Oseltamivir (Tamiflu®): Current Treatment Indications and Its Role in the Treatment/Prevention of Avian Influenza
Editors Note: It is difficult to turn on the news, read the newspaper or scan a journal without seeing dire warnings about a possible pandemic of Avian flu. As governments stockpile large amounts of oseltamivir and zanamivir, it is incumbent upon physicians to understand the role of these neuraminidase inhibitors in the management of this dreaded disease. This supplement to Internal Medicine Alert is designed to provide you with this information as well information about oseltamivir in influenza A and B. Stephen A. Brunton, MD
By Jessica C. Song, MA, PharmD, Assistant Professor of Pharmacy Practice, University of the Pacific, Stockton, CA, and Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center Dr. Song reports no consultant, stockholder, speaker’s bureau, research, or other financial relationship with companies having ties to this field of study.
Neuraminidase inhibitors are a class of antivirals that have activity against both influenza A and B viruses.1 Influenza neuraminidase cleaves terminal sialic acid residues and damages the receptors recognized by viral hemagglutinin, thereby facilitating release of virus from infected cells. In the presence of a neuraminidase inhibitor, release of virus from infected cells is impaired and the progeny viruses that are freed clump together, as sialic acid has not been cleaved.2 Two neuraminidase inhibitors are currently available for use in the United States and include oseltamivir (Tamiflu, released in 1999, Roche Pharmaceuticals, Nutley, New Jersey)3 and zanamivir (Relenza, released in 1999, GlaxoSmithKline, Research Triangle Park, North Carolina).4 Oseltamivir is approved for the treatment of uncomplicated acute illness due to influenza A/B for patients, 1 year and older, who have been symptomatic for no more than 48 hours,3 whereas, zanamivir is approved for treating patients 7 years and older.4 In addition, oseltamivir is approved for the prophylaxis of influenza in adult patients and adolescents who are 13 years and older.3 Current formulations of oseltamivir include capsules and oral powder for solution. In contrast, zanamivir is administered through inhalation by using a plastic device, a complicated process that may limit its utility for patients with limited manual dexterity.4
Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus, which was first identified in Italy over 100 years ago. Currently, there are 15 different viral subtypes; subtypes H5 and H7 are thought to cause a highly pathogenic form of the disease in birds, triggering a sudden onset of symptoms, severe illness, and rapid death, with mortality rates approaching 100%.5 Domestic poultry, such as chickens and turkeys are particularly susceptible to these subtypes. Although avian influenza viruses ordinarily do not infect species other than birds and pigs, the first documented infection of humans occurred in Hong Kong in 1997, when 18 humans experienced infections associated with severe respiratory disease, 6 of whom died. A total of 89 human infections with influenza A (H7N7), which began in the Netherlands in February 2003, resulted in one death and mild illness in other affected individuals.6 Since 2003, outbreaks of avian influenza (H5N1) have occurred in 8 countries in Asia, including Cambodia, China, Laos, Indonesia, Japan, South Korea, Thailand, and Vietnam. During December 2003 to August 5, 2005, over 100 human cases of avian influenza A (H5N1) were reported in Vietnam (90), Thailand (17), Cambodia (4), and Indonesia (1), with mortality rates ranging from 44% to 100%.7 Virtually all human cases have occurred in people who had direct contact with live, infected poultry. Recently, at least a few cases of possible human-to-human transmission of H5N1 virus have been identified in Hong Kong, Vietnam, and Thailand.8 In light of the fact that the currently available influenza vaccines do not protect against influenza A (H5N1 and H7N7), and that these strains are resistant to amantadine/rimantadine, it is of critical importance to evaluate the role of neuraminidase inhibitors in the treatment of avian influenza.7 This article will: 1) review the pharmacology, pharmacokinetics, and FDA/investigational indications of oseltamivir, 2) review its drug interactions and dosage, and 3) review the safety and efficacy of oseltamivir.
Pharmacologic/Other Clinical Properties of Oseltamivir
Table 1 summarizes the mechanism of action, spectrum of activity, FDA indications, pharmacokinetics, dosing/administration, contraindications, adverse effects, drug interactions, and cost of oseltamivir.
Activity of Oseltamivir and Zanamivir Against Avian Influenza Virus
To date, one in vitro study has compared the efficacies of various neuraminidase inhibitors against H5N1 and other avian influenza viruses.9 Govorkova and colleagues evaluated the inhibition of neuraminidase activity of 9 subtype avian influenza A viruses (N1-N9) by an investigational neuraminidase inhibitor (RWJ-270201), oseltamivir, and zanamivir. The drug concentrations required to reduce the neuraminidase activity by 50% (IC50) were 0.9-4.3 nM, 1.9-69.2 nM, and 2.2-30.1 nM, respectively, for RWJ-270201, oseltamivir, and zanamivir. In this same study, the inhibition of avian influenza viral replication (strains N1-N9) was determined by the EC50s (50% effective concentration) of RWJ-270201, oseltamivir, and zanamivir. The range of EC50 values yielded by RWJ-270201, oseltamivir, and zanamivir were 0.5-11.8 M, 1.0-42.0 M, and 4.0-58.3 M, respectively. Complete protection of H5N1-infected mice was achieved at a dosage of 0.1 mg/kg/day with oseltamivir and at a dosage of 10 mg/kg/day with RWJ-270201.
Clinical Efficacy of Oseltamivir
At present, no clinical studies have directly compared the efficacy of oseltamivir to that of zanamivir in the management of uncomplicated influenza infections. Clinical studies have shown that oseltamivir and zanamivir shorten the duration of influenza symptoms by 1-2 days if used within 48 hours of illness onset.10-16 Moreover, administration of oseltamivir is associated with protective efficacies of 74% and 90%, respectively, for seasonal prophylaxis and for individual household contacts of influenza-infected index cases.10 Table 2 summarizes the key findings of numerous clinical trials that evaluated the efficacy of oseltamivir for the treatment and prevention of influenza virus infections.
To date, reports of oseltamivir use in the treatment of avian influenza virus infections are scarce, as a total of 6 patients have been documented to receive this agent.6,8 Of the 6 patients with avian influenza who were given oseltamivir, 3 survived despite the fact that treatment was delayed (started after 48 hours of illness). The World Health Organization is recommending that oseltamivir 75 mg orally twice daily for 5 days should be started as soon as possible in the clinical course of acute influenza A (H5N1) infection in adults. Post-exposure prophylaxis with oseltamivir 75 mg orally once daily for 7 days is advised for healthcare personnel who may have been exposed to droplets from a patient. Recommended doses for children are highlighted in Table 1.17
Conclusion
There is a crucial need for antiviral agents that are effective against highly pathogenic avian influenza A strains, as the threat of a future avian influenza pandemic is possibly imminent. Currently, H5N1 viruses have been shown to be susceptible in a laboratory setting to the neuraminidase inhibitors, oseltamivir, and zanamivir. Oseltamivir has been used successfully in the management of 3 patients infected with avian influenza A (H5N1) virus, whereas the use of zanamivir has yet to be reported in patients infected with avian influenza A virus. Oral formulations of zanamivir are not available, and administration is limited to the inhalation route. This represents a potential disadvantage compared with oseltamivir, which is available as oral formulations (capsule, powder for solution). However, in the event that stockpiling of oseltamivir results in shortages of this agent at some institutions, use of zanamivir as an alternative agent for the treatment of acute avian influenza A viral infections should be considered.
References
1. Harper SA, et al. Prevention and Control of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54:1-40.
2. Monto AS. The Threat of an Avian Influenza Pandemic. N Engl J Med. 2005;352:323-325.
3. Oseltamivir (Tamiflu) Product Information. Nutley, New Jersey: Roche Pharmaceuticals; June 2004.
4. Zanamivir (Relenza) Product Information. Research Triangle Park, North Carolina: GlaxoSmithKline; April 2003.
5. World Health Organization Media Centre. Avian Influenza. www.who.int/mediacentre/factsheets/avian_influenza/en/ Accessed on August 10, 2005.
6. Tran TH, et al. Avian Influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med. 2004;350:1179-1188.
7. World Health Organization Communicable Disease Surveillance and Response. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) reported to WHO. www.who.int/csr/disease/avian_influenza/country/cases_table_2005_08_05/en/index.html Accessed on August 10, 2005.
8. Ungchusack K, et al. Probable Person-to-Person Transmission of Avian Influenza A (H5N1). N Engl J Med. 2005;352:333-340.
9. Govorkova EA, et al. Comparison of Efficacies of RWJ-270201, Zanamivir, and Oseltamivir Against H5N1, H9N2, and Other Avian Influenza Viruses. Antimicrob Agents Chemother. 2001;45:2723-2732.
10. Cooper NJ, et al. Effectiveness of Neuraminidase Inhibitors in Treatment and Prevention of Influenza A and B: Systematic Review and Meta-Analyses of Randomised Controlled Trials. BMJ. 2003;326:1235.
11. Aoki FY, et al. Early Administration of Oral Oseltamivir Increases the Benefits of Influenza Treatment. J Antimicrob Chemother. 2003;51:123-129.
12. Kaiser L, et al. Impact of Oseltamivir Treatment on Influenza-Related Lower Respiratory Tract Complications and Hospitalizations. Arch Intern Med. 2003;163:1667-1672.
13. 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.
14. Nicholson KG, et al. Efficacy and Safety of Oseltamivir in Treatment of Acute Influenza: A Randomised Controlled Trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355:1845-1850. Erratum in: Lancet. 2000;356:1856.
15. Hayden FG, et al. Use of the Selective Oral Neuraminidase Inhibitor Oseltamivir to Prevent Influenza. N Engl J Med. 1999;341:1336-1343.
16. Welliver R, et al. Effectiveness of Oseltamivir in Preventing Influenza in Household Contacts: A Randomized Controlled Trial. JAMA.. 2001;285:748-754.
17. World Health Organization. WHO Interim Guidelines on Clinical Management of Humans Infected by Influenza A (H5N1). www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage/en/ Accessed on August 10, 2005.
Neuraminidase inhibitors are a class of antivirals that have activity against both influenza A and B viruses. Influenza neuraminidase cleaves terminal sialic acid residues and damages the receptors recognized by viral hemagglutinin, thereby facilitating release of virus from infected cells. In the presence of a neuraminidase inhibitor, release of virus from infected cells is impaired and the progeny viruses that are freed clump together, as sialic acid has not been cleaved.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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