Intravenous Influenza Antiviral Medications and CDC Considerations Related to Investigational Use of Intravenous Zanamivir for 2013-2014 Influenza Season
Intravenous (IV) formulations have been developed for three neuraminidase inhibitor medications (oseltamivir, peramivir, zanamivir). However, IV peramivir and IV oseltamivir are currently not available via clinical trial, compassionate use, or Emergency Use Authorization.
IV Zanamivir: Background and Clinical Indications
Zanamivir is a neuraminidase inhibitor antiviral medication with the same mechanism of action as oseltamivir. The FDA-approved formulation of zanamivir is the inhaled dry powder (Relenza®) delivered via a diskhaler device, and its use is summarized elsewhere (Influenza Antiviral Medications: A Summary for Clinicians). IV zanamivir aqueous solution is an investigational product available only by enrollment in an ongoing clinical trial, or under an emergency investigational new drug (EIND) request to the manufacturer for use in hospitalized adult and pediatric patients with severe influenza.
- For the 2013-14 season (as of January 27, 2014) most tested influenza viruses have been susceptible to both oseltamivir and zanamivir; oseltamivir-resistant 2009 H1N1 viruses have been reported rarely to date.
- Enhanced surveillance for oseltamivir-resistant 2009 H1N1 viruses is ongoing.1 While oseltamivir resistance among circulating U.S. influenza viruses is low to date, resistance can emerge during or after oseltamivir treatment in certain patients with prolonged influenza virus shedding (e.g., severely immunosuppressed patients, such as hematopoietic stem cell transplant recipients) [1-3]. Most oseltamivir-resistant H1N1 viruses have remained susceptible to zanamivir in laboratory testing thus far [4-6].
- Clinical trials of approved neuraminidase inhibitors, oral oseltamivir and inhaled dry powder zanamivir, have demonstrated some reduction in median time to symptom improvement when used for treatment of acute, uncomplicated influenza illness in otherwise healthy persons [7-16]. CDC has made recommendations below for other uses based on observational data [17-29] and on expert opinion.
- The efficacy and safety of IV zanamivir for treatment of patients hospitalized with severe influenza have not been established, but are currently being evaluated in clinical trials. In view of the limited alternatives, CDC recommends that investigational use of IV zanamivir may be considered for severely ill patients with oseltamivir-resistant 2009 H1N1 virus infection (Antiviral Drug Resistance among Influenza Viruses) [30-32].
- For hospitalized patients and patients with severe or complicated illness, CDC recommends treatment with oral oseltamivir. Limited data suggest that oseltamivir delivered by oral or nasogastric administration is generally well absorbed in critically ill influenza patients, including those in the intensive care unit, on continuous renal replacement therapy, and/or on extracorporeal membrane oxygenation [33-41]. There have been rare reports of patients with suspected decreased oral oseltamivir absorption because of decreased gastric motility or gastrointestinal bleeding [35, 40].
- For patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, the use of investigational IV zanamivir may be considered.
- Currently, phase III trials are evaluating the effectiveness of IV zanamivir compared to oral oseltamivir for treatment of patients hospitalized with severe influenza. At this time there is no evidence that an IV formulation of a neuraminidase inhibitor would be more effective than oral oseltamivir, especially if there are no concerns regarding absorption and oseltamivir resistance.
- Controlled clinical trials of oral oseltamivir and inhaled dry powder zanamivir generally enrolled patients with acute uncomplicated influenza illness within 2 days of illness onset. All neuraminidase inhibitor medications work best when administered early. While it is generally expected that treatment is most effective if initiated within 2 days of illness onset [7-22, 24, 27-29, 42-47], some studies suggest there may be benefit if initiated up to 4 or 5 days after illness onset [22, 23, 25, 26, 28, 48-55]. However, delay in treatment initiation may result in reduced effectiveness.
- Oseltamivir and zanamivir, either inhaled or IV, should not be administered together .
- Inhaled zanamivir (Relenza®) is not recommended for use in patients with severe influenza disease because of the lack of data. The inhaled dry powder formulation of zanamivir (Relenza inhalation powder) must not be made into an extemporaneous solution for administration by nebulization or mechanical ventilation [57, 58]. Relenza Inhalation Powder must only be administered using the device provided.
How to Evaluate Clinical Trial Eligibility or Submit a Request for an IV Zanamivir Emergency IND
Ongoing clinical trials can be located at www.ClinicalTrials.gov. A request to determine a patient’s eligibility for an ongoing clinical trial, or use IV zanamivir under EIND if not able to enroll in an available clinical trial, may be made by contacting the GSK Clinical Support Help Desk via email (gskclinicalsupportHD@gsk.com) or by calling 1-877-626-8019 or 1-866-341-9160. Availability is 7 days a week, 24 hours/day, including holidays. The GSK Clinical Support Help Desk will assess eligibility for clinical trials, and will provide information and instructions on obtaining IV zanamivir (i.e., EIND process), and provide the Request for Patient Information Form that needs to be completed for FDA review if a patient is not eligible for enrollment in an ongoing clinical trial and the physician wishes to request an EIND.
The EIND paperwork does not need to be completed before contacting the FDA, so a requesting clinician should contact GSK first, and then quickly contact FDA. To contact FDA:
- During normal business hours (8:00 a.m. – 4:30 p.m. Eastern Time), please call DAVP at 301-796-1500 or email DAVPEINDREQUEST@fda.hhs.gov.
- After normal business hours (weekdays after 4:30 p.m. or before 8:00 a.m. Eastern Time; weekends or holidays), please call the FDA Emergency Coordinator at 1-866-300-4374 or 301-796-8240 or the CDER Emergency Coordinator at 301-796-9900.
1 A subset of influenza viruses collected for national surveillance and additional specimens from public health and academic laboratories are tested for resistance to neuraminidase inhibitors, and results are shared with CDC. This information is presented in the antiviral resistance section of the FluView report. Testing for oseltamivir resistant viruses at CDC can be requested via state laboratories.
- Hurt AC, Chotpitayasunondh T, Cox NJ, et al. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. The Lancet infectious diseases 2012; 12(3): 240-8.
- Renaud C, Kuypers J, Englund JA. Emerging oseltamivir resistance in seasonal and pandemic influenza A/H1N1. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 2011; 52(2): 70-8.
- Centers for Disease C, Prevention. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients - Seattle, Washington, 2009. MMWR Morbidity and mortality weekly report 2009; 58(32): 893-6.
- Gubareva LV, Trujillo AA, Okomo-Adhiambo M, et al. Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antiviral therapy 2010; 15(8): 1151-9.
- Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV. Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays. Antimicrobial agents and chemotherapy 2010; 54(9): 3671-7.
- Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports / Centers for Disease Control 2011; 60(1): 1-24.
- Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. The New England journal of medicine 1997; 337(13): 874-80.
- Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Lancet 1998; 352(9144): 1877-81.
- Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections. The Journal of infectious diseases 1999; 180(2): 254-61.
- Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis. The Journal of antimicrobial chemotherapy 1999; 44 Suppl B: 23-9.
- Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. The Pediatric infectious disease journal 2000; 19(5): 410-7.
- Nicholson KG, Aoki FY, Osterhaus AD, 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(9218): 1845-50.
- 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 : the journal of the American Medical Association 2000; 283(8): 1016-24.
- Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. The Pediatric infectious disease journal 2001; 20(2): 127-33.
- Heinonen S, Silvennoinen H, Lehtinen P, et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 51(8): 887-94.
- 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 : the journal of the American Medical Association 1999; 282(13): 1240-6.
- Hernan MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011; 53(3): 277-9.
- Hiba V, Chowers M, Levi-Vinograd I, Rubinovitch B, Leibovici L, Paul M. Benefit of early treatment with oseltamivir in hospitalized patients with documented 2009 influenza A (H1N1): retrospective cohort study. The Journal of antimicrobial chemotherapy 2011; 66(5): 1150-5.
- Hsu J, Santesso N, Mustafa R, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Annals of internal medicine 2012; 156(7): 512-24.
- Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. The New England journal of medicine 2009; 361(20): 1935-44.
- Lalezari J, Campion K, Keene O, Silagy C. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Archives of internal medicine 2001; 161(2): 212-7.
- Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2012; 55(9): 1198-204.
- Louie JK, Yang S, Samuel MC, Uyeki TM, Schechter R. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics 2013; 132(6): e1539-45.
- Muthuri SG, Myles PR, Venkatesan S, Leonardi-Bee J, Nguyen-Van-Tam JS. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients. The Journal of infectious diseases 2013; 207(4): 553-63.
- Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008; 46(8): 1323-4.
- McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2007; 45(12): 1568-75.
- Rodriguez A, Diaz E, Martin-Loeches I, et al. Impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza A. The Journal of antimicrobial chemotherapy 2011; 66(5): 1140-9.
- Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA : the journal of the American Medical Association 2010; 303(15): 1517-25.
- Yu H, Feng Z, Uyeki TM, et al. Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011; 52(4): 457-65.
- Dulek DE, Williams JV, Creech CB, et al. Use of intravenous zanamivir after development of oseltamivir resistance in a critically Ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 50(11): 1493-6.
- Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. The New England journal of medicine 2010; 362(1): 88-9.
- Writing Committee of the WHOCoCAoPI, Bautista E, Chotpitayasunondh T, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. The New England journal of medicine 2010; 362(18): 1708-19.
- Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2010; 182(4): 357-63.
- Eyler RF, Heung M, Pleva M, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy 2012; 32(12): 1061-9.
- Eyler RF, Klein KC, Mueller BA. The pharmacokinetics of oseltamivir and oseltamivir carboxylate in a critically ill pediatric patient receiving extracorporeal membrane oxygenation and continuous venovenous hemodialysis. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG 2012; 17(2): 173-6.
- Giraud C, Manceau S, Oualha M, et al. High levels and safety of oseltamivir carboxylate plasma concentrations after nasogastric administration in critically ill children in a pediatric intensive care unit. Antimicrobial agents and chemotherapy 2011; 55(1): 433-5.
- Kromdijk W, Sikma MA, van den Broek MP, Beijnen JH, Huitema AD, de Lange DW. Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique. Intensive care medicine 2013; 39(5): 977-8.
- Lemaitre F, Luyt CE, Roullet-Renoleau F, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Therapeutic drug monitoring 2012; 34(2): 171-5.
- Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. Anaesthesia and intensive care 2013; 41(1): 66-73.
- Wildschut ED, de Hoog M, Ahsman MJ, Tibboel D, Osterhaus AD, Fraaij PL. Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support. PloS one 2010; 5(6): e10938.
- Taylor WR, Thinh BN, Anh GT, et al. Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. PloS one 2008; 3(10): e3410.
- Cowling BJ, Chan KH, Fang VJ, et al. Comparative epidemiology of pandemic and seasonal influenza A in households. The New England journal of medicine 2010; 362(23): 2175-84.
- Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. The Journal of clinical investigation 1998; 101(3): 643-9.
- Sato M, Hosoya M, Kato K, Suzuki H. Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors. The Pediatric infectious disease journal 2005; 24(10): 931-2.
- Yu H, Liao Q, Yuan Y, et al. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. Bmj 2010; 341: c4779.
- Chemaly RF, Vigil KJ, Saad M, et al. A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: early therapy improves outcomes. Cancer 2012; 118(18): 4627-33.
- Kumar A. Early versus late oseltamivir treatment in severely ill patients with 2009 pandemic influenza A (H1N1): speed is life. The Journal of antimicrobial chemotherapy 2011; 66(5): 959-63.
- Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2007; 44(7): 964-7.
- Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M. Differences in clinical outcomes after 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood 2011; 117(19): 5050-6.
- Kumar D, Michaels MG, Morris MI, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. The Lancet infectious diseases 2010; 10(8): 521-6.
- Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York city. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 50(11): 1498-504.
- Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax 2010; 65(6): 510-5.
- Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. The Lancet infectious diseases 2013.
- Coffin SE, Leckerman K, Keren R, Hall M, Localio R, Zaoutis TE. Oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study. The Pediatric infectious disease journal 2011; 30(11): 962-6.
- Eriksson CO, Graham DA, Uyeki TM, Randolph AG. Risk factors for mechanical ventilation in U.S. children hospitalized with seasonal influenza and 2009 pandemic influenza A*. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2012; 13(6): 625-31.
- Duval X, van der Werf S, Blanchon T, et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS medicine 2010; 7(11): e1000362.
- Kiatboonsri S, Kiatboonsri C, Theerawit P. Fatal respiratory events caused by zanamivir nebulization. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 50(4): 620.
- Steel HM, Peppercorn AF. Fatal respiratory events caused by zanamivir nebulization. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 51(1): 121.