsules and as a syrup containing 50 mg/5ml. Indications: treatment and prevention of Influenza A. Dosage: 100 mg qd both for treatment and prophylaxis. For prophylaxis, amantadine should be started as soon as possible after exposure and continued for at least 10 days. Special Dosage: persons with reduced kidney function and elderly persons may need lower doses (or less frequent doses). Pharmacokinetics: good absorption with peak concentration after 3 hours and a half-life of 17 hours. Excreted unchanged in the urine by glomerular filtration and tubular secretion. Reduced clearance in individuals > 60 years and in patients with renal insufficiency: half-life is increased when creatinine clearance is less than 40 ml/min. Amantadine is not removed by haemodialysis. Contraindications: psychosis. Patients with insufficiently treated epileptic episodes. Interactions: central nervous system stimulants; quinine and quinidine; thioridazine. Side effects: gastrointestinal and CNS symptoms. Comments/Warnings: no well-controlled studies have been done in pregnant women to evaluate the safety of amantadine. Amantadine should not be prescribed to pregnant women. Amantadine is excreted in breast milk in low concentrations. Although no http://www.influenzareport.com/ir/drugs/amanta.htm information is available on the effects in infants, the manufacturer recommends that amantadine be used cautiously in nursing mothers. Patients receiving amantadine who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor co-ordination are important. Store amantadine at room temperature between 15 and 30°C (59 and 86°F). USA: http://influenzareport.com/link.php?id=6 1. Bean WJ, Threlkeld SC, Webster RG. Biologic potential of amantadine- resistant influenza A virus in an avian model. J Infect Dis 1989; 159: 1050-6. Abstract: http://amedeo.com/lit.php?id=2723453 2. Boivin G, Goyette N, Bernatchez H. Prolonged excretion of amantadine-resistant influenza a virus quasi species after cessation of antiviral therapy in an immunocompromised patient. Clin Infect Dis 2002; 34: Abstract: http://amedeo.com/lit.php?id=11807683 - Full text at http://www.journals.uchicago.edu/CID/journal/issues/v34n5/010857/010857.html 3. Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005; 366: 1175-81. Epub 2005 Sep 22. Abstract: http://amedeo.com/lit.php?id=16198766 4. Bryson YJ, Monahan C, Pollack M, Shields WD. A prospective double- blind study of side effects associated with the administration of amantadine for influenza A virus prophylaxis. J Infect Dis 1980; 141: 543-7. Abstract: http://amedeo.com/lit.php?id=7373087 5. CDC 2006. CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005-06 Influenza Season. Available from http://www.cdc.gov/flu/han011406.htm - Accessed 13 February 2006. 6. Demicheli V, Jefferson T, Rivetti D, Deeks J. Prevention and early treatment of influenza in healthy adults. Vaccine 2000; 18: 957-1030. Abstract: http://amedeo.com/lit.php?id=10590322 7. Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber- Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982; 307: 580-4. Abstract: http://amedeo.com/lit.php?id=7050702 8. Fleming DM. Zanamivir in the treatment of influenza. Expert Opin Pharmacother 2003; 4: 799-805. Abstract: http://amedeo.com/lit.php?id=12740002 http://www.influenzareport.com/ir/drugs/amanta.htm 9. Gaudry SE, Sitar DS, Smyth DD, McKenzie JK, Aoki FY. Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine. Clin Pharmacol Ther 1993; 54: 23-7. Abstract: http://amedeo.com/lit.php?id=8330461 10. Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH. The molecular basis of the specific anti-influenza action of amantadine. EMBO J 1985; 4: 3021-4. Abstract: http://amedeo.com/lit.php?id=4065098 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=4065098 11. Holsinger LJ, Nichani D, Pinto LH, Lamb RA. Influenza A virus M2 ion channel protein: a structure-function analysis. J Virol 1994; 68: 1551-63. Abstract: http://amedeo.com/lit.php?id=7508997 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=7508997 12. Jefferson T, Deeks JJ, Demicheli V, Rivetti D, Rudin M. Amantadine and rimantadine for preventing and treating influenza A in adults. Cochrane Database Syst Rev 2004; 0: Abstract: http://amedeo.com/lit.php?id=15266442 13. Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet 2006; 367: 303-13. Abstract: http://amedeo.com/lit.php?id=16443037 14. Kolbe F, Sitar DS, Papaioannou A, Campbell G. An amantadine hydrochloride dosing program adjusted for renal function during an influenza outbreak in elderly institutionalized patients. Can J Clin Pharmacol 2003; 10: 119-22. Abstract: http://amedeo.com/lit.php?id=14506511 15. Li KS, Guan Y, Wang J, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 2004; 430: 209-13. Abstract: http://amedeo.com/lit.php?id=15241415 16. Lim JK, Wooten D, Siegel R, Cheung RC. Amantadine in treatment of chronic hepatitis C virus infection? J Viral Hepat 2005; 12: 445-55. Abstract: http://amedeo.com/lit.php?id=16108758 17. Monto AS, Gunn RA, Bandyk MG, King CL. Prevention of Russian influenza by amantadine. JAMA 1979; 241: 1003-7. Abstract: http://amedeo.com/lit.php?id=368354 18. Reuman PD, Bernstein DI, Keefer MC, Young EC, Sherwood JR, Schiff GM. Efficacy and safety of low dosage amantadine hydrochloride as prophylaxis for influenza A. Antiviral Res 1989; 11: 27-40. Abstract: http://amedeo.com/lit.php?id=2712549 19. Sears SD, Clements ML. Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus. Antimicrob Agents Chemother 1987; 31: 1470-3. Abstract: http://amedeo.com/lit.php?id=3435099 http://www.influenzareport.com/ir/drugs/amanta.htm 20. Stephenson I, Nicholson KG. Influenza: vaccination and treatment. Eur Respir J 2001; 17: 1282-93. Abstract: http://amedeo.com/lit.php?id=11491177 - Full text at http://erj.ersjournals.com/cgi/content/full/17/6/1282 21. Sugrue RJ, Hay AJ. Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel. Virology 1991; 180: 617-24. Abstract: http://amedeo.com/lit.php?id=1989386 22. Symmetrel (package insert). Endo Pharmaceuticals Inc., Chadds Ford, 2003. http://influenzareport.com/link.php?id=6 23. Van Voris LP, Betts RF, Hayden FG, Christmas WA, Douglas RG Jr. Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA 1981; 245: 1128-31. Abstract: http://amedeo.com/lit.php?id=7007668 http://www.influenzareport.com/ir/drugs/amanta.htm

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