Oseltamivir ( Tamiflu ), an antiviral drug marketed in Canada since 1999, is indicated for the treatment of acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days1.
The drug is also indicated for the prevention of influenza illness in people over 13 years of age after close contact with an infected individual.

From Jan. 1, 1999, to Oct. 31, 2005, Health Canada received 19 reports of increased international normalized ratio ( INR ) suspected of being associated with the use of Oseltamivir.
These 19 reports involved patients aged 46 to 92 years ( median age 84 years ), and the indication for use of Oseltamivir was either treatment or prophylaxis of influenza.
All of the patients were taking Warfarin.
The reported onset of the adverse reaction ranged from the day treatment was started to 11 days after starting Oseltamivir. The increased INR ranged from 3.2 to 10.9.
Eleven of the reports were submitted by the same source and described a suspected interaction between Oseltamivir and Warfarin.
Creatinine clearances were provided in these cases; dosage adjustments of Oseltamivir were necessary in 3 cases, as recommended in patients with a creatinine clearance rate of 10-30 mL/min. Six patients required treatment with vitamin K. At the time of reporting, 12 patients had recovered, 2 patients had not yet recovered, and the outcome was unknown for the remaining 5 patients.

Causality assessment of these cases is difficult because some of the reports presented conflicting or insufficient clinical information, and numerous factors ( e.g., diet, medical conditions, fever ) are known to influence a patient's response to anticoagulants.
In 3 cases, the Warfarin dose was increased after the introduction of Oseltamivir; the increases in INR occurred following these dose changes. In 3 other cases, decreases in INR occurred during the course of Oseltamivir therapy without a reported change in Warfarin dose.
In 2 cases, Clarithromycin and Levofloxacin respectively were reported as co-suspect medications; these drugs are known to interact with Warfarin and may cause increases in INR.

Available data indicate that the potential for drug interactions with Oseltamivir is minimal.
Oseltamivir requires conversion to the active metabolite via esterases, located predominately in the liver.
Drug interactions involving this pathway have not been commonly documented.
The drug does not interact with substrates of various cytochrome P450 isoenzymes.
Oseltamivir is not extensively protein bound and, as a result, is not expected to contribute to drug interactions involving protein-binding displacement. In addition, clinically important drug interactions involving competition for renal tubular secretion are unlikely.

As with any drug prescribed to patients taking Warfarin, more frequent monitoring of INRs may be prudent when Oseltamivir is prescribed concurrently with Warfarin.
Health Canada continues to monitor adverse reactions suspected of being associated with the use of Oseltamivir.
Health care professionals are encouraged to report any cases of INR fluctuation in patients receiving Warfarin and Oseltamivir concomitantly.

Source: Health Canada, 2006


XagenaMedicine2006