Oseltamivir and Warfarin: Interaction Details

a) A retrospective cohort study conducted within the Veterans Health Administration included patients on warfarin who received oseltamivir for influenza prophylaxis (7 to 21 days). The primary endpoint was change in INR from baseline to day 10 of oseltamivir treatment. Secondary endpoints included change in INR based on renal function and duration of oseltamivir prophylaxis, trend in INR, and frequency of bleeding and thrombosis events. A total of 1041 patients were included and received oseltamivir for a mean of 12.9 days. A majority of the patients were Caucasian, male, with a mean age of 73, who were prescribed oseltamivir in the inpatient setting, which included patients residing in VA long-term care facilities. Oseltamivir 75 mg once daily was the most common dose prescribed and the average length of prophylactic treatment was less than 2 weeks. Most patients had a creatinine clearance greater than 90 mL/min. The mean post-oseltamivir INR was significantly increased compared to the pre-oseltamivir INR (2.39 to 2.52). Regarding renal function, only patients with a creatinine clearance of 31 to 60 mL/min had a significant increase in INR (2.40 to 2.59). There was a significant increase in INR when oseltamivir was used for 7 or 8 to 10 days but not when used for 11 to 14 days or 15 to 21 days. Of the 1041 patients included, 299 (28.7%) had an INR outside the goal range (2 to 3 +/-0.2) around day 10 following oseltamivir initiation. Of these patients, 156 (52.2%) were below the INR goal and 143 (47.8%) were above. A total of 67 (6.4%) patients had 71 bleeding or thrombosis events recorded during oseltamivir use. If concomitant use occurs, INR should be checked within 7 to 10 days following oseltamivir initiation; patients with impaired renal function may require closer INR monitoring ².

b) Addition of oseltamivir therapy resulted in a 56% to 289% elevation of international normalized ratio (INR) levels in patients who had previously stable INR levels on warfarin therapy, according to a retrospective case series (n=15). Patients included in the study had INR test results available within 10 days of initiating oseltamivir, had been taking warfarin for at least 8 months, and had no dose changes or INR level more than 1 standard deviation outside of their 1-year mean level for at least 3 months prior to initiating oseltamivir therapy. All patients received oseltamivir 150 mg orally daily for 5 days. Increased INR levels were observed between 2 and 9 days after initiation of therapy. At a mean 5.7 +/- 2.5 days after the first dose of oseltamivir, the INR level was increased in 46.7% of patients (7 of 15) from a 1-year mean of 2.08 +/- 0.46 to a mean of 5.15 +/- 2.00. Hospitalization was required in 3 patients due to bleeding events (blood-tinged sputum, in 2 patients, INR 5.28 and 5.64; underlying hepatoma with bloody ascites in 1 patient, INR 5.22). Warfarin was discontinued in all 3 patients, and the INR level recovered within 2 to 5 days. After discontinuation of oseltamivir, the INR level was maintained at the previous stable value in all 7 patients who experienced elevations. Positivity for influenza A H1N1 was similar among both groups; however, in the elevated-INR group, concomitant medications may have been contributory in 3 patients (azithromycin and levofloxacin, 1 patient each; prednisolone and paracetamol, 1 patient). This study demonstrated a temporal association between initiation of oseltamivir therapy and increased INR level in patients receiving warfarin; however, no probable mechanism was elucidated ¹.