Correspondence

Use of Ribavirin to Treat Influenza

N Engl J Med 2009; 361:1713-1714October 22, 2009

Article

To the Editor:

Ribavirin, an antiviral drug with in vitro activity against both DNA and RNA viruses, is approved in the United States for the treatment of hepatitis C and respiratory syncytial virus.1 Hepatitis C is treated with approved oral formulations in combination with interferon products; respiratory syncytial virus is treated with an aerosol formulation. Intravenous ribavirin is not currently approved in the United States.

With the current H1N1 influenza pandemic, questions have arisen regarding the potential for ribavirin as a treatment option. Possible reasons for interest in ribavirin may include resistance issues in drugs that are used to treat circulating human seasonal H3N2 virus (adamantanes) and H1N1 virus (oseltamivir), as well as pandemic H1N1 virus (adamantanes and potentially oseltamivir).2 Although ribavirin shows in vitro activity against influenza viruses, clinical data are not consistent with in vitro data in many cases.1,3 We reviewed published studies, using the search criteria “influenza” and “ribavirin,” and identified 12 randomized, controlled clinical trials of ribavirin — equally divided between oral and aerosolized formulations — in subjects with influenza (either naturally acquired infection or challenge studies) (Table 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In addition to having small sample sizes, these studies were limited by multiple factors, including differences in the subjects who were enrolled, the dose and duration of ribavirin treatment, the timing between the initiation of therapy and the onset of symptoms (or viral inoculation in challenge studies), and the reporting of clinical outcomes, microbiologic data, and adverse events. Reported adverse events were consistent with the labeling of approved aerosol and oral formulations.4,5

Since the late 1980s, clinicians have requested access to intravenous ribavirin from the manufacturer to treat patients with life-threatening conditions (including influenza) through an emergency investigational new drug (EIND) application. The Food and Drug Administration (FDA) grants EINDs on a case-by-case basis. We recently reviewed data on the use of intravenous ribavirin under EIND provisions.3 From February 1997 through December 2008, the FDA granted 608 EIND requests for the use of intravenous ribavirin, of which 18 (3%) were for the treatment of influenza. Our analysis of EIND data focusing on the use of ribavirin to treat influenza was limited by the inadequate reporting of clinical outcomes and adverse events.

In our opinion, the studies that we identified in the published literature regarding the use of oral or aerosolized formulations of ribavirin and data on EIND use of intravenous ribavirin are inconclusive regarding the potential clinical benefit of the drug for the treatment of influenza. Substantial safety issues, such as the risk of hemolytic anemia and of teratogenicity, present further challenges to address if ribavirin is to be used for the treatment of influenza.4,5 To further address these issues, formal trials of ribavirin should be conducted to assess safety and efficacy.

Kirk M. Chan-Tack, M.D.
Jeffrey S. Murray, M.D., M.P.H.
Debra B. Birnkrant, M.D.
Food and Drug Administration, Silver Spring, MD

The views expressed in this letter are those of the authors and do not necessarily reflect the official position of the FDA.

5 References

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   Update: novel influenza A (H1N1) virus infections -- worldwide, May 6, 2009. MMWR Morb Mortal Wkly Rep 2009;58:453-458
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   Riner A, Chan-Tack KM, Murray JS. Intravenous ribavirin -- review of the FDA's Emergency Investigational New Drug database (1997-2008) and literature for. Postgrad Med 2009;121:139-146
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   Virazole (ribavirin) powder, for solution: prescribing information. Rev. Costa Mesa, CA: Valeant Pharmaceuticals, March 2007. (Accessed October 1, 2009, at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=5115.)
   

5. 5

   Rebetol (ribavirin) capsule: prescribing information. Rev. Kenilworth, NJ: Schering, December 2007. (Accessed October 1, 2009, at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6312.)
   

Citing Articles (7)

Citing Articles

1. 1

   Sotirios G. Zarogiannis, James W. Noah, Asta Jurkuvenaite, Chad Steele, Sadis Matalon, Diana L. Noah. (2012) Comparison of ribavirin and oseltamivir in reducing mortality and lung injury in mice infected with mouse adapted A/California/04/2009 (H1N1). Life Sciences
   CrossRef

2. 2

   Christian Renaud, Jane Kuypers, Janet A. Englund. (2011) Emerging oseltamivir resistance in seasonal and pandemic influenza A/H1N1. Journal of Clinical Virology 52:2, 70-78
   CrossRef

3. 3

   Paolo Preziosi. (2011) Influenza pharmacotherapy: present situation, strategies and hopes. Expert Opinion on Pharmacotherapy 12:10, 1523-1549
   CrossRef

4. 4

   Ronald B. Moss, Roy T. Steigbigel, Rebecca L. Sanders, Fang Fang. (2011) Perspective: Emerging Challenges in the Treatment of Influenza and Parainfluenza in Transplant Patients. Advances in Virology 2011, 1-8
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5. 5

   T. Rowe, D. Banner, A. Farooqui, D. C. K. Ng, A. A. Kelvin, S. Rubino, S. S. H. Huang, Y. Fang, D. J. Kelvin. (2010) In vivo ribavirin activity against severe pandemic H1N1 influenza A/Mexico/4108/2009. Journal of General Virology 91:12, 2898-2906
   CrossRef

6. 6

   Jonathan P Wong, Mary E Christopher, Satya Viswanathan, Glen Schnell, Xiaojiang Dai, Donald Van Loon, Eric R Stephen. (2010) Aerosol and nasal delivery of vaccines and antiviral drugs against seasonal and pandemic influenza. Expert Review of Respiratory Medicine 4:2, 171-177
   CrossRef

7. 7

   C. Casper, J. Englund, M. Boeckh. (2010) How I treat influenza in patients with hematologic malignancies. Blood 115:7, 1331-1342
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