Alternative Dosing of Oseltamivir for Specific Patient Populations: Critically Ill and Renally Impaired
Abstract & Commentary
By Oliver Hsu, PharmD Candidate, at the University of the Pacific.
Linda Truong, PharmD Candidate, at the University of the Pacific.
Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care is Associate Editor for Infectious Disease Alert.
Oliver Hsu, Linda Truong, and Jessica C. Song report no financial relationships relevant to this field of study.
Oseltamivir (tamiflu®) is an fda-approved drug for the treatment and prevention of influenza.1 With the anticipated emergence of seasonal influenza virus cases in October,2 and the recent discoveries of novel H5N1 (avian) and 2009 H1N1 (swine) influenza viruses, it is imperative to understand how to appropriately dose oseltamivir.
In the past, oseltamivir has mainly been used for seasonal influenza in children, the elderly, pregnant patients, people with certain chronic conditions, and people who need to be hospitalized.3 It has gained much more attention recently because of the discovery of the 2009 H1N1 influenza virus. The 2009 H1N1 viruses are generally susceptible to oseltamivir, making the drug vital for the treatment of H1N1 infections.3
In treating influenza, the recommended dose of oseltamivir for healthy adults is 75 mg twice daily for five days; for prophylaxis, the dose is 75 mg once daily for at least 10 days.1 However, there is little guidance in dosing for certain high-risk patient populations, such as the critically ill and renally impaired patients.
The purpose of this article is to describe the dosing of oseltamivir in patient populations where there are currently no official recommendations. This article will discuss clinical research where clinicians experimented with off-label dosing of oseltamivir.
Dosing in Critically Ill Patients
In June 2009, 10 patients in a Michigan surgical intensive care unit (SICU) presented with 2009 influenza A (H1N1).4 Nine of the 10 patients had body mass indices (BMIs) of 30 kg/m2 or higher, and seven had BMIs of at least 40 kg/m2. All 10 patients had refractory ARDS (acute respiratory distress syndrome) and were admitted to the ICU for advanced mechanical ventilation. Since these patients were transferred from other hospitals, the timing of antiviral treatment initiation could not be established, but the estimated number of days from onset of illness to initiation of treatment was eight days. All 10 patients received amantadine and oseltamivir for a total duration in excess of the standard five-day course. Also, the hospital used higher doses of oseltamivir (up to 150 mg orally twice daily), with dose adjustments for patients with decreased renal function.4
The outcomes of using amantadine with high-dose oseltamivir in the Michigan SICU varied: one patient remained in critical care, one remained on mechanical ventilation, five patients' conditions stabilized sufficiently to allow for transfer to their original hospitals, and three died.4 Autopsies on two patients attributed the deaths to the 2009 H1N1 viral infection, evidenced by bilateral severe hemorrhagic viral pneumonitis, diffuse alveolar damage, and bilateral pulmonary emboli. The report noted no significant adverse events associated with their treatment, giving credence to the use of high-dose oseltamivir (150 mg twice daily) beyond the recommended five days in obese patients with severe H1N1 viral infection.4
Treatment with high-dose oseltamivir can be considered for various situations, such as in the treatment of the critically ill obese patients and in oseltamivir-resistant influenza strains, which appears to be on the rise. As the 2009 H1N1 rose to prominence this year, the number of case reports of oseltamivir-resistant influenza A has also increased. In some cases, despite the initial susceptibility of 2009 H1N1 virus to oseltamivir, resistance developed over the course of treatment. In one case report from Seattle, the patient underwent successful treatment with high-dose oseltamivir (150 mg orally twice daily) after reported resistance to oseltamivir.5 Patients presenting with oseltamivir-resistant strains of influenza can also be treated with zanamivir, but poor tolerance and the difficulty of drug administration limits the practicality of its use.
In comparison to conventional oseltamivir dosing (75 mg orally twice daily), 150 mg twice daily regimens have been associated with slightly larger decreases in the duration (~ 2 hours; statistically nonsignificant) and severity of illness.6 These slight improvements in the duration and severity of illness may not be significant in previously healthy patients presenting with influenza but, in critically ill patients, there is a strong possibility that inadequate drug concentrations can adversely affect therapeutic outcomes. The dose recommended in uncomplicated influenza may be insufficient in critically ill patients presenting with concomitant diarrhea, requiring a higher therapeutic dose to effectively eradicate the virus.7 Wattanagoon et al suggest administering a loading dose 25% higher than the maintenance dose in severely ill patients.8
A dose-ranging study conducted by Hayden et al revealed a greater than two-fold higher rate of upper gastrointestinal effects, such as nausea, in patients receiving 200 mg doses of oseltamivir, compared with the rates observed in patients receiving lower doses (20 mg, 100 mg).9 In contrast, studies of oseltamivir-treated patients receiving doses ranging from 75 mg twice a day to 150 mg twice a day have not shown significantly different rates of upper gastrointestinal adverse effects.6,10 Nicholson et al found that, in patients who were previously healthy, the incidence of nausea and vomiting differed by a mere 2% (nonsignificant difference) between conventional dose and high-dose oseltamivir groups.10 Similarly, Treanor et al determined that higher-dose oseltamivir did not result in significantly higher rates of nausea and vomiting compared with conventional doses of oseltamivir.6
Oseltamivir is a prodrug that is converted by hepatic carboxylesterases to its active metabolite, oseltamivir carboxylate. After the administration of multiple doses, it displays linear and dose-proportional pharmacokinetics up to doses of 500 mg twice daily.11 Moreover, gender, age, or weight does not appear to modify the pharmacokinetic properties of oseltamivir or oseltamivir carboxylate.11 Aside from being given at a higher dose to increase therapeutic levels, oseltamivir can also be given concomitantly with probenecid.8 Probenecid decreases the renal clearance of oseltamivir and, thus, increases the AUC (area under the concentration time-curve). Wattanagoon et al found that the coadministration of oseltamivir with probenecid 500 mg led to a reduction in the renal clearance of oseltamivir by 61% and an increase in the AUC of oseltamivir by 154%.8
In severely ill patients presenting with influenza, it is imperative to effectively treat the patient and prevent catastrophic sequelae. It is possible that this may be accomplished by increasing the dose of oseltamivir in order to reach therapeutic levels more quickly. When dosing obese patients, there is a concern about sufficient distribution of the drug, as well as increased elimination. Obese patients have more functional nephrons and, because oseltamivir carboxylate undergoes renal elimination, it is cleared faster in obese patients. Decreasing the time required to reach therapeutic levels can be accomplished in several ways: administering oseltamivir at a higher dose (150 mg orally twice daily), administering oseltamivir with a loading dose 25% higher than the maintenance dose, or administering oseltamivir with probenecid.
Dosing in Renally Impaired Patients
Since 99% of the active metabolite of oseltamivir is renally cleared through both glomerular filtration and tubular secretion, a potential dosing problem emerges in those with impaired renal function, a common problem in the United States (11% prevalence of chronic kidney disease).12
The manufacturer of oseltamivir recommends a dosing regimen of oseltamivir 75 mg once daily for five days in patients with a creatinine clearance between 10 and 30 mL/minute.1 However, per the manufacturer, patients with more advanced chronic kidney disease (receiving hemodialysis/peritoneal dialysis, creatinine clearance < 10 mL/minute) should not receive oseltamivir.1
Research published on the dosing of oseltamivir for dialysis patients is scarce, but some investigators have attempted to further elucidate the pharmacokinetics of oseltamivir in this patient population. Robson et al administered oseltamivir to 12 hemodialysis and 12 continuous peritoneal dialysis patients who did not have an active influenza infection.13 The patients' Cmax (peak plasma concentration) and AUC of oseltamivir carboxylate were measured after the first dose and multiple doses of oseltamivir. Hemodialysis patients received nine doses of 30 mg oseltamivir oral suspension over 6.5 weeks; they received a dose one hour after every other hemodialysis session, which took place three times a week. Peritoneal dialysis patients received six doses of 30 mg oseltamivir oral suspension, given once a week after dialysate exchange.
Although the methods of dosing differed based on the type of dialysis, the average Cmax and AUC of oseltamivir carboxylate after multiple doses approached comparable levels for hemodialysis (Cmax 1120 ng/mL, AUC0-last 60,400 ng h/mL; 38-43 days) and peritoneal dialysis (Cmax: 849 ng/mL, AUC0-last 60,800 ng h/mL; 36-43 days) patients.13 In general, these ESRD patients had substantially higher Cmax and AUC0-last than healthy patients taking standard doses of oseltamivir, as values of Cmax and AUC in healthy subjects have been reported to be 225 ng/mL and 21,752 ng h/mL, respectively.
Despite the higher levels of active oseltamivir in ESRD patients, none of the patients withdrew from the study. The main side effects reported included diarrhea and vomiting; however, researchers decided that only two of the 18 reported adverse reactions were probably related to the drug.13 Therefore, administering oseltamivir 30 mg after alternating hemodialysis sessions or 30 mg once a week after a peritoneal dialysis session represent safe and potentially effective regimens for ESRD patients. These doses could be used for treatment of active influenza or prophylaxis.
Conclusion
Oseltamivir and zanamivir are the only antivirals available that can treat both influenza A and B in patients. Because of the difficulty in administering zanamivir, oseltamivir has emerged as the preferred agent for use in influenza prophylaxis and treatment of influenza due to susceptible storms. With the advent of pandemic H1N1 in early 2009, and the onset of the 2009 flu season, it has become imperative for clinicians to be aware of effective dosing, especially for certain patient populations who lack FDA-approved dosing guidelines. With the increase in the use of oseltamivir to prophylax for, or to treat, influenza, the cases of resistance reported will also begin to increase. By properly treating patients with effective doses, clinicians will be able to achieve better patient outcomes and limit the spread of influenza's resistance to oseltamivir. This will be especially critical in patient populations who are likely to be susceptible to influenza but may not respond well to conventional doses of oseltamivir.
References
- Centers for Disease Control and Prevention (CDC). Emergency use authorization of Tamiflu®; fact sheet for health care providers. CDC. 2009;1-3.
- The Flu Season. CDC. 14 July 2009. 9 September 2009. <http://www.cdc.gov/flu/about/season/flu-season.htm>
- Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 Season. CDC. September 8-9, 2009. http://www.cdc.gov/H1N1flu/recommendations.htm
- Centers for Disease Control and Prevention (CDC). Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR. 2009;58:749-752.
- Centers for Disease Control and Prevention (CDC). Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients - Seattle, Washington, 2009. MMWR. 2009;58:893-896.
- Treanor JJ, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA. 2000;283:1016-1024.
- Gambotto A, et al. Human infection with highly pathogenic H5N1 influenza virus. Lancet. 2008;371:1464-1475.
- Wattanagoon Y, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009;53:945-952.
- Hayden FG, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999;282:1240-1246.
- Nicholson KG, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: A randomized controlled trial. Lancet. 2000;355:1845-1850.
- Dutkowski R, et al. Safety and pharmacology of oseltamivir in clinical use. Drug Saf. 2003;26:787-801.
- Karie S, et al. Pharmacokinetics and dosage adjustment of oseltamivir and zanamivir in patients with renal failure. Nephrol Dial Transplant. 2006;12:3606-3608.
- Robson R, et al. The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 2006; 9:2556-2562.
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