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Overview of Oseltamivir Phosphate (Tamiflu®) and Key Points

Monthly Clinical Issues in Biosecurity Series

By Luciana L. Borio, M.D., Eric Toner, M.D., and John Bartlett, M.D., August 11, 2005

Mechanism of Action | Indications | Efficacy | Prophylaxis | Resistance | Dosage | Drug Interactions | Safety and Tolerability | Pregnancy | Conclusion | References

Oseltamivir is a neuraminidase inhibitor approved for the treatment and prophylaxis of influenza A and B. Zanamivir (Relenza®), another available neuraminidase inhibitor is FDA-approved only for the treatment of influenza A and B. Both drugs are structurally similar and are comparably potent for inhibition of neuraminidase and influenza A and B virus replication in vitro.

The federal government is in the process of stockpiling significant amounts of oseltamivir for use in the event of an influenza pandemic. Although limited in supply, oseltamivir is the preferred drug, since most influenza isolates from Southeast Asia are resistant to adamantanes (amantadine, rimantadine) [1]. There are no published data on the efficacy of early treatment with neuraminidase inhibitors against avian influenza in humans. However, oseltamivir is effective against H5N1 in vitro and in animal studies [2].

Mechanism of Action

Oseltamivir inhibits the neuraminidase enzyme, which is expressed on the viral surface. The enzyme promotes release of virus from infected cells and facilitates viral movement within the respiratory tract. In the presence of neuraminidase inhibitors, virions stay attached to the membrane of infected cells and are also entrapped in respiratory secretions [3].

Indications

Oseltamivir is licensed for the treatment of acute, uncomplicated influenza infection in patients older than 1 year of age who have been infected for no more than 2 days, and for the prophylaxis of influenza in persons aged 13 years and older.

Efficacy

Cell culture assays suggest that oseltamivir is active against the neuraminidase of a wide range of influenza viral strains, including the avian H5N1 virus that caused the outbreak in Hong Kong in 1997 [4]. However, in vitro activity may vary significantly depending on the assay method and virus tested. A recent study that used a mouse model of disease suggests that treatment of H5N1 infection may require a longer course and higher dosage of oseltamivir [2]. (Please refer to CBN weekly bulletin of 7/26/05)

Oseltamivir reduces the severity and duration of symptoms of acute, uncomplicated influenza, but efficacy depends on the lag time between symptom onset and start of therapy; earlier treatment has a greater impact. Oseltamivir has never been tested for efficacy against influenza pneumonia. However, oseltamivir therapy reduces viral shedding [5] and is used at times in hospitalized patients with influenza in an attempt to prevent nosocomial transmission. To date, all of the randomized clinical trials designed to test the efficacy of oseltamivir were done on non-avian strains of influenza. Oseltamivir therapy did not affect the outcome for patients with avian influenza in Vietnam between December 2003 and January 2004 [6]. However, as described, treatment was begun late, after symptoms were well established.

In two placebo-controlled, double-blind clinical trials, the median time to symptomatic improvement was 1.3 days in 849 adult patients infected with influenza who started oseltamivir within 40 hours of symptom onset. Patients were treated with oseltamivir 75 mg po bid for 5 days. Efficacy was improved when therapy was started within 24 hours of onset of symptoms, but it was not affected by higher doses (150 mg po bid for 5 days) [7,8]. Results were similar in a trial of pediatric patients [9].

Oseltamivir may also reduce hospitalization and secondary complications of influenza [10,11]. In one study, pneumonia, bronchitis, sinusitis, and otitis media were reduced by 50% in patients who received oseltamivir as compared with those who received placebo [7].

Prophylaxis

The efficacy of oseltamivir in preventing influenza has been studied in seasonal prophylaxis trials, experimental inoculation, and postexposure prophylaxis in households. In a randomized, double-blind, placebo-controlled trial with 1559 unvaccinated healthy subjects, oseltamivir prophylaxis demonstrated 74% protective efficacy during a peak period of local influenza activity. The incidence of influenza illness was 1.2% with oseltamivir prophylaxis for 6 weeks, and 4.8% with placebo. Two episodes of breakthrough influenza occurred in the oseltamivir group; both viral isolates were susceptible to oseltamivir [12].

In a randomized, double-blind, placebo-controlled trial in 37 healthy, unvaccinated subjects between 18 and 40 years of age, oseltamivir prophylaxis demonstrated 61% efficacy against experimental influenza A (intranasal inoculation). Subjects were randomized to one of three regimens (100 mg po qd, 100 mg po bid, or placebo) 26 hours prior to viral inoculation. Prophylaxis was continued for 5 days. Laboratory-confirmed infection occurred in 67% of patients in the placebo group compared with 38% of patients in the oseltamivir group. None of the subjects who received oseltamivir developed symptoms of an upper respiratory tract infection, as compared with 33% of placebo group subjects [13]. In another randomized double-blind, placebo-controlled study to evaluate the efficacy of oseltamivir in preventing disease in household contacts of influenza-infected persons, oseltamivir’s protective efficacy was 89% for individuals and 84% for households. Index cases were not treated with the drug [14].

Resistance

Resistance may be associated with mutations in the viral neuraminidase or hemagglutinin or both. Serial passage of influenza virus in cell culture in the presence of oseltamivir leads to resistance, and clinical isolates from treated patients have been found to be resistant as well [7,15]. Cross-resistance between oseltamivir and zanamivir may also occur depending on the location of the amino acid substitution. Other mutations may lead only to variable cross-resistance between the neuraminidase inhibitors. Although resistant strains replicate efficiently in vitro, they show lessened infectivity and virulence in animal models [16].

In a pediatric trial with 50 children, 9 (18%) children with confirmed influenza A infection who were treated within 48 hours of symptom onset developed resistance to oseltamivir beginning at day 4 of treatment. Some of the mutations identified would confer cross-resistance to any other neuraminidase-inhibitor medication, such as zanamivir. However, in this study, children weighing less than 15 kg received a dose of oseltamivir lower than recommended [17]. Evidence suggests that dose or duration of treatment or prophylaxis other than what has been FDA-approved may not be effective and may contribute to emergence of viral resistance [5].

Dosage (Healthy Adults)

  • Treatment: 75 mg po bid x 5 days, within 48 hours of onset of influenza symptoms

  • Prophylaxis: 75 mg po qd, within 48 hours of exposure, for at least 7 days following close contact exposure or up to 6 weeks during a community outbreak

According to the Center for Disease Control and Prevention, if an exposed person is vaccinated, the course of oseltamivir prophylaxis could be shortened to 14 days, the time it takes on average for antibodies to develop in adults [18].

Dose should be adjusted for those with a serum creatinine clearance of <30 mL/min. Children are dosed according to weight. Please refer to the Complete Product Information for additional information on dosage and administration.

Drug Interactions

Neuraminidase inhibitors are likely to reduce the replication and immunogenicity of intranasal, live-attenuated influenza vaccines. Neuraminidase inhibitors do not impair the antibody response to injected, inactivated influenza vaccine.

Safety and Tolerability

Oseltamivir is well-tolerated; the most common adverse events are nausea and vomiting.

 Treatment Prophylaxis 
Adverse EventPlacebo N=716Oseltamivir N=724Placebo N=1434Oseltamivir N=1480
Nausea40 (5.6%)72 (9.9%)56 (3.9%)104 (7.0%)
Vomiting21 (2.9%)68 (9.4%)15 (1.0%)31 (2.1%)

                   

Pregnancy

Oseltamivir is a Pregnancy Category C drug due to insufficient data regarding its risks to pregnant women and developing fetuses. Zanamivir, the other licensed neuraminidase inhibitor, is administered via inhalation and reaches systemic concentrations lower than that of oseltamivir. For this reason, at their last joint meeting in 2005, the National Vaccine Advisory Committee and the Advisory Committee on Immunization Practices discussed whether zanamivir should be the preferred neuraminidase inhibitor for unvaccinated pregnant women in the event of an influenza pandemic. No official recommendation has been issued yet.

Conclusion

Oseltamivir is safe and well-tolerated. Early treatment of uncomplicated influenza reduces disease severity and duration. Efficacy in the setting of infection with avian influenza is still unknown. The National Vaccine Advisory Committee and the Advisory Committee on Immunization Practices have recommended that the U.S. government stockpile at least 40 million treatment courses of oseltamivir to support critical influenza pandemic responses. (Please refer to CBN weekly bulletin of 8/2/05) However, the drug is expensive, and supplies and production capacity remain limited. Resistance may develop during therapy at a relatively low rate, but it is conceivable that resistance may develop more frequently during times of wide-scale use. Clinical studies to determine the efficacy of oseltamivir against H5N1 infection are needed. Studies to determine the efficacy of oseltamivir to treat severe, complicated influenza infection and for reducing influenza transmission to contacts are also needed.

References

  1. Normile D, Enserink M. Infectious diseases. Lapses worry bird flu experts. Science. Jun 24 2005;308(5730):1849-1851.

  2. Yen HL, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic a/vietnam/1203/04 influenza virus in mice. J Infect Dis. Aug 15 2005;192(4):665-672.

  3. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. Mar 4 2000;355(9206):827-835.

  4. Doucette KE, Aoki FY. Oseltamivir: a clinical and pharmacological perspective. Expert Opin Pharmacother. Oct 2001;2(10):1671-1683.

  5. Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. Feb 2005;55 Suppl 1:i5-i21.

  6. Hien TT, de Jong M, Farrar J. Avian influenza--a challenge to global health care structures. N Engl J Med. Dec 2 2004;351(23):2363-2365.

  7. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. Feb 23 2000;283(8):1016-1024.

  8. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother. Jan 2003;51(1):123-129.

  9. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. Feb 2001;20(2):127-133.

  10. Nordstrom BL, Sung I, Suter P, Szneke P. Risk of pneumonia and other complications of influenza-like illness in patients treated with oseltamivir. Curr Med Res Opin. May 2005;21(5):761-768.

  11. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med. Jul 28 2003;163(14):1667-1672.

  12. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. Oct 28 1999;341(18):1336-1343.

  13. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. Oct 6 1999;282(13):1240-1246.

  14. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA. Feb 14 2001;285(6):748-754.

  15. McKimm-Breschkin JL. Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance. Treat Respir Med. 2005;4(2):107-116.

  16. Carr J, Ives J, Kelly L, et al. Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res. May 2002;54(2):79-88.

  17. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. Aug 28-Sep 3 2004;364(9436):759-765.

  18. Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. Jul 29 2005;54(RR-8):1-40.

Draft Pandemic Influenza Response and Preparedness Plan

Material presented at the Joint Meeting of the National Vaccine Advisory Committee and the Advisory Committee on Immunization Practices on July 19, 2005