190 Drug Profiles

ous system toxicity. There is no specific antidote. For more information, please check the prescribing information (Symmetrel 2003).

Efficacy

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).

Resistance

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.

Drug Interactions

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’s disease.

Recommendations for Use

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.

Amantadine 191

EU

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.

US

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.

Warnings

Amantadine is contraindicated in severe renal impairment and patients with 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.