Neuraminidase Inhibitors for Treatment of Influenza A and B Infections

Please note: An erratum has been published for this article. To view the erratum, please click here.

Andrea G. Winquist, M.D.
Keiji Fukuda, M.D., M.P.H.
Carolyn B. Bridges, M.D.
Nancy J. Cox, Ph.D.

Influenza epidemics are responsible for an average of approximately 20,000 deaths per year in the United States. The main method for preventing influenza and its severe complications is influenza vaccination. Influenza-specific antiviral drugs are an important adjunct to vaccine but are not a substitute for vaccine. In the United States, four antiviral agents are approved for preventing or treating influenza: amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine has been available in the United States since 1976, and rimantadine has been available since 1993. This report provides information on two neuraminidase inhibitors, zanamivir and oseltamivir, which were approved in 1999. Neuraminidase inhibitors are a new class of antiviral drugs that inhibit influenza A and B viruses. Zanamivir is approved for treatment of uncomplicated acute illness caused by influenza virus in persons aged greater than or equal to 12 years who have been symptomatic for no more than 2 days. Oseltamivir is approved for treatment of uncomplicated illness caused by influenza infection in adults aged greater than or equal to 18 years who have been symptomatic for no more than 2 days. Neither zanamivir nor oseltamivir is approved for influenza prophylaxis. This report and the Advisory Committee on Immunization Practices (ACIP) 1999 recommendations on influenza prevention and control (MMWR 1999;48[No.RR-4]:1-28) can be accessed at the website for the Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC, at <http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm> or at the MMWR website at <http://www2.cdc.gov/mmwr/>.

Uncomplicated influenza is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis) (1,2). However, in some persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease) or lead to secondary bacterial pneumonia or primary influenza viral pneumonia (1). Epidemics of influenza occur during the winter months nearly every year and are responsible for an average of approximately 20,000 deaths per year in the United States (3,4). The main method for preventing influenza and its more severe complications is immunoprophylaxis with inactivated (i.e., killed-virus) vaccine (1). Influenza-specific antiviral drugs for chemoprophylaxis or therapy are an important adjunct to vaccine, but they are not a substitute for influenza vaccine. In the United States, four antiviral agents are approved for preventing or treating influenza: amantadine hydrochloride and rimantadine hydrochloride as well as two recently approved neuraminidase inhibitors, zanamivir and oseltamivir.

Amantadine and rimantadine are chemically related antiviral drugs active against influenza A viruses but not influenza B viruses. After influenza A viruses enter cells, these drugs inhibit the uncoating of influenza A viruses by blocking the ion-channel activity of the viral M2 protein (5-10). Amantadine was approved in 1976 for treatment and prophylaxis of influenza type A infection in adults and children aged greater than or equal to 1 year. Rimantadine was approved in 1993 for treatment and prophylaxis of influenza type A infection in adults. For children, rimantadine was approved only for prophylaxis; however, many experts consider rimantadine appropriate for treatment of influenza A in children (1). (For information on the use of amantadine and rimantadine, see Recommendations for the Use of Antiviral Agents for Influenza A in the Advisory Committee on Immunization Practices 1999 recommendations on influenza prevention and control [1].)

Zanamivir and oseltamivir, both approved in 1999 by the U.S. Food and Drug Administration, are members of a new class of antiviral agents that selectively inhibit the neuraminidase of both influenza A and B viruses. Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of host cells and influenza virus envelopes; this process promotes the release of progeny viruses from infected cells (11,12). Neuraminidase inhibitors are analogues of sialic acid. Their proposed mechanism of action is to block the active site of neuraminidase and leave uncleaved sialic acid residues on the surfaces of host cells and influenza viral envelopes. Viral hemagglutinin binds to the uncleaved sialic acid residues; the result is viral aggregation at the host cell surface and a reduction in the amount of virus that is released and can infect other cells (13).

The appropriate treatment of patients with viral respiratory illness depends on accurate and timely diagnosis. The early diagnosis of influenza can help reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. Influenza surveillance information as well as diagnostic testing (e.g., viral culture and rapid tests for influenza) can aid clinical judgment and help guide treatment decisions.

Influenza surveillance by state and local health departments and CDC can provide information about the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza.

Several commercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect influenza viruses within 30 minutes (2). Some of these rapid tests detect only influenza A viruses, whereas other rapid tests detect both influenza A and B viruses but do not distinguish between the two types. Additional commercial diagnostic tests are available for use by laboratories performing tests of high complexity (2).

Despite the availability of rapid diagnostic tests, the collection of clinical specimens for viral culture is important because only culture isolates can provide specific information on circulating influenza subtypes and strains. This information is needed to compare current circulating influenza strains and vaccine strains, to guide decisions about influenza treatment and prophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance.

Zanamivir is approved for treatment of uncomplicated acute illness caused by influenza virus in adults and adolescents aged greater than or equal to 12 years who have been symptomatic for no more than 2 days.* This indication was based on studies in which the predominant influenza infections were influenza A and a limited number of patients with influenza B were also enrolled (14). Zanamivir is not approved for use in children aged less than 12 years.

Oseltamivir is approved for treatment of uncomplicated acute illness caused by influenza infection in adults agedgreater than or equal to 18 years who have been symptomatic for no more than 2 days.** This indication was based on studies of naturally occurring influenza in which the predominant infection was influenza A and influenza challenge studies in which the antiviral activity of oseltamivir was supported for influenza A and B (15). Oseltamivir is not approved for use in children (aged less than 18 years).

When administered within 2 days of illness onset among otherwise healthy adults, zanamivir and oseltamivir can reduce by approximately 1 day the duration of moderate or severe symptoms of uncomplicated influenza (16-23). The evidence for the efficacy of both drugs is based primarily on data from patients with fever greater than or equal to 37.8 C (100 F) at the time therapy was started.

More clinical data are available concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection. However, in vitro data (24-29) and data from treatment in mice and ferrets (26,27,30,31) document that zanamivir and oseltamivir have activity against influenza B viruses. Limited data from clinical trials of zanamivir (17,32) and from studies of oseltamivir treatment of experimental influenza B infections (33) also suggest that zanamivir and oseltamivir are effective for treatment of infections caused by influenza B viruses.

Neither zanamivir nor oseltamivir has been demonstrated to be effective in preventing serious influenza-related complications, such as bacterial or viral pneumonia or exacerbation of chronic diseases. Data are limited and inconclusive concerning the effectiveness of zanamivir for treatment of influenza in persons at high risk for serious complications of influenza (17,18,20,34). No published data are available concerning the effectiveness of oseltamivir for treatment of influenza in high-risk populations. No clinical data are available regarding the safety or efficacy of zanamivir or oseltamivir for pregnant women.

Zanamivir and oseltamivir are not approved for prophylactic use. However, recently published studies of zanamivir and oseltamivir for prophylaxis of influenza in community settings demonstrated both drugs to be similarly effective in preventing laboratory-confirmed clinical influenza with fever (efficacy: zanamivir, 84%; oseltamivir, 82%) (35,36). Experience with prophylactic use of these agents in institutional settings is limited (37-39). Vaccination remains the best prophylaxis for influenza.

The recommended dosage of zanamivir for treatment of influenza in persons aged greater than or equal to 12 years is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days (14).

The recommended dosage of oseltamivir for treatment of influenza in persons aged greater than or equal to 18 years is 75 mg orally twice daily for 5 days (15). A reduction in dosage is recommended for persons with creatinine clearance less than 30 mL/min (see Persons with Impaired Renal Function) (15).

Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Although the plastic device is similar to devices used to deliver some asthma medications, use of this device should be restricted to delivery of zanamivir (40). Delivery of the medication requires loading of a medication disk into the plastic device each day. Patients will benefit from instruction and demonstration of proper use of the device. Zanamivir is packaged in a disk with four blisters of medication, each containing a powder mixture of 5 mg of zanamivir and 20 mg of lactose (14).

Oseltamivir is administered orally. It is available as 75-mg capsules (15).

In studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (41,42). Approximately 4%-17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (14,43).

Approximately 80% of orally administered oseltamivir is absorbed systemically (33). Absorbed oseltamivir is metabolized to GS4071 (oseltamivir carboxylate), the active neuraminidase inhibitor, primarily by hepatic esterases. GS4071 has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (15,44). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (44).

Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir in prelicensure studies, decreases in renal clearance and increases in half-life and systemic exposure to zanamivir were observed (14,45). However, a small number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were much higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (43,46). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (45).

Among patients with impaired renal function, serum concentrations of oseltamivir carboxylate increase with declining renal function (15,33). A reduction of the dose of oseltamivir to 75 mg once daily is recommended for patients with creatinine clearance less than 30 mL/min (15). No data are available concerning the safety or efficacy of oseltamivir in patients with creatinine clearance less than 10 mL/min.

The pharmacokinetics of zanamivir and oseltamivir have not been studied in patients with impaired hepatic function (14,15).

In clinical treatment studies of inhaled zanamivir, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone) (14,16-21,47). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections (14,16,17,19,20). Each of these symptoms was reported by less than 5% of persons in the clinical treatment studies combined (14). Caution is advised if zanamivir is prescribed for patients with underlying chronic respiratory disease. In a phase I study of persons with mild or moderate asthma who did not have influenza-like illness, 1 of 13 patients experienced bronchospasm following administration of zanamivir (14). In addition, preliminary results of a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease indicated that more patients receiving zanamivir than placebo experienced a greater than 20% decline in forced expiratory volume in 1 second (FEV1) or peak expiratory flow rates after treatment (14). Patients with asthma or chronic obstructive pulmonary disease are advised to a) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and to b) stop using zanamivir and contact their physician if they develop difficulty breathing (14). Nausea and vomiting were reported more frequently among persons receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (15,22,23,48). However, few persons enrolled in the clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (15). Nausea and vomiting might be less severe if oseltamivir is taken with food (15,48).

Although clinical data are limited regarding drug interactions with zanamivir, no known drug interactions with zanamivir have been reported, and no clinically important drug interactions have been predicted on the basis of in vitro data and data from studies in rats (14,49). Zanamivir does not affect the cytochrome P450 isoenzymes in human liver microsomes (14,49) and is not expected to alter the metabolism of other drugs metabolized by these enzymes. Treatment with zanamivir has not been found to impair the immunologic response to influenza vaccine (14,50). No published data are available concerning the safety or efficacy of coadministering amantadine or rimantadine with zanamivir.

Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and its active metabolite, GS4071, are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in a reduction in the clearance of GS4071 by approximately 50% and a corresponding approximate twofold increase in the plasma levels of GS4071 (15,44). Oseltamivir and GS4071 are not substrates for the cytochrome P450 isoenzymes and are not expected to alter the metabolism of other drugs metabolized by these enzymes (15). No published data are available concerning the safety or efficacy of coadministering amantadine or rimantadine with oseltamivir.

Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (51-58), but induction of resistance requires several passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (10,59). Whether these in vitro findings indicate that clinical drug resistance will occur less frequently with zanamivir and oseltamivir than with amantadine and rimantadine is unknown. Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (15,18,60,61). Currently available diagnostic tests are not optimal for detecting clinical resistance, and better tests as well as more testing are needed before firm conclusions can be reached. Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is planned.

Zanamivir, oseltamivir, amantadine, and rimantadine vary in terms of the types of influenza viruses they inhibit, route of administration, and approved use in different age groups (Table 1). No studies have directly compared the effectiveness of these drugs for treatment of influenza A; however, available information indicates that all four agents are roughly comparable in reducing the duration of uncomplicated acute illness due to influenza A when treatment is started shortly after onset of symptoms. None of the four agents has been shown to decrease serious complications of influenza (e.g., pneumonia, hospitalization). Information about the use of zanamivir and oseltamivir among persons at high risk for influenza complications is limited.

The side effects and cost of zanamivir and oseltamivir differ from those of amantadine and rimantadine. Central nervous system side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) have been associated with amantadine and to a lesser extent with rimantadine (1). Amantadine has also been associated with an increased incidence of seizures among patients with a history of seizure disorders (1). Whether rimantadine is associated with an increased incidence of seizures among patients with a history of seizure disorders has not been adequately evaluated (1). Central nervous system side effects have been infrequently reported among patients taking zanamivir and oseltamivir (14,15). Because some persons with underlying asthma or chronic obstructive pulmonary disease have experienced reduced FEV1 or peak expiratory flow rate following treatment with zanamivir, caution is advised if zanamivir is used by patients with underlying chronic respiratory disease. Oseltamivir has been associated with nausea and vomiting. The dose of amantadine, rimantadine, and oseltamivir must be reduced for patients with renal failure. Finally, zanamivir and oseltamivir are more expensive than rimantadine, which is more expensive than amantadine (62,63).

Amantadine has been available since 1976, and rimantadine has been available since 1993; both drugs have been extensively used for treatment and prophylaxis of influenza A. Zanamivir and oseltamivir offer new options for treatment of influenza. Antiviral agents for influenza -- including amantadine, rimantadine, zanamivir, and oseltamivir -- are an adjunct to vaccine and are not a substitute for vaccine. Immunoprophylaxis with inactivated (i.e., killed-virus) vaccine remains the principal means for reducing influenza-related morbidity and death.

References

1. CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(No. RR-4).
2. Cox NJ, Subbarao K. Influenza. Lancet 1999;354:1277-82.
3. Simonsen L, Schonberger LB, Stroup DF, Arden NH, Cox NJ. The impact of influenza on mortality in the USA. In: Brown LE, Hampson AW, Webster RG, eds. Options for the control of influenza III. Amsterdam: Elsevier Science BV, 1996:26-33.
4. Lui K-J, Kendal AP. Impact of influenza epidemics on mortality in the United States from October 1972 to May 1985. Am J Public Health 1987;77:712-6.
5. Skehel JJ. Amantadine blocks the channel. Nature 1992;358:110-1.
6. Helenius A. Unpacking the incoming influenza virus. Cell 1992;69:577-8.
7. Pinto LH, Holsinger LJ, Lamb RA. Influenza virus M2 protein has ion channel activity. Cell 1992;69:517-28.
8. Martin K, Helenius A. Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import. Cell 1991;67:117-30.
9. Bukrinskaya AG, Vorkunova NK, Kornilayeva GV, Narmanbetova RA, Vorkunova GK. Influenza virus uncoating in infected cells and effect of rimantadine. J Gen Virol 1982;60:49-59.
10. Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH. The molecular basis of the specific anti-influenza action of amantadine. EMBO J 1985;4:3021-4.
11. Calfee DP, Hayden FG. New approaches to influenza chemotherapy: neuraminidase inhibitors. Drugs 1998;56:537-53.
12. Liu C, Eichelberger MC, Compans RW, Air GM. Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly or budding. J Virol 1995;69:1099-106.
13. Palese P, Compans RW. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol 1976;33:159- 63.
14. Glaxo Wellcome Inc. Relenza® (zanamivir for inhalation) [package insert]. Research Triangle Park, NC: Glaxo Wellcome, Inc., 1999.
15. Roche Laboratories, Inc. Tamiflu^TM (oseltamivir phosphate) capsules [package insert]. Nutley, NJ: Roche Laboratories Inc., 1999.
16. Hayden FG, Osterhaus ADME, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. N Engl J Med 1997;337:874-80.
17. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998;352:1877-81.
18. Fleming D, Makela M, Pauksens K, Man CY, Webster A, Keene ON. "High risk" and otherwise healthy patients demonstrate alleviation of influenza symptoms 2.5 days earlier following inhaled zanamivir treatment; European study, winter 1997/8 [Abstract 789]. In: Abstracts of the Infectious Diseases Society of America 36th Annual Meeting. Alexandria, VA: Infectious Diseases Society of America, 1998:249.
19. Matsumoto K, Ogawa N, Nerome K, et al. Safety and efficacy of the neuraminidase inhibitor zanamivir in treating influenza virus infection in adults: results from Japan. Antiviral Ther 1999;4:61-8.
20. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999;180:254-61.
21. Lalezari J, Klein T, Stapleton J, Elliott M, Flack N, Keene O. The efficacy and safety of inhaled zanamivir in the treatment of influenza in otherwise healthy and 'high risk' individuals in North America. [Abstract P8]. J Antimicrob Chemother 1999;44(suppl A):42.
22. Treanor JJ, Vrooman PS, Hayden FG, Kinnersley N, Ward P, Mills RG. Efficacy of oral GS4104 in treating acute influenza [Abstract LB-4]. In: Final Program and Exhibits Addendum of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1998:21.
23. Aoki F, Osterhaus A, Rimmelzwaan G, Kinnersley N, Ward P. Oral GS4104 successfully reduces duration and severity of naturally acquired influenza [Abstract LB-5]. In: Final Program and Exhibits Addendum of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1998:22.
24. Woods JM, Bethell RC, Coates JAV, et al. 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993;37:1473-9.
25. Hayden FG, Rollins BS, Madren LK. Anti-influenza virus activity of the neuraminidase inhibitor 4-guanidino-Neu5Ac2en in cell culture and in human respiratory epithelium. Antiviral Res 1994;25:123-31.
26. Mendel DB, Tai CY, Escarpe PA, et al. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother 1998;42:640-6.
27. Sidwell RW, Huffman JH, Barnard DL, et al. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Antiviral Res 1998;37:107-20.
28. Hayden FG, Rollins BS. In vitro activity of the neuraminidase inhibitor GS4071 against influenza viruses [Abstract 159]. Antiviral Res 1997;34:A86.
29. Mendel DB, Tai CY, Escarpe PA, et al. GS 4071 is a potent and selective inhibitor of the growth and neuraminidase activity of influenza A and B viruses in vitro [Abstract 111]. Antiviral Res 1997;34:A73.
30. Ryan DM, Ticehurst J, Dempsey MH, Penn CR. Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase). Antimicrob Agents Chemother 1994;38:2270-5.
31. Ryan DM, Ticehurst J, Dempsey MH. GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a potent inhibitor of influenza virus in ferrets. Antimicrob Agents Chemother 1995;39:2583-4.
32. Osterhaus ADM, Makela MJ, Webster A, Keene ON. The efficacy of inhaled zanamivir in the treatment of influenza B [Abstract 281]. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1999:420.
33. Bardsley-Elliot A, Noble S. Oseltamivir. Drugs (in press).
34. Lalezari J, Elliott M, Keene O. The efficacy and safety of inhaled zanamivir in the treatment of influenza A and B in 'high risk' individuals-results of phase II and III clinical studies [Abstract 282]. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1999:420.
35. Monto AS, Robinson DP, Herlocher ML, Hinson JM, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999;282:31-5.
36. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999;341:1336-43.
37. Schilling M, Povinelli L, Krause P, et al. Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks. Vaccine 1998;16:1771-4.
38. Lee C, Loeb M, Phillips A, et al. Use of zanamivir (ZA) to control an outbreak of influenza A (FluA) [Abstract 283]. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1999:421.
39. Hirji Z, O'Grady S, Bonham J, et al. Utility of zanamivir (Z) for the treatment and prophylaxis of concomitant influenza A (IA) and B (IB) infection in a complex continuing care (CCC) and medical rehabilitation (MR) population [Abstract 1701]. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy.Washington, DC: American Society for Microbiology, 1999:637.
40. Glaxo Wellcome Inc. Patient instructions for use: Relenza® (zanamivir for inhalation). Research Triangle Park, NC: Glaxo Wellcome Inc; 1999.
41. Newman SP, Brown J, Pickford M, Fayinka S, Cass L. Deposition pattern in the respiratory tract of the neuraminidase inhibitor zanamivir; a gamma scintigraphic study [Abstract H-134]. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1997:237.
42. Cass LMR, Brown J, Pickford M, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet 1999;36(suppl 1):21-31.
43. Cass LMR, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 1999;36 (suppl 1):1-11.
44. He G, Massarella J, Aitken M, et al. The pharmacokinetics and safety of the oral neuraminidase inhibitor Ro 64-0796/GS4104 when administered concurrently with cimetidine or probenecid in healthy subjects [Abstract P17]. J Antimicrob Chemother 1999;44(suppl A):44.
45. Cass LMR, Efthymiopoulos C, Marsh J, Bye A. Effect of renal impairment on the pharmacokinetics of intravenous zanamivir. Clin Pharmacokinet 1999;36(suppl 1):13-9.
46. Calfee DP, Peng AW, Cass LM, Lobo M, Hayden FG. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999;43:1616-20.
47. Hayden FG, Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA 1996;275:295-9.
48. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA 1999;282:1240-6.
49. Daniel MJ, Barnett JM, Pearson BA. The low potential for drug interactions with zanamivir. Clin Pharmacokinet 1999;36(suppl 1):41-50.
50. Webster A, Boyce M, Edmundson S, Miller I. Coadministration of orally inhaled zanamivir with inactivated trivalent influenza vaccine does not adversely affect the production of antihaemagglutinin antibodies in the serum of healthy volunteers. Clin Pharmacokinet 1999;36(suppl 1):51-8.
51. Gubareva LV, Robinson MJ, Bethell RC, Webster RG. Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en. J Virol 1997;71:3385-90.
52. Colacino JM, Laver WG, Air GM. Selection of influenza A and B viruses for resistance to 4-guanidino-Neu5Ac2en in cell culture. J Infect Dis 1997;176(suppl 1):S66-8.
53. Gubareva LV, Bethell R, Hart GJ, Murti KG, Penn CR, Webster RG. Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. J Virol 1996;70:1818-27.
54. Blick TJ, Tiong T, Sahasrabudhe A, et al. Generation and characterization of an influenza virus neuraminidase variant with decreased sensitivity to the neuraminidase-specific inhibitor 4-guanidino-Neu5Ac2en. Virology 1995;214:475-84.
55. McKimm-Breschkin JL, Blick TJ, Sahasrabudhe A, et al. Generation and characterization of variants of NWS/G70C influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en. Antimicrob Agents Chemother 1996;40:40-6.
56. Staschke KA, Colacino JM, Baxter AJ, et al. Molecular basis for the resistance of influenza viruses to 4-guanidino-Neu5Ac2en. Virology 1995;214:642-6.
57. McKimm-Breschkin JL, Sahasrabudhe A, Blick TJ, et al. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J Virol 1998;72:2456-62.
58. Tai CY, Escarpe PA, Sidwell RW, et al. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother 1998;42:3234-41.
59. Appleyard G. Amantadine-resistance as a genetic marker for influenza viruses. J Gen Virol 1977;36:249-55.
60. Barnett J, Dempsey M, Tisdale M, Rothbarth PH, De Groot R, Osterhaus ADME. Susceptibility monitoring of influenza virus clinical isolates to the neuraminidase inhibitor zanamivir (GG167) during phase II clinical efficacy trials [Abstract H-93]. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1997:230.
61. Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998;178:1257-62.
62. Jefferson TO, Demicheli V, Deeks JJ, Rivetti D. Review: amantadine and rimantadine effectively prevent and treat influenza in healthy adults, but rimantadine is better tolerated. ACP J Club 1999;131:68.
63. Anonymous. Two neuraminidase inhibitors for treatment of influenza. Med Lett Drugs Ther 1999;41:91-3.

* No data are available to support zanamivir's efficacy if treatment is initiated greater than 48 hours after onset of illness (14).

** No data are available to support oseltamivir's efficacy if treatment is initiated greater than 40 hours after onset of illness (15).

Disclaimer   All MMWR HTML versions of articles are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the electronic PDF version and/or the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

Page converted: 12/15/1999

HOME  |  ABOUT MMWR  |  MMWR SEARCH  |  DOWNLOADS  |  RSS |  CONTACT POLICY  |  DISCLAIMER  |  ACCESSIBILITY

Morbidity and Mortality Weekly Report Centers for Disease Control and Prevention 1600 Clifton Rd, MailStop E-90, Atlanta, GA 30333, U.S.A Department of Health and Human Services

This page last reviewed 5/2/01