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Clinical Use of Approved Influenza Antivirals

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Clinical Use of Approved Influenza Antivirals DOI:10.1111/irv.12046 www.influenzajournal.com Original Article Clinical use of approved influenza antivirals: therapy and prophylaxis Michael G. Ison Divisions of Infectious Diseases & Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Correspondence: Michael G. Ison, Division of Infectious Diseases, 645 N. Michigan Avenue Suite 900, Chicago, IL 60654, USA. E-mail: [email protected] Currently, there are two commonly used classes of antiviral agents immunocompromised patients infected with seasonal, pandemic, approved for the prevention of and treatment for influenza: the or avian H5N1 influenza, these agents are widely used for these M2 Inhibitors (amantadine and rimantadine) and the indications. This article reviews the pharmacokinetics and clinical neuraminidase inhibitors (oseltamivir, laninamivir, peramivir and data available relative to the use of commercially available zanamivir). These agents have been proven to be safe and effective antiviral agents for the prevention of and treatment for influenza. alone or in combination for the treatment of uncomplicated Keywords Adamantanes, antiviral agents, influenza, M2 influenza in otherwise healthy individuals. Although there are few inhibitors, neuraminidase inhibitors. prospective, randomized studies of these antivirals for the treatment of pregnant women, hospitalized patients, and Please cite this paper as: Ison. (2012) Clinical use of approved influenza antivirals: therapy and prophylaxis. Influenza and Other Respiratory Viruses 7(Suppl. 1), 7–13. Introduction rimantadine inhibit the M2 proton channel that allows for uncoating of the virus in the endosome, thereby inhibiting Currently, there are two commonly used classes of antiviral the replication of susceptible influenza A viruses at low agents approved for the prevention of and treatment for concentrations (<1Æ0 lg ⁄ ml).1,2 Although these agents are influenza: the M2 Inhibitors (amantadine and rimantadine) approved for prevention of and treatment for influenza A, and the neuraminidase inhibitors (oseltamivir, laninamivir, widespread resistance among most currently circulating peramivir and zanamivir). These agents have been proven viruses precludes their use in most cases.3,4 Both agents to be safe and effective alone or in combination for the have excellent bioavailability and reach peak serum levels treatment of uncomplicated influenza in otherwise healthy around 4 hours following ingestion.1,2 Amantadine is pre- individuals. Although there are few prospective, random- dominately excreted unchanged in the urine by glomerular ized studies of these antivirals for the treatment of filtration and tubular secretion with a plasma elimination pregnant women, hospitalized patients, and immunocom- half-life of approximately 11–15 hours in patients with nor- promised patients infected with seasonal, pandemic, or mal renal function; elimination is prolonged in patients avian H5N1 influenza, these agents are widely used for with renal insufficiency and in the elderly.1,2 Rimantadine these indications. The basic pharmacokinetics and data undergoes extensive metabolism in the liver before being supporting the use of these agents are reviewed. Guidelines excreted in the urine, resulting in a plasma half-life of 24– for the use of existing antivirals are updated regularly and 36 hours and therefore only needs dose adjustment with should be consulted prior to use (see Table 1). serious renal (creatinine clearance £10 ml ⁄ min) or hepatic insufficiency.1,2 Both agents are pregnancy class C drugs, M2 Inhibitors which means that animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate Pharmacokinetics and well-controlled studies in humans, but potential bene- The commercially available M2 inhibitors amantadine and fits may warrant use of the drug in pregnant women rimantadine come as 100 mg tablets (and capsules in the despite potential risks. Major side effects include central case of amantadine) in addition to an oral solution and nervous system side effects (confusion, disorientation, syrup (10 mg ⁄ ml) (See Table 2).1,2 Both amantadine and mood alterations, memory disturbances, delusions, night- ª 2012 Blackwell Publishing Ltd 7 Ison Table 1. Existing guidelines for the treatment and prevention of Therapy influenza Both M2 inhibitors have been studied and approved for the treatment of influenza. In placebo-controlled studies, amantadine and rimantadine treatment is able to shorten World Health Organization 5,6 WHO guidelines for pharmacological management of pandemic the duration of fever by about 1 day. Treatment is also influenza A(H1N1) 2009 and other influenza viruses associated with more rapid symptom resolution, functional http://www.who.int/csr/resources/publications/swineflu/ recovery, and, in some studies, resolution of small airway h1n1_guidelines_pharmaceutical_mngt.pdf functional abnormalities.2,5,6 M2 inhibitors are associated US Advisory Committee on Immunization Practices (ACIP) with decreased progression to pneumonia and death in Fiore AE, et al. Antiviral agents for the treatment and chemopro- phylaxis of influenza. MMWR. 2011; 60(RR01): 1–244 hematopoietic stem cell transplant patients and shorter http://www.cdc.gov/flu duration of fever and hospitalization in hospitalized UK National Institute for Health and Clinical Excellence adults.5,6 Available data suggest that the M2 inhibitors are TA168: Amantadine, oseltamivir, and zanamivir for the treatment safe and efficacious in reducing length of fever and illness of influenza in children older than 2 years of age, but data are far more http://egap.evidence.nhs.uk/amantadine-oseltamivir-and-zanami- 7,8 vir-for-the-treatment-of-influenza-ta168 limited in younger children. Resistance Resistance to the two agents occurs as a result of amino Table 2. Commercially available M2 inhibitors (adamantanes)1,2 acid substitutions in the transmembrane portion of the M2 protein (position 26, 27, 30, 31, or 34) which result in reduced binding of the M2 inhibitors or in enlargement of Antiviral Amantadine Rimantidine (flumadine) (symmetrel) the pore diameter; by either mechanism, the inherent func- tion of the M2 pore is preserved in the presence of the inhibitor.6 Resistance mutations emerging in vivo do not Structure affect transmissibility or replication fitness as compared with wild-type viruses; documented transmission from per- son to person has been well established.6 Resistance affects both drugs in the class equally and appears to be persistent over time. Mutants may rapidly emerge within 2–4 days Prophylaxis dosing* 100 mg BID 100 mg BID Treatment dosing* 100 mg BID 100 mg BID after the start of therapy in up to 30% of patients, more 2,6 Route of administration Oral Oral frequently in immunosuppressed individuals. More recently, widespread resistance, as a result of the S31N *For normal renal function; see package insert for dosing with renal mutation, among circulating influenza A(H3N2) and 2009 insufficiency. Reduce to QD dosing is recommended for adults pandemic A(H1N1) viruses has rendered this class of anti- ‡65 years of age for amantadine. virals ineffective.3,4,6,9 The M2 inhibitors are also ineffective against all influenza B viruses. Resistance may be detected by plaque assays, which are not readily available, or by mares, ataxia, tremors, dizziness, anxiety, irritability, head- sequencing or pyrosequencing of the M2 gene.6 ache, slurred speech, visual disturbances, delirium, occulo- gyric episodes and hallucinations), gastrointestinal upset Neuraminidase inhibitors and anti-muscarinic effects.1,2 Compared to amantadine, ri- mantadine causes significantly fewer CNS side effects in There are currently two neuraminidase inhibitors (NAIs) both young and elderly adults.1,2,5 approved in most countries: oseltamivir (GS4104; Tami- fluÒ, Genentech, South San Francisco, CA, USA, and Chu- Prophylaxis gai Pharmaceutical Co, Japan) and zanamivir (GG167; Both M2 inhibitors have been studied and approved for RelenzaÒ, GlaxoSmithKline, Research Triangle Park, NC, the prevention of influenza (34–85% effective).5,6 Compar- USA) and two NAIs that are approved in more limited ative effectiveness studies between the two agents suggest markets: laninamivir (CS08958; Inavir, Daiichi Sankyo, similar efficacy.5,6 Post-exposure prophylaxis also appears Japan, and Biota Holdings Ltd, Australia; approved in to be effective with these agents for susceptible strains, but Japan only) and peramivir (BCX-1812 and previously not in households when the index case is also given treat- RWJ-270201; RapiactaÒ in Japan and Peramiflu in South ment because of the transmission of M2 inhibitor-resistant Korea, BioCryst Pharmaceuticals, Birmingham, AL, USA) variants.5,6 (See Table 3).6 All 4 compounds inhibit the virus 8 ª 2012 Blackwell Publishing Ltd Ison – approved influenza antivirals Table 3. Commercially available neuraminidase inhibitors6 Antiviral Laninamivir (Inavir) Oseltamivir (Tamiflu) Peramivir (Rapiacta, PeramiFlu) Zanamivir (Relenza) Structure H C 13 7 Prophylaxis dosing* Not indicated 75 mg QD for 10 days Not indicated 10 mg QD for 10–28 days Treatment dosing* 40 mg single dose 75 mg BID for 5 days 600 mg QD for 5–10 days 10 mg BID for 5 days Route of administration Inhaled Oral** Parenteral Inhaled** *For normal renal function; see package insert for dosing with renal insufficiency. **Parenteral formulations under development. neuraminidase and thereby prevent destruction of sialic Oseltamivir acid-bearing receptors that are recognized
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