Oseltamivir Phosphate (Tamiflu)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
In october, the fda approved oseltamivir (Tamiflu—Roche), the second neuraminidase inhibitor for the treatment of influenza. This comes three months after the FDA approved zanamivir (Relenza) (Intern Med Alert 1999;21:133). The major difference between these agents is the route of delivery—zanamivir is administered by oral inhalation while oseltamivir is orally active. Neuraminidase inhibitors exert their action by inhibiting viral replication.1
Indications
Oseltamivir is indicated for the treatment of uncomplicated acute illness due to influenza infection in adults who have been symptomatic for no more than two days.
Dosage
The recommended dose is 75 mg twice daily for five days. Treatment should be initiated within two days of symptom onset. Oseltamivir may be taken without regard to meals although food may reduce the gastrointestinal side effects.2,5 No dosage adjustment is necessary in patients with creatinine clearance above 30 mL/min. The dose should be reduced to 75 mg daily for five days in patients with creatinine clearance between 10-30 mL/min.2 No dose adjustment is necessary for patients with hepatic impairment. Patients should be advised to take any missed doses as soon as possible unless it is within two hours of the next scheduled dose. Oseltamivir is supplied as 75 mg capsules.
Potential Advantages
Oseltamivir is orally active and, thus, is more convenient to administer than zanamivir, which requires administration by oral inhalation using a Diskhaler. In a published trial, about 12% of patients on zanamivir withdrew due to adverse events. In contrast, withdrawal in the unpublished oseltamivir trials were less than 1% due to the major side effects, nausea and vomiting. In addition, unlike zanamivir, the oseltamivir labeling does not contain a precaution for use in patients with underlying respiratory diseases. Bronchospasm or decline in lung function has been reported in some patients treated with zanamivir.3
Potential Disadvantages
The most common side effects compared to placebo are nausea (9.9% vs 5.6%) and vomiting (9.4% vs 2.9%).2 Oseltamivir is approved for use in patients 18 year of age and older. Zanamivir is approved for use in younger teens aged 12 years and older. Post-treatment influenza with reduced susceptibility to oseltamivir has been demonstrated in challenge studies and in studies with naturally acquired infections.2 These varied from 3% in the challenged studies to 1.3% in the natural studies.
Comments
Oseltamivir is the ethyl ester prodrug of oseltamivir carboxylate. The prodrug is converted to the active drug mainly by hepatic esterases. Clinical study results (n = 849) demonstrated that oseltamivir, initiated within 40 hours of onset of symptoms, produces a reduction of 1.3 days (30%) in the median time-to-symptom improvement. Patients (18-65 years old) were eligible if they had fever higher than 100°F with at least one respiratory symptom (cough, nasal symptoms, or score throat) and one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache).2 Study end points were self-assessed by the patient. Time to improvement was determined from onset of therapy to time when all symptoms were assessed as "none" or "mild." Details of these pivotal trials have not been published. While it is difficult to compare across studies, the magnitude of effect appears to be very similar to those seen with zanamivir.3,4 Oseltamivir has not been evaluated in high-risk patients such as those with chronic cardiac or respiratory disease or the elderly (> 65 years). These trials are ongoing.
While cross-resistance between zanamivir-resistant strains and oseltamivir-resistant strains has not been adequately studied, cross-resistance may be expected due to their mechanisms of action. Oseltamivir, has been reported to be effective for the prevention of influenza as well.5,6 However, the FDA has not approved either drug for this indication.
The cost for a five-day course of treatment for oseltamivir is $53 compared to $44.40 for zanamivir.
Clinical Implications
The benefit of the current neuraminidase inhibitors (zanamivir and oseltamivir) are modest, reducing the duration of illness of uncomplicated influenza by 1-1.5 days if initiated within 36-48 hours. Initiating treatment early may be problematic, as most adults may not seek treatment within that time frame. Oseltamivir does offer the advantage of a much more convenient route of administration. There are no indications that these drugs can reduce complications of influenza illness in patients at risk. In addition, the clinical and pharmacoeconomic effects of a modest benefit in illness duration are not known. They are not substitutes for vaccination, which is the primary strategy to control influenza.
References
1. Waghorn SL, et al. Drugs 1998;55(5):721-725.
2. Tamiflu Product Information. October 1999. Roche Pharmaceuticals.
3. Relenza Product Information. July 1999. Glaxo Wellcome Inc.
4. MIST Study Group. Lancet 1998;352:1877-1881.
5. Hayden FG, et al. JAMA 1999;282:1240-1246.
6. Hayden FG. N Engl J Med 1999;341:1336-1343.
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