The Medical Letter. on Drugs and Therapeutics. Antiviral Drugs for Seasonal Influenza p 1. Important Copyright Message

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1 The Medical Letter on Drugs and Therapeutics Volume 60 ISSUE ISSUE No Volume 56 IN THIS ISSUE Antiviral Drugs for Seasonal Influenza p 1 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc. publications are protected by U.S. and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with U.S. and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: Published by The Medical Letter, Inc. A Nonprofit Organization medicalletter.org

2 The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: The Medical Letter on Drugs and Therapeutics Volume 60 (Issue 1537) Take CME Exams Antiviral Drugs for Seasonal Influenza Antiviral drugs can be used for treatment and prophylaxis of influenza. Frequently updated information on influenza activity, testing for influenza, and antiviral resistance is available from the CDC at RECOMMENDATIONS FOR TREATMENT The CDC recommends starting antiviral treatment as soon as possible after illness onset, without waiting for the results of influenza testing. Antiviral treatment is recommended for all persons with suspected or confirmed influenza who have severe, complicated, or progressive illness, require hospitalization, or are at higher risk for complications, including children <5 years old (especially those <2 years old), persons <19 years old receiving longterm aspirin therapy, adults 65 years old, morbidly obese persons (BMI 40), women who are pregnant or 2 weeks postpartum, persons of American Indian/ Alaska Native heritage, residents of nursing homes or other chronic care facilities, and persons who are immunosuppressed or have certain chronic medical conditions (including pulmonary, cardiovascular, renal, hepatic, hematological, metabolic, neurologic, or neurodevelopmental disorders). Antiviral treatment can be considered for previously healthy persons with suspected or confirmed influenza if it can be started within 48 hours of illness onset. 1,2 RECOMMENDATIONS FOR CHEMOPROPHYLAXIS Antiviral prophylaxis is not recommended for healthy persons exposed to influenza. It can be considered after exposure for persons at high risk for complications who cannot receive the influenza vaccine or received it within the last 2 weeks, and for those who are unlikely to respond to vaccination. Prophylaxis is recommended to help control confirmed influenza outbreaks in nursing homes; antiviral medication should be given to residents and to unvaccinated healthcare workers. DRUGS OF CHOICE Neuraminidase inhibitors remain the drugs of choice for treatment and prophylaxis of influenza. They are active against both Recommendations for Treatment of Seasonal Influenza Neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir, IV peramivir) are the drugs of choice. Treatment should be started as soon as possible; it is most effective when started within 48 hours of illness onset. Treatment is recommended for persons with suspected or confirmed influenza who are at higher risk for complications (including pregnant women), have severe illness, or are hospitalized. Treatment can be considered for previously healthy persons with suspected or confirmed influenza if it can be started within 48 hours of illness onset. Oseltamivir is preferred for treatment of pregnant women and hospitalized patients. influenza A and B viruses. Oral oseltamivir (Tamiflu, and generics) and inhaled zanamivir (Relenza) are FDA-approved for treatment and prophylaxis of influenza. IV peramivir (Rapivab) is FDA-approved only for treatment of influenza. 3 Use of amantadine or rimantadine is not recommended because of high levels of resistance to these drugs among currently circulating influenza A viruses; they are not active against influenza B viruses. EFFECTIVENESS Use of neuraminidase inhibitors for treatment of uncomplicated influenza shortens the duration of symptoms by about one day in adults. 4,5 A meta-analysis of randomized trials in children with influenza found that treatment with oseltamivir within 48 hours of symptom onset reduced illness duration by about 18 hours overall (by 30 hours when trials that enrolled only children with asthma were excluded from the analysis) and lowered the risk of developing otitis media. 6 Although most controlled trials of these drugs have not been powered to assess their efficacy in preventing serious influenza complications, experts have generally interpreted the combined results of controlled trials, observational studies, and meta-analyses as showing that early antiviral treatment of high-risk patients with influenza may reduce the risk of complications. 7,8 When used for prophylaxis against susceptible strains of seasonal influenza A or B viruses, neuraminidase inhibitors have generally been about 70-90% effective. 9 Published by The Medical Letter, Inc. A Nonprofit Organization medicalletter.org 1

3 Table 1. Antiviral Drugs for Seasonal Influenza Drug Oseltamivir (Tamiflu) Zanamivir (Relenza) 1 Peramivir (Rapivab) Formulations 30, 45, 75 mg caps 2 ; 5 mg/blister for inhalation mg/20 ml single-use vials 6 mg/ml oral susp Cost 4 generic: $98.60 $59.00 $ Tamiflu: $ Treatment of Uncomplicated Influenza Adult Dosage 75 mg PO bid x 5 days 5 2 inhalations bid x 5 days 600 mg IV once 5 Pediatric Dosage mg 6 PO bid x 5 days 5 7 yrs: 2 inhalations bid x 5 days 2-12 yrs: 12 mg/kg (max 600 mg) IV once 5 13 yrs: 600 mg IV once 5 Dosage for Adults 7 : CrCl ml/min: 30 mg bid No dosage adjustment required 2-12 yrs: Renal CrCl >10-30 ml/min: 30 mg once/d for renal impairment CrCl ml/min: 4 mg/kg once Impairment HD: 30 mg after every HD 8 CrCl ml/min: 2 mg/kg once CAPD: 30 mg after exchange 13 yrs: ESRD not on HD: not recommended CrCl ml/min: 200 mg once CrCl ml/min: 100 mg once HD: administer dose (based on CrCl) after HD Prophylaxis of Influenza Adult Dosage 75 mg PO once/d x 7 days 9,10 2 inhalations once/d x 7 days 9,10 Not FDA-approved for prophylaxis Pediatric Dosage mg 6 PO once/d x 7 days 9,10 5 yrs: 2 inhalations once/d Not FDA-approved for prophylaxis x 7 days 9,10 Dosage for Adults 7 : CrCl ml/min: 30 mg once/d No dosage adjustment required Not FDA-approved for prophylaxis Renal CrCl >10-30 ml/min: 30 mg every other day for renal impairment Impairment HD: 30 mg after every other HD 11 CAPD: 30 mg once/week after exchange ESRD not on HD: not recommended CAPD = continuous ambulatory peritoneal dialysis; ESRD = end-stage renal disease; HD = hemodialysis 1. Inhaled zanamivir is not recommended for use in patients with underlying respiratory disease such as asthma or COPD, or in patients with severe influenza, including hospitalized patients. It is contraindicated in patients with a history of milk protein allergy. 2. Capsules can be opened and the contents mixed in a thick sweetened liquid to mask the bitter taste and consumed immediately. 3. Available in a carton containing 5 rotadisks (each rotadisk contains four 5-mg blisters of the active drug in a lactose carrier) and a Diskhaler inhalation device. Zanamivir should not be used in a nebulizer. 4. Approximate WAC for 5 days treatment with oseltamivir capsules or zanamivir, or for a single dose of peramivir, at the adult dosage. WAC = wholesaler acquisition cost or manufacturer s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource Monthly. December 5, Reprinted with permission by First Databank, Inc. All rights reserved policies/drug-pricing-policy. 5. In hospitalized, critically ill, or immunocompromised patients, a longer treatment course of oseltamivir (e.g., 10 days) is often used. Oseltamivir can be administered by oro/nasogastric tube to patients who are unable to swallow capsules. IV peramivir (for at least 5 days) may be considered for those who cannot take oseltamivir. Investigational IV zanamivir is not currently available. 6. FDA-approved doses for children 1-12 yrs old: 15 kg: 30 mg; kg: 45 mg; kg: 60 mg; 40.1 kg: 75 mg. Dose for adolescents 13 years old is 75 mg.the FDA-approved dosage for treatment of infants 2 weeks to <1 year old is 3 mg/kg bid; the CDC recommends the same dosage for treatment of children <2 weeks old. The American Academy of Pediatrics has recommended a dose of 3.5 mg/kg for infants 9-11 months old based on the results of a study showing that a higher dose was needed to achieve the target exposure in this age group (DW Kimberlin et al. J Infect Dis 2013; 207:709). Although not FDA-approved for prophylaxis in children <1 year old, the ACIP and CDC recommend that children 3-11 months old receive 3 mg/kg once/d. For treatment of premature infants, refer to CDC recommendations ( 7. The CDC recommends the same dosage adjustments for children with renal impairment who weigh >40 kg. 8. Treatment can be started immediately if influenza symptoms develop between HD sessions. 9. Duration of prophylaxis recommended by the CDC is 7 days after the last known exposure. The recommended duration in the labeling for oseltamivir and zanamivir is 10 days. 10. For control of outbreaks in institutions, the CDC recommends administering prophylaxis for at least 2 weeks and continuing it for 1 week after the end of the outbreak. For prophylaxis during community outbreaks, taking oseltamivir for up to 42 days, or zanamivir for up to 28 days has been shown to be effective and safe. Some experts would use twice-daily therapeutic doses for post-exposure prophylaxis in highly immunocompromised persons. 11. Initial dose can be administered before start of HD. TIMING AND DURATION Treatment of influenza with a neuraminidase inhibitor is most effective when started within 48 hours of illness onset; however, the results of some observational studies in hospitalized and critically ill patients suggest that treatment started as late as 4-5 days after illness onset may reduce the risk of complications such as pneumonia, respiratory failure, and death The usual duration of treatment for patients with uncomplicated influenza is 5 days with oseltamivir or zanamivir and 1 day with peramivir. Oseltamivir is recommended for hospitalized, critically ill, or immunocompromised patients, in whom viral replication may be protracted; in such patients, a longer treatment course (e.g., 10 days) is often used. Peramivir (for at least 5 days) may be considered for those who cannot take oseltamivir. 1 When indicated, prophylaxis with oseltamivir or zanamivir should be started within 48 hours after exposure to the influenza virus and continued for 7 days after the last known exposure. Longer durations of prophylaxis are often recommended for institutional and community outbreaks (see Table 1). PREGNANCY Pregnant women are at increased risk for severe complications of influenza, including death. 13 Oseltamivir and zanamivir appear to be safe for use during pregnancy. 14 Prompt treatment, preferably 2

4 with oseltamivir, is recommended for women with suspected or confirmed influenza who are pregnant or 2 weeks postpartum Antiviral prophylaxis can be considered for pregnant women who have had close contact with someone likely to have been infected with influenza. Zanamivir may be preferred for prophylaxis because of its limited systemic absorption, but oseltamivir is a reasonable alternative, especially for women at increased risk for respiratory problems. RESISTANCE Nearly all (>99%) of the recently circulating influenza virus strains tested by World Health Organization (WHO) Collaborating Centres around the world, including the CDC, have been susceptible to neuraminidase inhibitors. 18 Resistance of some virus strains (particularly influenza A [H1N1]) to oseltamivir or peramivir can emerge during or after treatment, especially in immunocompromised patients with prolonged viral shedding. 19,20 Resistant isolates have generally remained susceptible to zanamivir, but reduced susceptibility to zanamivir has been reported. 21,22 ADVERSE EFFECTS Nausea, vomiting, and headache are the most common adverse effects of oseltamivir; taking the drug with food may minimize GI adverse effects. Diarrhea, nausea, sinusitis, fever, and arthralgia have been reported with zanamivir. Inhalation of zanamivir can cause bronchospasm; the drug should not be used in patients with underlying airway disease. Diarrhea and neutropenia have occurred with peramivir. Neuropsychiatric events, including self-injury and delirium, have been reported in patients taking neuraminidase inhibitors, but a cause-and-effect relationship has not been established, and neuropsychiatric dysfunction is a known complication of influenza illness itself. 23 DRUG INTERACTIONS Neuraminidase inhibitors administered within 48 hours before or <2 weeks after administration of the intranasal live-attenuated influenza vaccine (FluMist Quadrivalent) may interfere with the vaccine s efficacy. The live-attenuated vaccine is not recommended for use during the influenza season because it has been less effective than the inactivated vaccine in recent seasons. 24 Inactivated influenza vaccine can be given at any time relative to use of a neuraminidase inhibitor. 1. CDC. Influenza antiviral medications: summary for clinicians. Available at: summary-clinicians.htm. Accessed December 19, Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, Pediatrics 2017; 140:e Peramivir (Rapivab): an IV neuraminidase inhibitor for treatment of influenza. Med Lett Drugs Ther 2015; 57: J Dobson et al. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 2015; 385: IDSA. Statement by the Infectious Disease Society of America (IDSA) on the recent publication on Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. April Available at: statement.aspx. Accessed December 19, RE Malosh et al. Efficacy and safety of oseltamivir in children: systematic review and individual patient data meta-analysis of randomized controlled trials. Clin Infect Dis 2017 Nov 23 (epub). 7. In brief: Concerns about oseltamivir (Tamiflu). Med Lett Drugs Ther 2015; 57: MK Doll et al. Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses. J Antimicrob Chemother 2017; 72: AE Fiore et al. Antiviral agents for the treatment and chemoprophylaxis of influenza recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60: JK Louie et al. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics 2013; 132:e SG Muthuri et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014; 2: JK Louie et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 2012; 55: MH Yudin. Risk management of seasonal influenza during pregnancy: current perspectives. Int J Womens Health 2014; 6: S Graner et al. Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study. BMJ 2017; 356:j IK Oboho et al. Benefit of early initiation of influenza antiviral treatment to pregnant women hospitalized with laboratoryconfirmed influenza. J Infect Dis 2016; 214: LM Ghulmiyyah et al. Influenza and its treatment during pregnancy: a review. J Neonatal Perinatal Med 2015; 8: CDC. Recommendations for obstetric health care providers related to use of antiviral medications in the treatment and prevention of influenza. Available at: professionals/antivirals/avrec_ob.htm. Accessed December 19, LV Gubareva et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, Antiviral Res 2017; 146: QM Le et al. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med 2010; 362: C Renaud et al. H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients. Emerg Infect Dis 2011; 17: E Takashita et al. Influenza A(H1N1)pdm09 virus exhibiting enhanced cross-resistance to oseltamivir and peramivir due to a dual H275Y/G147R substitution, Japan, March Euro Surveill 2016; 21:pii= R Trebbien et al. Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, Euro Surveill 2017; 22:pii= S Toovey et al. Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review. Adv Ther 2012; 29: Influenza vaccine for Med Lett Drugs Ther 2017; 59:163. 3

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