Drug Information Center

• Drug Information Group
• Department of Pharmacy Practice
• About Us
• People
• Potential Partnerships
• The RxPress
• Residency Program
• Frequently Asked Questions
• Contact Us
• Feedback

What place in therapy does oseltamivir 150 mg twice daily have for treatment of H1N1?

Introduction

The first cases of human infection with novel influenza A (H1N1), which is now referred to as 2009 H1N1, were reported in the United States in April 2009, and the virus continues to spread.¹ According to epidemiologic data from the Centers for Disease Control and Prevention (CDC), 2009 H1N1 is the predominant strain responsible for almost all cases of influenza so far this season.² Furthermore, data reveal that hospitalizations and deaths due to influenza are higher than expected for this time of year.^2,3 Rapid progression of lower respiratory tract disease may result in respiratory failure, or worse, acute respiratory distress syndrome (ARDS), leading to hospital admission and prolonged stay in the intensive care unit (ICU).¹ High-dose oseltamivir (150 mg orally twice daily as opposed to the traditional 75 mg twice daily) has been reported at some institutions for treatment of more severely ill patients. The purpose of this article is to provide a brief overview of the interim recommendations for 2009 H1N1, discuss pharmacokinetic parameters of oseltamivir that may allow for higher, non-traditional dosing, and review the body of evidence supporting high-dose oseltamivir therapy

Interim recommendations (CDC)

The CDC recommends treatment with oseltamivir or zanamivir in all patients with suspected or confirmed influenza requiring hospitalization.⁴ Patients at higher risk for complications should be considered for early empiric treatment in the outpatient setting. These include:

When indicated, treatment should be initiated as soon as possible (within 48 hours of onset of symptoms) to provide the most benefit and reduce the risk of severe outcomes such as severe illness or even death.⁴ Currently, the 2009 H1N1 strain is reported to be susceptible to oseltamivir and zanamivir. The CDC mentions that some experts have suggested doubling the dose of oseltamivir (to 150 mg twice daily) for patients severely ill with 2009 H1N1 influenza; however, efficacy data are lacking. A physician resource available on the American Medical Association’s website provides potential rationale for using higher doses or prolonged treatment courses in patients with H1N1 who are severely ill.⁵ Theories include concerns regarding a potential for decrease in oseltamivir absorption, impaired distribution to damaged tissue in the severely ill, and increased viral loads.

Oseltamivir

Oseltamivir is a pro-drug hepatically converted to oseltamivir carboxylate.⁶ As a pro-drug, it is readily absorbed from the gastrointestinal tract with the active metabolite displaying bioavailability of 75% to 80%. After single doses of up to 1000 mg, plasma concentrations of drug and metabolite were proportional to dose indicating that higher doses produce higher levels without saturable absorption. Oseltamivir displays linear, dose-proportional kinetics at doses up to 500 mg twice daily. Following conversion by first-pass metabolism, oseltamivir and its metabolite undergo exclusive renal elimination. Oseltamivir carboxylate reaches measurable plasma concentrations within 30 minutes, and near-maximal levels are reached 2 to 3 hours post-dose. Plasma concentrations rapidly decline with a 1 to 3 hour elimination half-life, but twice daily administration is appropriate since the active metabolite sustains plasma concentrations with a half-life of 6 to 10 hours.

Review of the literature

General influenza data

High-dose oseltamivir 150 mg twice daily, with increased duration up to 10 days, has been suggested for treatment of avian influenza A (H5N1).⁷ This dosing strategy is suggested due to the high levels of replication and progression of disease despite patient receipt of standard-dose oseltamivir within 1 to 3 days of symptoms. Nicholson and colleagues have shown high-dose oseltamivir (150 mg twice daily) to have similar tolerability to traditional doses of oseltamivir (75 mg twice daily) in previously healthy adults with influenza-like illness (66% with laboratory-confirmed influenza).⁸ The trial was not powered to detect a difference in efficacy between the 2 dosing regimens; however, both were superior to placebo in terms of reducing the duration of illness.

Treanor and colleagues studied oseltamivir in 627 previously healthy adults aged 18 to 65 who presented with influenza symptoms and were randomized to treatment for 5 days with either oseltamivir 75 mg (n=201) or 150 mg orally twice daily (n=208), or placebo (n=209).⁹ The primary endpoint was time to symptom resolution. Overall, both doses of oseltamivir reduced the duration of illness by about 1 day compared to placebo (4.3 days placebo, 3 days 75 mg, 2.9 days 150 mg). The severity of influenza symptoms was also reduced with oseltamivir 75 mg and 150 mg doses compared to placebo (p<0.001 and p=0.006, respectively). No differences were found between the doses of active treatment. Oseltamivir was well tolerated, and no drug-related serious adverse events occurred. Gastrointestinal side effects such as nausea and/or vomiting occurred more frequently in patients receiving oseltamivir, but rates were similar for 75 mg and 150 mg doses. Nausea occurred in 35 (17%) of 206 patients on 75 mg versus 39 (19%) of 205 receiving 150 mg, and rates of vomiting for 75 mg versus 150 mg were 27/206 (13.1%) and 31/205 (15.1%), respectively. The occurrence of nausea and vomiting was significantly greater with active therapy compared to placebo (placebo rates: 7.4% nausea and 3.4% vomiting). The number of patients withdrawing from therapy due to adverse effects was 3%, 1.5%, and 2% for placebo, 75 mg, and 150 mg doses, respectively.

Data from the above studies confirm that oseltamivir is generally well tolerated at doses of 150 mg orally twice daily.^8,9

2009 H1N1 specific data

Several case reports have emerged using oseltamivir 150 mg orally twice daily for 2009 H1N1 influenza.^1,10 The University of Michigan Health System (UMHS) surgical intensive care unit (SICU) specializes in evaluation and treatment of adults with severe ARDS. They reported 10 confirmed cases of H1N1 in May and June 2009.¹ All 10 patients received oseltamivir 150 mg orally twice daily plus amantadine longer than the standard 5-day duration. Of these, 9 patients were obese (body mass index [BMI] ≥30), 7 were extremely obese (BMI ≥40), and all 10 required mechanical ventilation. Six of the patients required continuous renal replacement therapy (CRRT). It is unknown whether obesity is a risk factor for severe complications due to 2009 H1N1, but the presence of comorbid conditions generally places patients at an increased risk for complications of influenza. At the time of publication, 3 of the 10 patients had expired, 5 were stable, and 2 were still receiving care in the SICU.

Reports of resistance have begun to infiltrate the United States. One such incidence, from Seattle, WA in August 2009, reported 2 cases of immunosuppressed patients with oseltamivir-resistant 2009 H1N1.¹⁰ Both patients were initially infected with oseltamivir-susceptible viruses. Later isolates showed resistance had developed during antiviral treatment. Pyrosequencing revealed a mutation in the neuraminidase resulting in a histidine-to-tyrosine substitution at position 275 (H275Y). This resistance occurred in the presence of high-dose oseltamivir (150 mg twice daily, prolonged course) indicating that resistance may not be overcome by increased doses. The authors suggest that immunocompromised patients receiving prolonged courses of antiviral therapy should be monitored for development of resistance.

Summary

Data to support the use of 150 mg twice daily oseltamivir for 2009 H1N1 are limited to case reports in severely ill patients; however, the tolerability of this regimen can be extrapolated from clinical trials involving other types of influenza. This dosing regimen is mentioned in the CDC 2009-2010 influenza treatment recommendations, and may be an option for patients with underlying pulmonary disease, immunocompromised patients or those severely ill and hospitalized. Higher doses may be an option in obese patients as well since comorbid conditions often predispose them to an increased risk of influenza complications. Viral resistance to oseltamivir can still develop with use of higher doses as evidenced in the Seattle case series. High-dose oseltamivir is well tolerated with no significant increase in adverse effects compared with traditional doses and is a reasonable treatment strategy for 2009 H1N1 influenza.

References

By Ashley Hall, PharmD