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Neuraminidase inhibitors
The major drawbacks of older drugs for the treatment of influenza (amantadine and rimantadine) include lack of activity against influenza B, a considerable frequency of adverse reactions, and probably a higher likelihood of resistance. With the development of inhibitors of the viral neuraminidase, a more specific class of drugs has been added to the antiviral armamentarium. After the description of the crystal structure of the viral neuraminidase, a surface glycoprotein, specific inhibitors were designed. Two derivatives of sialic acid, the natural substrate of the neuraminidase, are currently in use, oseltamivir and zanamivir. These drugs were designed to bind strongly to a conserved region of the cleavage site of the virus, which resulted in a class of compounds with limited risk of viral resistance. In fact, resistance is rare during the use of these drugs [1]. Oseltamivir is administered as an oral capsule and zanamivir by inhalation. Inhaled zanamivir causes fewer adverse reactions than oral oseltamivir, but there are concerns about its use in young and elderly patients, who are generally unable to achieve the inspiratory flow rate needed to ensure adequate lung deposition [2]. Oral oseltamivir is more convenient and easier to administer, but needs to be given with food to lower the frequency of gastrointestinal adverse reactions.
Zanamivir has been evaluated in the prevention and treatment of influenza A and B, and was effective against both viruses. In placebo-controlled trials, the adverse events profile, including local nasal irritation, did not differ significantly between zanamivir and placebo [3,7–9]. In phase II and III clinical studies, zanamivir by peroral inhalation or combined peroral and intranasal inhalation slightly shortened the duration and severity of influenza symptoms and in high-risk patients reduced the risk of complications [1,10]. Typical doses are 10 mg by peroral inhalation and 6.4 mg by intranasal inhalation. Dosing frequency is 2–6 times/day. In placebo-controlled studies its adverse reactions profile was similar to that of placebo. A review of the use of zanamivir in 6000 patients in clinical studies has confirmed its favorable safety profile [11]. To date there is still an optimistic impression that the adverse reactions pattern is no different from that of placebo and that interactions are also unlikely, since it does not inhibit CYP isoenzymes [12]. Zanamivir has been evaluated in hospitalized patients with serious influenza [13]. Zanamivir þ rimantadine was compared with rimantadine þ placebo in a randomized blinded design in seven centers. The study was terminated prematurely after approval of zanamivir made enrolment untenable (41 patients, calculated sample size 100). There were no differences in the proportions of patients shedding virus by treatment day 3, or duration of hospitalization, or use of oxygen. More patients taking zanamivir had a slight cough on day 3.
Oseltamivir
DRUG STUDIES
Oseltamivir (GS4104) is an ester prodrug, whose active metabolite (GS4071), to which it is rapidly hydrolysed by hepatic carboxylesterases, is a potent selective inhibitor of influenza virus neuraminidase. The metabolite is completely excreted by the kidneys by filtration and tubular secretion. In animals oseltamivir had a wide safety margin, with no evidence of teratogenicity or adverse effects on fertility. Oseltamivir has also been studied in the treatment and prevention of influenza A and B. Headache was the most frequent complaint and mild to moderate gastrointestinal adverse reactions (nausea, diarrhea) have been described [3], as has hepatotoxicity. Oseltamivir has been reviewed [4]. Transient gastrointestinal disturbances are the major adverse reactions and are reduced when the drug is taken with a light snack. In the clinical trials program, severe adverse events were reported at the same frequency as with placebo (1.3% with 75 mg bd, 0.7% with 150 mg bd, 1.2% with placebo).
Observational studies
Neuraminidase inhibitors GENERAL INFORMATION
Zanamivir In mice zanamivir strongly reduced viral replication [5]. It has poor oral systemic availability. Intranasal administration slightly increases its availability. In vitro, zanamivir does not significantly inhibit human lysosomal neuraminidases, and so the potential for severe adverse reactions is low [6].
ã 2016 Elsevier B.V. All rights reserved.
In 730 residents of nursing homes who took oseltamivir prophylaxis for a median of 9 days (range 5–12), adverse reactions were identified in 30 (4.1%), of whom 20 had one adverse effect and 10 had two [14]. The most common adverse reactions were diarrhea (n ¼ 12), nausea or vomiting (n ¼ 7), cough (n ¼ 5), and confusion (n ¼ 4). In seven patients with influenza (three type A and four type B) after allografting, inhaled zanamivir (10 mg bd) was used until excretion of virus ceased (median duration 15, range 5–44, days); there was rapid resolution of the influenza and no adverse effects attributable to zanamivir [15]. In several large postmarketing studies there were no increases in cardiovascular, neuropsychiatric, or respiratory complications [16], nor in skin reactions [17]. In a large Japanese prospective multicenter study during the influenza season of 2002–3 oseltamivir was given to 803 patients with influenza A and 684 patients with influenza B; amantadine was given to 676 patients with influenza A [18]. In each group, the duration of fever (body temperature over 37.5 ºC) was significantly shorter in patients who were treated within 12 hours after the onset of symptoms than in those who were treated more than 12 hours after the onset. The type of influenza, the highest body temperature, and the time between the onset of symptoms and the start of treatment independently affected the
Neuraminidase inhibitors duration of fever. Only minor adverse reactions were reported by 19 patients with influenza A given oseltamivir, eight patients given amantadine, and one patient with influenza B given oseltamivir. In a model of cost effectiveness comparing annual influenza immunization against empirical amantadine and rapid testing followed by oseltamivir if the results were positive, antiviral therapy without immunization was associated with the lowest overall costs ($234 per person per year for amantadine, $237 for oseltamivir). The cost of annual immunization was $239 per person and was associated with 0.0409 quality-adjusted days saved, for a marginal cost-effectiveness ratio of $113 per quality-adjusted day gained or $41 000 per quality-adjusted life-year saved compared with antiviral therapy [19]. Adverse reactions were included in the model at estimated baseline probabilities from published work. Adverse reactions to influenza vaccine included minor effects, such as local soreness at the injection site, estimated at a probability of 0.64, and rarely Guillain–Barre´ syndrome. The authors estimated that adverse reactions other than Guillain–Barre´ syndrome lasted 2 days. Minor adverse reactions due to drugs were also included with a probability of 0.09 for amantadine and 0.1 for oseltamivir.
Placebo-controlled studies In a large placebo-controlled efficacy study in adolescents, mild gastrointestinal symptoms were the major adverse reactions, in 14% (oseltamivir) versus 8% (placebo); vomiting was reported in 8% versus 3% [20].
Systematic reviews Trials of the neuraminidase inhibitors for influenza have been reviewed [21]. The percentage of patients with serious or minor adverse reactions associated with administration of neuraminidase inhibitors was as follows for zanamivir: serious or life-threatening reactions were allergic or allergic-like reactions, dysrhythmias, bronchospasm, dyspnea, facial edema, rash, seizure, syncope, and urticaria (<1.5%). Minor adverse reactions included headache (2%), dizziness (2%), nausea (3%), diarrhea (adults, 3%; children, 2%), vomiting (adults, 1%; children, 2%), sinusitis (3%), bronchitis (2%), cough (2%), other nasal signs and symptoms (2%), and infections (ear, nose, and throat: adults, 2%; children, 5%). For oseltamivir the serious or life-threatening events were aggravation of diabetes, dysrhythmias, confusion, hepatitis, pseudomembranous colitis, pyrexia, rash, seizures, swelling of the face or tongue, toxic epidermal necrolysis, and unstable angina (<1%) The minor reactions were insomnia (adults, 1%), vertigo (1%), nausea (10%), and vomiting (9%). Adverse reactions to oseltamivir prophylaxis were similar to those reported during treatment, but generally with lower incidences. More common with prophylactic use were headache (20%), fatigue (8%), cough (6%), and diarrhea (3%). A meta-analysis of adverse reactions to zanamivir in children showed that it was no worse than placebo [22]. ã 2016 Elsevier B.V. All rights reserved.
49
ORGANS AND SYSTEMS Respiratory Zanamivir is administered by inhalation of a powder in a lactose vehicle. It can cause bronchospasm [23]. A 63-year-old man with oxygen-dependent chronic obstructive
pulmonary disease was given zanamivir because of an exacerbation attributed to influenza. Shortly after each inhalation of the drug he reported increasing respiratory difficulty and wheezing. After 3 days he developed respiratory distress, hypoxia, and wheezing, and was treated with bronchodilators, glucocorticoids, and antibiotics.
Patients taking zanamivir are advised to stop using it if bronchospasm occurs, and those with underlying lung disease are advised to have a fast-acting bronchodilator to hand. The bronchospasm can be reduced in frequency by using an inhaled b2-adrenoceptor agonist before zanamivir. Proper drug deposition depends on flow rate and inhaler technique, so young and elderly patients may not be the best to treat in this way [2,24].
Psychiatric Oseltamivir was associated with abnormal behavior in four children, including meaningless speech, disorientation, fearful responses, and running around the room; there were no neurological sequelae [25]. Oseltamivir-induced worsening of delirium has been reported in an 83-year-old man, whose symptoms resolved 2 days after withdrawal [26]. Japanese authorities advised against using oseltamivir in adolescents aged 10–19 years after two suicides during 2007 and more than 100 reports of neuropsychiatric events identified during post-marketing surveillance, including delirium, convulsions, and encephalitis [27]. However, it is not clear whether these events were due to the influenza or the drug; in phase III trials there were similar incidences of neurological and psychiatric events in both treated and untreated patients [28]. Of 1113 patients enrolled in a Japanese neuraminidase inhibitor treatment study, 11 had neuropsychiatric symptoms, in four cases before the start of treatment [29]. The FDA and EMA have advised doctors to monitor patients for abnormal behavior throughout treatment [27].
Gastrointestinal Upper gastrointestinal reactions (nausea or nausea with vomiting) have been reported more often in those taking oseltamivir in placebo-controlled studies [30,31]. Despite this mild gastrointestinal intolerance, withdrawal rates have been low. Nausea and vomiting have led to drug withdrawal in less than 1% of the subjects in clinical trials [32]. While nausea was equally frequent with once-daily influenza prophylaxis (8%) and twice-daily treatment (7%), the incidence of vomiting increased from 4.5% during prophylaxis to 10% when the drug was taken twice a day [33]. A similar pattern was found in the pediatric subgroup, with vomiting incidences of 10% and 20% respectively.
50
Neuraminidase inhibitors
The oral capsule of oseltamivir can be used in any patient who can swallow. However, it must be given with food, to reduce the frequency of nausea and gastrointestinal discomfort. Of 695 children aged 1–12 years, 14% had vomiting compared with 8.5% of those who took placebo [34]. In a meta-analysis of trials, there was a reduction in the duration of symptoms of about 1 day [35]. Oseltamivir caused significantly more gastrointestinal symptoms (dyspepsia or nausea) than placebo; the effect increased with dose. Similarly, zanamivir caused significantly more gastrointestinal symptoms than placebo (OR ¼ 2.6; 95% CI ¼ 1.6, 4.2). Acute hemorrhagic colitis has been associated with oral oseltamivir in a 61-year-old man, who developed abdominal pain, diarrhea, and hematochezia after taking two doses of oseltamivir [36]. In a systematic review of three trials of neuraminidase inhibitors for preventing and treating influenza in 1500 children, 977 of whom had laboratory confirmed influenza, those who took oseltamivir had vomiting more often than untreated children but withdrawal was rarely required [22].
LONG-TERM EFFECTS Drug resistance Resistance occurs in under 1% of healthy adults but occurs more often in children, from 5.5% up to 18% in one study, although a lower dosage regimen was used in that study. Resistance is often seen among immunocompromised patients. It was reported in two of eight patients infected with H5N1 and was associated with a fatal outcome. Resistance is associated with loss of fitness [37]. In 2008 widespread resistance emerged in H1N1 influenza, but it remains to be seen whether its circulation is sustained after the emergence of oseltamivir-sensitive swine vH1N1.
SUSCEPTIBILITY FACTORS Genetic There was no evidence of a difference in AUC1!20 of oseltamivir or its active metabolite oseltamivir carboxylate between 14 Japanese subjects and 14 Caucasian subjects, or between children aged 1–2 years old and adults [38].
Age Exposure (AUC) to both the parent drug and its active metabolite were more than 80% higher in five very elderly subjects compared with young volunteers [39].
Renal disease Gastrointestinal adverse reactions and dizziness can occur with increasing doses of oseltamivir, particularly in patients with renal failure [40]. ã 2016 Elsevier B.V. All rights reserved.
Liver disease A single oral dose of oseltamivir 75 mg has been studied in 11 subjects with liver disease (all with cirrhosis, seven alcohol-induced) and paired controls. Mean BMI and estimated serum creatinine clearance were matched. In hepatic impairment the values of oseltamivir and oseltamivir carboxylate Cmax were <6% and <19% lower and their AUCs 33% higher and <19% lower respectively. Thus, the metabolism of oseltamivir is not compromised in hepatic impairment and no dosage adjustment is required [41].
DRUG–DRUG INTERACTIONS See also Sotalol
Amoxicillin In healthy subjects amoxicillin had no effect on the pharmacokinetics of oral oseltamivir [42].
Cimetidine In healthy subjects cimetidine had no effect on the pharmacokinetics of oral oseltamivir [42].
Probenecid In healthy subjects probenecid completely blocked the renal secretion of the active metabolite of oseltamivir after oral administration, increasing its AUC by 2.5 times [42]. In vitro studies of the metabolite on the human renal organic anionic transporter I (hOAT1) were investigated in Chinese hamster ovary cells stably transfected with the transporter. The metabolite was a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOATl-mediated transport of para-aminohippuric acid. Probenecid inhibited the transport of the metabolite, para-aminohippuric acid, and amoxicillin via hOAT1.
REFERENCES [1] Waghorn SL, Goa KL. Zanamivir. Drugs 1998; 55(5): 721–5. [2] McNicholl IR, McNicholl JJ. Neuraminidase inhibitors: zanamivir and oseltamivir. Ann Pharmacother 2001; 35(1): 57–70. [3] Calfee DP, Peng AW, Cass LM, Lobo M, Hayden FG. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999; 43(7): 1616–20. [4] Dutkowski R, Thakrar B, Froehlich E, Suter P, Oo C, Ward P. Safety and pharmacology of oseltamivir in clinical use. Drug Saf 2003; 26: 787–801. [5] Ryan DM, Ticehurst J, Dempsey MH, Penn CR. Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral
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neuraminidase (sialidase). Antimicrob Agents Chemother 1994; 38(10): 2270–5. Woods JM, Bethell RC, Coates JA, Healy N, Hiscox SA, Pearson BA, Ryan DM, Ticehurst J, Tilling J, Walcott SM, Penn CR. 4-Guanidino-2,4-dideoxy-2,3dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993; 37(7): 1473–9. Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG, Bohnen AM, Hirst HM, Keene O, Wightman K. GG167 Influenza Study Group. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med 1997; 337(13): 874–80. Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282(1): 31–5. Monto AS, Fleming DM, Henry D, de Groot R, Makela M, Klein T, Elliott M, Keene ON, Man CY. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999; 180(2): 254–61. Anonymous. 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. Freund B, Gravenstein S, Elliott M, Miller I. Zanamivir: a review of clinical safety. Drug Saf 1999; 21(4): 267–81. Daniel MJ, Barnett JM, Pearson BA. The low potential for drug interactions with zanamivir. Clin Pharmacokinet 1999; 36(Suppl. 1): 41–50. Ison MG, Gnann JW Jr, Nagy-Agren S, Treannor J, Paya C, Steigbigel R, Elliott M, Weiss HL, Hayden FG. NIAID Collaborative Antiviral Study Group. Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther 2003; 8: 183–90. Bowles SK, Lee W, Simor AE, Vearncombe M, Loeb M, Tamblyn S, Fearon M, Li Y, McGeer A, Marguerite V, Baker D, Collins V, VanHorne E, Louie MA, Friedman P, Kam A, Goette M, Lam J, LaRue M, MacDonald M, McArthur MA, Mazzulli T, McDougall R, Satchell S, Simpson M, Stanton S, Warshawsky B, Wier H. Oseltamivir Compassionate Use Program Group. Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999–2000. J Am Geriatr Soc 2002; 50(4): 608–16. Johny AA, Clark A, Price N, Carrington D, Oakhill A, Marks DI. The use of zanamivir to treat influenza A and B infection after allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 29(2): 113–5. Enger C, Nordstrom BL, Thakrar B, Sacks S, Rothman KJ. Health outcomes among patients receiving oseltamivir. Pharmacoepidemiol Drug Saf 2004; 13(4): 227–37. Nordstrom BL, Oh K, Sacks ST, L0 Italien GJ. Skin reactions in patients with influenza treated with oseltamivir: a retrospective cohort study. Antivir Ther 2004; 9(2): 187–95. Kawai N, Ikematsu H, Iwaki N, Satoh I, Kawashima T, Maeda T, Miyachi K, Hirotsu N, Shigematsu T, Kashiwagi S. Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002–2003 influenza season. Clin Infect Dis 2005; 40(9): 1309–16. Rothberg MB, Rose DN. Vaccination versus treatment of influenza in working adults: a cost-effectiveness analysis. Am J Med 2005; 118(1): 68–77.
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[20] Singh S, Barghoorn J, Bagdonas A, Adler J, Treanor J, Kinnersley N, Ward P. Clinical benefits with oseltamivir in treating influenza in adult populations: results of a pooled and subgroup analysis. Clin Drug Investig 2003; 23: 561–9. [21] Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005; 353(13): 1363–73. [22] Matheson NJ, Harnden AR, Perera R, Sheikh A, Symmonds-Abrahams M. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev 2007; 1, CD002744. [23] Williamson JC, Pegram PS. Respiratory distress associated with zanamivir. N Engl J Med 2000; 342(9): 661–2. [24] 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. Arch Intern Med 2001; 161(2): 212–7. [25] Okumura A, Kubota T, Kato T, Morishima T. Oseltamivir and delirious behavior in children with influenza. Pediatr Infect Dis J 2006; 25(6): 572. [26] Kohen I. Oseltamivir-induced delirium in a geriatric patient. Int J Geriatr Psychiatry 2007; 22(9): 935–6. [27] Maxwell SR. Tamiflu and neuropsychiatric disturbance in adolescents. BMJ 2007; 334(7606): 1232–3. [28] Whitley RJ. The role of oseltamivir in the treatment and prevention of influenza in children. Expert Opin Drug Metab Toxicol 2007; 3(5): 755–67. [29] Kawai N, Ikematsu H, Iwaki N, Maeda T, Kanazawa H, Kawashima T, Tanaka O, Yamauchi S, Kawamura K, Nagai T, Horii S, Hirotsu N, Kashiwagi S. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. J Infect 2008; 56(1): 51–7. [30] Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. US Oral Neuraminidase Study Group. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA 2000; 283(8): 1016–24. [31] Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rode A, Kinnersley N, Ward P. 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. [32] Roche Laboratories Inc. Tamiflu (oseltamivir phosphate) capsules [package insert]. Nutley, NJ: Roche Laboratories Inc., 2000. [33] Hayden FG, Belshe R, Villanueva C, Lanno R, Hughes C, Small I, Dutkowski R, Ward P, Carr J. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004; 189(3): 440–9. [34] Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D, Mills RG, Ward P. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20(2): 127–33. [35] Pitts SR. Evidence-based emergency medicine/systematic review abstract. Use of the neuraminidase inhibitor class of antiviral drugs for treatment of healthy adults with an acute influenza-like illness. Ann Emerg Med 2002; 39(5): 552–4. [36] Matsushita M, Nishihara H, Nishiyama R, Kobayashi Y. Acute hemorrhagic colitis associated with oral administration of oseltamivir for the treatment of influenza A. J Infect Chemother 2007; 13(4): 267–9. [37] Ong AK, Hayden FG, John F. Enders Lecture 2006. Antivirals for influenza. J Infect Dis 2007; 196(2): 181–90.
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[38] Schentag JJ, Hill G, Chu T, Rayner CR. Similarity in pharmacokinetics of oseltamivir and oseltamivir carboxylate in Japanese and Caucasian subjects. J Clin Pharmacol 2007; 47(6): 689–96. [39] Abe M, Smith J, Urae A, Barrett J, Kinoshita H, Rayner CR. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann Pharmacother 2006; 40(10): 1724–30. [40] Karie S, Launay-Vacher V, Janus N, Izzedine H, Deray G. Pharmacokinetics and dosage adjustment of oseltamivir and zanamivir in patients with renal failure. Nephrol Dial Transplant 2006; 21(12): 3606–8. [41] Snell P, Dave N, Wilson K, Rowell L, Weil A, Galitz L, Robson R. Lack of effect of moderate hepatic impairment
ã 2016 Elsevier B.V. All rights reserved.
on the pharmacokinetics of oral oseltamivir and its metabolite oseltamivir carboxylate. Br J Clin Pharmacol 2005; 59(5): 598–601. [42] Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos 2002; 30(1): 13–9.
Zanamivir has been evaluated in the prevention and treatment of influenza A and B, and was effective against both viruses. In placebo-controlled trials, the adverse events profile, including local nasal irritation, did not differ significantly between zanamivir and placebo [3,7–9]. In phase II and III clinical studies, zanamivir by peroral inhalation or combined peroral and intranasal inhalation slightly shortened the duration and severity of influenza symptoms and in high-risk patients reduced the risk of complications [1,10]. Typical doses are 10 mg by peroral inhalation and 6.4 mg by intranasal inhalation. Dosing frequency is 2–6 times/day. In placebo-controlled studies its adverse reactions profile was similar to that of placebo. A review of the use of zanamivir in 6000 patients in clinical studies has confirmed its favorable safety profile [11]. To date there is still an optimistic impression that the adverse reactions pattern is no different from that of placebo and that interactions are also unlikely, since it does not inhibit CYP isoenzymes [12]. Zanamivir has been evaluated in hospitalized patients with serious influenza [13]. Zanamivir þ rimantadine was compared with rimantadine þ placebo in a randomized blinded design in seven centers. The study was terminated prematurely after approval of zanamivir made enrolment untenable (41 patients, calculated sample size 100). There were no differences in the proportions of patients shedding virus by treatment day 3, or duration of hospitalization, or use of oxygen. More patients taking zanamivir had a slight cough on day 3.
Oseltamivir
DRUG STUDIES
Oseltamivir (GS4104) is an ester prodrug, whose active metabolite (GS4071), to which it is rapidly hydrolysed by hepatic carboxylesterases, is a potent selective inhibitor of influenza virus neuraminidase. The metabolite is completely excreted by the kidneys by filtration and tubular secretion. In animals oseltamivir had a wide safety margin, with no evidence of teratogenicity or adverse effects on fertility. Oseltamivir has also been studied in the treatment and prevention of influenza A and B. Headache was the most frequent complaint and mild to moderate gastrointestinal adverse reactions (nausea, diarrhea) have been described [3], as has hepatotoxicity. Oseltamivir has been reviewed [4]. Transient gastrointestinal disturbances are the major adverse reactions and are reduced when the drug is taken with a light snack. In the clinical trials program, severe adverse events were reported at the same frequency as with placebo (1.3% with 75 mg bd, 0.7% with 150 mg bd, 1.2% with placebo).
Observational studies
Neuraminidase inhibitors GENERAL INFORMATION
Zanamivir In mice zanamivir strongly reduced viral replication [5]. It has poor oral systemic availability. Intranasal administration slightly increases its availability. In vitro, zanamivir does not significantly inhibit human lysosomal neuraminidases, and so the potential for severe adverse reactions is low [6].
ã 2016 Elsevier B.V. All rights reserved.
In 730 residents of nursing homes who took oseltamivir prophylaxis for a median of 9 days (range 5–12), adverse reactions were identified in 30 (4.1%), of whom 20 had one adverse effect and 10 had two [14]. The most common adverse reactions were diarrhea (n ¼ 12), nausea or vomiting (n ¼ 7), cough (n ¼ 5), and confusion (n ¼ 4). In seven patients with influenza (three type A and four type B) after allografting, inhaled zanamivir (10 mg bd) was used until excretion of virus ceased (median duration 15, range 5–44, days); there was rapid resolution of the influenza and no adverse effects attributable to zanamivir [15]. In several large postmarketing studies there were no increases in cardiovascular, neuropsychiatric, or respiratory complications [16], nor in skin reactions [17]. In a large Japanese prospective multicenter study during the influenza season of 2002–3 oseltamivir was given to 803 patients with influenza A and 684 patients with influenza B; amantadine was given to 676 patients with influenza A [18]. In each group, the duration of fever (body temperature over 37.5 ºC) was significantly shorter in patients who were treated within 12 hours after the onset of symptoms than in those who were treated more than 12 hours after the onset. The type of influenza, the highest body temperature, and the time between the onset of symptoms and the start of treatment independently affected the
Neuraminidase inhibitors duration of fever. Only minor adverse reactions were reported by 19 patients with influenza A given oseltamivir, eight patients given amantadine, and one patient with influenza B given oseltamivir. In a model of cost effectiveness comparing annual influenza immunization against empirical amantadine and rapid testing followed by oseltamivir if the results were positive, antiviral therapy without immunization was associated with the lowest overall costs ($234 per person per year for amantadine, $237 for oseltamivir). The cost of annual immunization was $239 per person and was associated with 0.0409 quality-adjusted days saved, for a marginal cost-effectiveness ratio of $113 per quality-adjusted day gained or $41 000 per quality-adjusted life-year saved compared with antiviral therapy [19]. Adverse reactions were included in the model at estimated baseline probabilities from published work. Adverse reactions to influenza vaccine included minor effects, such as local soreness at the injection site, estimated at a probability of 0.64, and rarely Guillain–Barre´ syndrome. The authors estimated that adverse reactions other than Guillain–Barre´ syndrome lasted 2 days. Minor adverse reactions due to drugs were also included with a probability of 0.09 for amantadine and 0.1 for oseltamivir.
Placebo-controlled studies In a large placebo-controlled efficacy study in adolescents, mild gastrointestinal symptoms were the major adverse reactions, in 14% (oseltamivir) versus 8% (placebo); vomiting was reported in 8% versus 3% [20].
Systematic reviews Trials of the neuraminidase inhibitors for influenza have been reviewed [21]. The percentage of patients with serious or minor adverse reactions associated with administration of neuraminidase inhibitors was as follows for zanamivir: serious or life-threatening reactions were allergic or allergic-like reactions, dysrhythmias, bronchospasm, dyspnea, facial edema, rash, seizure, syncope, and urticaria (<1.5%). Minor adverse reactions included headache (2%), dizziness (2%), nausea (3%), diarrhea (adults, 3%; children, 2%), vomiting (adults, 1%; children, 2%), sinusitis (3%), bronchitis (2%), cough (2%), other nasal signs and symptoms (2%), and infections (ear, nose, and throat: adults, 2%; children, 5%). For oseltamivir the serious or life-threatening events were aggravation of diabetes, dysrhythmias, confusion, hepatitis, pseudomembranous colitis, pyrexia, rash, seizures, swelling of the face or tongue, toxic epidermal necrolysis, and unstable angina (<1%) The minor reactions were insomnia (adults, 1%), vertigo (1%), nausea (10%), and vomiting (9%). Adverse reactions to oseltamivir prophylaxis were similar to those reported during treatment, but generally with lower incidences. More common with prophylactic use were headache (20%), fatigue (8%), cough (6%), and diarrhea (3%). A meta-analysis of adverse reactions to zanamivir in children showed that it was no worse than placebo [22]. ã 2016 Elsevier B.V. All rights reserved.
49
ORGANS AND SYSTEMS Respiratory Zanamivir is administered by inhalation of a powder in a lactose vehicle. It can cause bronchospasm [23]. A 63-year-old man with oxygen-dependent chronic obstructive
pulmonary disease was given zanamivir because of an exacerbation attributed to influenza. Shortly after each inhalation of the drug he reported increasing respiratory difficulty and wheezing. After 3 days he developed respiratory distress, hypoxia, and wheezing, and was treated with bronchodilators, glucocorticoids, and antibiotics.
Patients taking zanamivir are advised to stop using it if bronchospasm occurs, and those with underlying lung disease are advised to have a fast-acting bronchodilator to hand. The bronchospasm can be reduced in frequency by using an inhaled b2-adrenoceptor agonist before zanamivir. Proper drug deposition depends on flow rate and inhaler technique, so young and elderly patients may not be the best to treat in this way [2,24].
Psychiatric Oseltamivir was associated with abnormal behavior in four children, including meaningless speech, disorientation, fearful responses, and running around the room; there were no neurological sequelae [25]. Oseltamivir-induced worsening of delirium has been reported in an 83-year-old man, whose symptoms resolved 2 days after withdrawal [26]. Japanese authorities advised against using oseltamivir in adolescents aged 10–19 years after two suicides during 2007 and more than 100 reports of neuropsychiatric events identified during post-marketing surveillance, including delirium, convulsions, and encephalitis [27]. However, it is not clear whether these events were due to the influenza or the drug; in phase III trials there were similar incidences of neurological and psychiatric events in both treated and untreated patients [28]. Of 1113 patients enrolled in a Japanese neuraminidase inhibitor treatment study, 11 had neuropsychiatric symptoms, in four cases before the start of treatment [29]. The FDA and EMA have advised doctors to monitor patients for abnormal behavior throughout treatment [27].
Gastrointestinal Upper gastrointestinal reactions (nausea or nausea with vomiting) have been reported more often in those taking oseltamivir in placebo-controlled studies [30,31]. Despite this mild gastrointestinal intolerance, withdrawal rates have been low. Nausea and vomiting have led to drug withdrawal in less than 1% of the subjects in clinical trials [32]. While nausea was equally frequent with once-daily influenza prophylaxis (8%) and twice-daily treatment (7%), the incidence of vomiting increased from 4.5% during prophylaxis to 10% when the drug was taken twice a day [33]. A similar pattern was found in the pediatric subgroup, with vomiting incidences of 10% and 20% respectively.
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The oral capsule of oseltamivir can be used in any patient who can swallow. However, it must be given with food, to reduce the frequency of nausea and gastrointestinal discomfort. Of 695 children aged 1–12 years, 14% had vomiting compared with 8.5% of those who took placebo [34]. In a meta-analysis of trials, there was a reduction in the duration of symptoms of about 1 day [35]. Oseltamivir caused significantly more gastrointestinal symptoms (dyspepsia or nausea) than placebo; the effect increased with dose. Similarly, zanamivir caused significantly more gastrointestinal symptoms than placebo (OR ¼ 2.6; 95% CI ¼ 1.6, 4.2). Acute hemorrhagic colitis has been associated with oral oseltamivir in a 61-year-old man, who developed abdominal pain, diarrhea, and hematochezia after taking two doses of oseltamivir [36]. In a systematic review of three trials of neuraminidase inhibitors for preventing and treating influenza in 1500 children, 977 of whom had laboratory confirmed influenza, those who took oseltamivir had vomiting more often than untreated children but withdrawal was rarely required [22].
LONG-TERM EFFECTS Drug resistance Resistance occurs in under 1% of healthy adults but occurs more often in children, from 5.5% up to 18% in one study, although a lower dosage regimen was used in that study. Resistance is often seen among immunocompromised patients. It was reported in two of eight patients infected with H5N1 and was associated with a fatal outcome. Resistance is associated with loss of fitness [37]. In 2008 widespread resistance emerged in H1N1 influenza, but it remains to be seen whether its circulation is sustained after the emergence of oseltamivir-sensitive swine vH1N1.
SUSCEPTIBILITY FACTORS Genetic There was no evidence of a difference in AUC1!20 of oseltamivir or its active metabolite oseltamivir carboxylate between 14 Japanese subjects and 14 Caucasian subjects, or between children aged 1–2 years old and adults [38].
Age Exposure (AUC) to both the parent drug and its active metabolite were more than 80% higher in five very elderly subjects compared with young volunteers [39].
Renal disease Gastrointestinal adverse reactions and dizziness can occur with increasing doses of oseltamivir, particularly in patients with renal failure [40]. ã 2016 Elsevier B.V. All rights reserved.
Liver disease A single oral dose of oseltamivir 75 mg has been studied in 11 subjects with liver disease (all with cirrhosis, seven alcohol-induced) and paired controls. Mean BMI and estimated serum creatinine clearance were matched. In hepatic impairment the values of oseltamivir and oseltamivir carboxylate Cmax were <6% and <19% lower and their AUCs 33% higher and <19% lower respectively. Thus, the metabolism of oseltamivir is not compromised in hepatic impairment and no dosage adjustment is required [41].
DRUG–DRUG INTERACTIONS See also Sotalol
Amoxicillin In healthy subjects amoxicillin had no effect on the pharmacokinetics of oral oseltamivir [42].
Cimetidine In healthy subjects cimetidine had no effect on the pharmacokinetics of oral oseltamivir [42].
Probenecid In healthy subjects probenecid completely blocked the renal secretion of the active metabolite of oseltamivir after oral administration, increasing its AUC by 2.5 times [42]. In vitro studies of the metabolite on the human renal organic anionic transporter I (hOAT1) were investigated in Chinese hamster ovary cells stably transfected with the transporter. The metabolite was a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOATl-mediated transport of para-aminohippuric acid. Probenecid inhibited the transport of the metabolite, para-aminohippuric acid, and amoxicillin via hOAT1.
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