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oseltamivir (Tamiflu)

1st generic approved Aug 2016 [23] Indications: - influenza* - treatment of influenza A & influenza B - prophylaxis for influenza A & influenza B [4] - for use (start of therapy) within 2 days of symptom onset - marginal benefit in prevention & treatment of influenza [19] - older, sicker patients with flu-like syndrome may benefit from oseltamivir with or without confirmed influenza infection [25] * shortens duration of influenza symptoms (4 vs 5 days) [20] * lowers risk of hospitalization (0.6 vs 1.7%) [20] * oseltamivir is not associated with a reduced risk of hospitalization but is associated with increased GI events [26] Contraindications: 1) do NOT use in infants < 2 weeks of age [4] 2) resistance to influenza A-H1N1 (2008-2009) has been reported; monotherapy not recommended; use with rimantidine [8] Benefit/risk: - small benefit for preventing influenza-like illness [19] - number needed to treat: 33 - no benefit for reducing transmission [19] - number needed to harm - 7 for nausea; 37 for vomiting [21] Dosage: 1) dosed in mg NOT mL; potential dosage errors may occur [9] 2) 75 mg PO BID for 5 days (QD dosing for prevention) - doubling the dose of no benefit for severe influenza [18] 3) start therapy within 48 hours* of onset -> more effective if started within 12 hours* of onset [3] 4) take with food to reduce nausea 5) prophylaxis: a) 2 weeks until IgG antibodies from influenza vaccine appear [14] b) otherwise, 4-6 weeks * if started within 12 hours of symptom onset, can reduce duration of symptoms by more than 3 days; NO benefit to therapy begun after 48 hours Capsule: 75 mg Suspension: Tamiflu suspension 12 mg/mL for children: - 30-75 mg BID for 5 days (depending upon weight) - new formulation (2011) 6 mg/mL to reduce froth when shaken [13] - generic oral suspension FDA-approved Sept 2017 [24] Dosage adjustment in renal failure: creatinine clearance dosage > 50-90 mL/min 75 mg every 12 hours 10-50 mL/min 75 mg every 24 hours < 10 mL/min no data (avoid) Pharmacokinetics: 1) metabolized in liver 2) eliminated in urine, tubular secretion [12] 3) elimination 1/2life 1-3 hours Adverse effects: 1) GI effects (9%); nausea, vomiting 2) reports of delirium & self-injury [7] hallicunations, fatal injury [8] most cases occur in setting of encephalopathy or encephalitis [8] Drug interactions: - probenecid increases levels of oseltamivir [12] Mechanism of action: 1) neuraminidase inhibitors 2) reduces severity & duration of flu symptoms [22] - does not reduce viral shedding or transmission among household contacts [22] 3) resistance of influenza A is emerging [5] 4) contains shikimic acid [6] 5) effective if administered early [17] Notes: - oseltamivir & zanamivir are modestly effective for symptoms of influenza in otherwise healthy adults - when used prophylactically, they have no effect against in preventing influenza-like illness or asymptomatic influenza - the drugs reduce influenza's symptoms by about a day - benefit for very ill people in hospital is without supporting data [11] - benefit in question [16]

Interactions

drug interactions drug adverse effects of neuraminidase inhibitor(s)

Related

neuraminidase zanamivir (Relenza)

General

neuraminidase inhibitor

Properties

INHIBITS: neuraminidase

Database Correlations

PUBCHEM correlations

References

  1. The Prescriber's Letter, vol 6 #11, Nov 1999
  2. Journal Watch, Mass Med Soc 19(23):182 (Dec) 1999
  3. Prescriber's Letter 7(10):57 2000
  4. Prescriber's Letter 11(1):1 2004 Journal Watch 24(6):45-46, 2004 Hayden FG et al, J Infect Dis 189:440, 2004 PMID: 14745701
  5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, Hayden FG, Sugaya N, Kawaoka Y. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004 Aug 28;364(9436):759-65. PMID: 15337401 - Moscona A. Oseltamivir-resistant influenza? Lancet. 2004 Aug 28;364(9436):733-4. No abstract available. PMID: 15337382
  6. Prescriber's Letter 13(1): 2006 FDA alerts to Protect Public form Fraudelent Avian Flu Therapies Detail-Document#: 220113 (subscription needed) http://www.prescribersletter.com
  7. FDA Medwatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#tamiflu http://www.fda.gov/medwatch/safety/2006/safety06.htm#tamiflu - Prescriber's Letter 13(12): 2006 Tamiflu (Oseltamir) Pediatric Adverse Effects Detail-Document#: 221203 (subscription needed) http://www.prescribersletter.com
  8. Prescriber's Letter 16(2): 2009 CDC's Interim Influenza Antiviral Guidance for 2008-09 Detail-Document#: 250201 (subscription needed) http://www.prescribersletter.com
  9. FDA MedWatch Tamiflu (oseltamivir) for Oral Suspension: Potential Medication Errors http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm183714.htm
  10. Prescriber's Letter 16(11): 2009 CHART: Tamiflu Expiration Date Extension COMMENTARY: Potential Medication Errors with Tamiflu Oral Suspension COMMENTARY: 2009-2010 Influenza Season: Issues Concerning Tamiflu and Relenza PDF: Tamiflu Emergency Compounding Detail-Document#: 251104 (subscription needed) http://www.prescribersletter.com
  11. Jefferson T et al Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis BMJ 2009;339:b5106 PMID: 19995812 http://www.bmj.com/cgi/content/full/339/dec07_2/b5106 http://dx.doi.org/10.1136/bmj.b5106 - Freemantle N and Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults? BMJ 2009 Dec 8; 339:b5248. PMID: 19995814 http://dx.doi.org/10.1136/bmj.b5248 - Doshi P. Neuraminidase inhibitors - The story behind the Cochrane review. BMJ 2009 Dec 8; 339:b5164. PMID: 19995813 http://dx.doi.org/10.1136/bmj.b5164 - Godlee F and Clarke M. Why don't we have all the evidence on oseltamivir? BMJ 2009 Dec 8; 339:b5351. PMID: 19995815 http://dx.doi.org/10.1136/bmj.b5351 - Smith J. Roche replies to the authors of the Cochrane review on oseltamivir. BMJ 2009 Dec 8; 339:b5364. http://dx.doi.org/10.1136/bmj.b5364 - Smith J. Point-by-point response from Roche to BMJ questions. BMJ 2009 Dec 8; 339:b5374. http://dx.doi.org/10.1136/bmj.b5374
  12. Medical Knowledge Self Assessment Program (MKSAP) 15, American College of Physicians, Philadelphia 2009
  13. FDA MedWatch 07/11/2011 Tamiflu (oseltamivir phosphate) for Oral Suspension: Label Change-New Concentration (6 mg/mL) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm262432.htm
  14. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
  15. FDA News Release: Dec. 21, 2012 FDA expands Tamiflu's use to treat children younger than 1 year. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333205.htm
  16. Krumholz HM et al Tamiflu: 14 flu seasons and still questions BMJ 2013;346:f547 PMID: 23355545 http://www.bmj.com/content/346/bmj.f547
  17. Muthuri SG et al. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A (H1N1) pandemic: A systematic review and metaanalysis in hospitalized patients. J Infect Dis 2013 Feb 15; 207:553. PMID: 23204175 - Aoki FY and Hayden FG. The beneficial effects of neuraminidase inhibitor drug therapy on severe patient outcomes during the 2009-2010 influenza A virus subtype H1N1 pandemic. J Infect Dis 2013 Feb 15; 207:547. PMID: 23204176
  18. South East Asia Infectious Disease Clinical Research Network Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ 2013;346:f3039 PMID: 23723457 http://www.bmj.com/content/346/bmj.f3039
  19. Jefferson T et al Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545 PMID: 24811411 http://www.bmj.com/content/348/bmj.g2545 - Loder E et al The Tamiflu trials. BMJ 2014;348:g2630 PMID: 24811414 http://www.bmj.com/content/348/bmj.g2630 - Krumholz HM and Hines HH Neuraminidase inhibitors for influenza BMJ 2014;348:g2548 PMID: 24811413 http://www.bmj.com/content/348/bmj.g2548
  20. Dobson J et al Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet. Jan 29, 2015 PMID: 25640810 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2962449-1/abstract
  21. The NNT: Neuraminidase Inhibitors Given for Influenza. http://www.thennt.com/nnt/neuraminidase-inhibitors-for-influenza/
  22. Cheung DH et al. Association of oseltamivir treatment with virus shedding, illness, and household transmission of influenza viruses. J Infect Dis 2015 Aug 1; 212:391 PMID: 25646354 http://jid.oxfordjournals.org/content/212/3/391
  23. FDA Postmarker Drug Safety Information. Aug 3, 2016 The FDA approves first generic version of widely used influenza drug, Tamiflu. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm514854.htm
  24. Brooks M FDA Clears First Generic Tamiflu for Oral Suspension. Medscape - Sep 15, 2017. http://www.medscape.com/viewarticle/885766
  25. Butler CC, van der Velden AW, Bongard E et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: An open-label, pragmatic, randomised controlled trial. Lancet 2020 Jan 4; 395:42 PMID: 31839279
  26. Hanula R et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: A systematic review and meta-analysis. JAMA Intern Med 2023 Jun 12; [e-pub] PMID: 37306992 PMCID: PMC10262060 Free PMC article https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2805976
  27. Tamiflu Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021087s068,021246s051lbl.pdf