Tamiflu and Dosing in Obese Patients
What is Tamiflu
Tamiflu (oseltamivir) is an influenza neuraminidase inhibitor indicated for treatment of acute, uncomplicated influenza (flu) in patients who are older than 2 weeks old, and with onset of symptoms for ≤ 48 hours. It is also indicated for the prophylaxis (prevention) of influenza in patients who are older than 1 year old.
Common Side Effects and Precautions of Tamiflu
The common side effects of Tamiflu are nausea, vomiting, diarrhea, and abdominal pain. Tamiflu could also cause serious skin reactions, such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme. Confusion and abnormal behavior were also observed in pediatric patients in their early illness.
Usual Dosing of Tamiflu
Adults and adolescents (≥13 years): 75 mg twice daily for 5 days
Pediatric patients 1 to 12 years: weight based twice daily for 5 days
Pediatric patients (2 weeks to ≤ 1 year): 3mg/kg twice daily for 5 days
Adults and adolescents (≥13 years): 75 mg once daily for at least 10 days
Pediatrics (1 to 12 years of age): weight based once daily for 10 days
Renal Impairment (CrCl = 10-30 ml/min)
Treatment: 75 mg once daily for 5 days
Prophylaxis: 75 mg every other day or 30 mg daily
Obesity and Influenza
Obesity is commonly seen in patients infected with H1N1 influenza. Obesity is also one of the risk factors of ICU admissions for H1N1 patients. Other risk factors are asthma, older age, longer duration of symptoms, leukocytosis. Studies also show that extreme obesity increases mortality rate in H1N1 patients. Therefore, flu vaccines should be administered to obese population. Since there are poor outcomes and high mortality rate in obese H1N1patients, some health care professionals have recommended dose adjustment of anti-viral medications such as Tamiflu in this population.
Should the dose of Tamiflu be doubled in obese patients?
Physicians in some institutions double the dose of Tamiflu to 150 mg twice a day for obese or critically ill patients based on their clinical judgment. Unfortunately, there are no guidelines about Tamiflu dosing in obese patients. The only available studies were based on pharmacokinetic (PK) parameters of Tamiflu. The lack of studies could be due to the nature of difficulty to measure the efficacy of Tamiflu, because many patients already presented flu symptoms more than 48 hours before admitted to ICU, and Tamiflu would not be efficacious 48hr after onset of symptoms. And patients might not only be infected with H1N1, but they could also be co-infected with bacteria or fungal. Patients who have suspected H1N1influenza are also on broad spectrum antibiotics in ICU.
The followings are current studies on Tamiflu dosing in obese patients
One study was conducted in three cities in Spain and Canada to study the PK parameters of Tamiflu in ICU patients with suspected or confirmed H1N1 influenza. A total 41 patients age ≥18 yr, weight range of 50 to 200 kg , and BMI of 36 were included. Blood samples were drawn at baseline, 2, 4, 6, 9, and 12 hours after the fourth or later dose of Tamiflu. Tamiflu 75 mg twice a day was given in most subjects, and 150 mg twice a day was given to some patients based on obesity and severity of illness based on clinical judgment. The correlations between patient body weight and Tamiflu PK parameters were calculated.
The study concluded that adjusting the dose of Tamiflu in critically ill patients with body weight ranging between 50 to 200 kg was unnecessary based on the correlation with PK parameters. The correlation showed that body weight was not associated with volume of distribution (Vd) of Tamiflu and its active metabolite (oseltamivir carboxylate). Therefore, dose adjustment for obese patients is not necessary. However, the study had no control group, namely, the comparison of Tamiflu PK parameters between obese patients and non-obese patients was missing. Also, the efficacy of Tamiflu could not be solely based on PK parameters such as volume of distribution.
Another phase four, open-label, cohort study was done on 21 healthy adult volunteers with Class III obesity (BMI ≥ 40kg/m2). Subjects self-administered Tamiflu 75 mg twice a day. Plasma samples were collected at different time intervals and analyzed to generate PK parameters. The result showed that there was a poor correlation between body size and apparent clearance (Cl) of Tamiflu and its active metabolite (oseltamivir carboxylate). The study concluded that dose modification of Tamiflu based on weight was not needed. Similar to the previous study, there was no control group comparing obese patients versus non-obese patients or patients receiving a doubled dose versus a regular dose. Also the conclusions of the study were based on the apparent clearance of Tamiflu.
The only controlled study (OPTIMO trial) was a single-center, open-label, non-randomized PK study of single dose Tamiflu and steady state Tamiflu. The study compared PK parameters in healthy, morbidly obese (BMI >40) with healthy, non-obese (BMI <30) subjects. Tamiflu 75 mg was administered on day 1 to both groups followed by 75 mg twice a day on day 2 to day 5. The PK parameters for Tamiflu and the active metabolite were evaluated.
The study showed that the systemic exposure of Tamiflu was reduced in morbid obese subjects (BMI>40) (Cmax: 33 vs. 68, p = 0.009, AUC0-12: 85 vs. 134, p=0.001). However, the active metabolite was unchanged (Tmax: 370 vs. 430, P =0.123, AUC0-12: 2800 vs. 3600, p = 0.075). Therefore, the study recommended that dose adjustment of Tamiflu in obese patients was not needed.
Several PK studies showed that there was no significant correlation between body size and PK parameters (Cmax, Vd, AUC, Cl) of Tamiflu. These studies could support future randomized clinical trials on the efficacy and safety studies of doubled dose Tamiflu in obese patients. However, it is difficult for healthcare professionals to make clinical judgment solely based on current PK studies. At the same time, renal function needs to be monitored closely when Tamiflu dose is doubled in obese patients especially for patients with CrCl <30ml/min.
Tamiflu Prescribing Information. Access on 01/20/2013
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Louie, J. K., Acosta, M. et al. A Novel Risk Factor for a Novel Virus: Obesity and 2009 Pandemic Influenza A (H1N1). CID 2011:52
Ariano, R. E., et al. Enteric Absorption and Pharmacokinetics of Oseltamivir in Critically Ill Patients with Pandemic (H1N1) Influenza. CMAJ 2010. 182:357–363.
Pai, M. P., Lodise, T. P. Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults: Dose Modification for Weight Is Not Necessary. Antimicrobial Agents and Chemotherapy, Dec. 2011, p. 5640–5645.
Thorne-Humphrey, L.M., Goralski, K.B. et al. Oseltamivir Pharmacokinetics in Morbid Obesity (OPTIMO trial). Journal of Antimicrobial Chemotherapy 2011. 66: 2083 – 2091
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