Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Glaxo Wellcome UK Ltd trading as GlaxoSmithKline UK, 980 Great West Road, Brentford, Middlesex, TW8 9GS
Pharmacotherapeutic group: Antiviral, neuraminidase inhibitor
ATC code: J05AH01
Zanamivir is a selective inhibitor of neuraminidase, the influenza virus surface enzyme. Neuraminidase inhibition occurred in vitro at very low zanamivir concentrations (50% inhibition at 0.64nM–7.9nM against influenza A and B strains). Viral neuraminidase aids the release of newly formed virus particles from infected cells, and may facilitate access of virus through mucus to epithelial cell surfaces, to allow viral infection of other cells. The inhibition of this enzyme is reflected in both in vitro and in vivo activity against influenza A and B virus replication, and encompasses all of the known neuraminidase subtypes of influenza A viruses.
The activity of zanamivir is extracellular. It reduces the propagation of both influenza A and B viruses by inhibiting the release of infectious influenza virions from the epithelial cells of the respiratory tract. Influenza viral replication occurs in the superficial epithelium of the respiratory tract. The efficacy of topical administration of zanamivir to this site has been confirmed in clinical studies.
Resistance selection during zanamivir treatment is rare. Reduced susceptibility to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Neuraminidase substitutions conferring reduced susceptibility to zanamivir have emerged during treatment with zanamivir in human viruses and those with zoonotic potential: E119D, E119G, I223R, R368G, G370D, N434S (A/H1N1); N294S, T325I (A/H3N2); R150K (B); R292K (A/H7N9). The neuraminidase substitution Q136K (A/H1N1 and A/H3N2), confers high level resistance to zanamivir but is selected during adaptation to cell culture and not during treatment.
The clinical impact of reduced susceptibility in these viruses is unknown, and the effects of specific substitutions on virus susceptibility to zanamivir may be strain-dependent.
Cross resistance between zanamivir and oseltamivir or peramivir has been observed in neuraminidase inhibition assays. A number of neuraminidase amino acid substitutions that arise during oseltamivir or peramivir treatment result in reduced susceptibility to zanamivir. The clinical impact of substitutions associated with reduced susceptibility to zanamivir and other neuraminidase inhibitors is variable and may be strain-dependent.
The H275Y substitution is the most common neuraminidase resistance substitution and is associated with reduced susceptibility to peramivir and oseltamivir. This substitution has no effect on zanamivir; therefore, viruses with the H275Y substitution retain full susceptibility to zanamivir.
Relenza alleviates the symptoms of influenza and reduces their median duration by 1.5 days (range 1.0–2.5 days) in adults as detailed in the table below. The median time to alleviation of influenza symptoms in elderly subjects (≥65 years) and in children aged 5-6 years, was not significantly reduced. The efficacy of Relenza has been demonstrated in otherwise healthy adults when treatment is initiated within 48 hours, and in otherwise healthy children when treatment is initiated within 36 hours, after the onset of symptoms. No treatment benefit has been documented for patients with afebrile disease (<37.8°C).
1. Six key Phase III randomised, placebo-controlled, parallel-group, multicentre treatment studies (NAIB3001, NAIA3002, NAIB3002, NAI30008, NAI30012 and NAI30009) have been conducted with zanamivir for the treatment of naturally acquired influenza A and B. Study NAI30008 recruited only patients with asthma (n=399), COPD (n=87), or asthma and COPD (n=32), study NAI30012 recruited only elderly (≥65 years) patients (n=358) and study NAI30009 (n=471) recruited paediatric patients, 5-12 years. The Intent to Treat population of these six studies comprised 2942 patients of which 1490 received 10 mg zanamivir b.i.d by oral inhalation. The primary endpoint was identical for all six Phase III studies, i.e. time to alleviation of clinically significant signs and symptoms of influenza. For all six phase III studies, alleviation was defined as no fever, i.e. temperature <37.8°C and feverishness score of ‘none’(‘same as normal/none’ in NAI30012), and headache, myalgia, cough and sore throat recorded as ‘none’ (‘same as normal/none’ in NAI30012) or ‘mild’ and maintained for 24 hours.
Comparison of Median Time (Days) to Alleviation of Influenza Symptoms:
| Influenza Positive Population | ||||
|---|---|---|---|---|
| Study | Placebo | Zanamivir 10mg inhaled twice daily | Difference in Days | (95% CI) p-value |
| NAIB3001 | n=160 6.0 | n=161 4.5 | 1.5 | 0.004 |
| NAIA3002 | n=257 6.0 | n=312 5.0 | 1.0 | 0.078 |
| NAIB3002 | n=141 7.5 | n=136 5.0 | 2.5 | <0.001 |
| Combined analysis of NAIB3001, NAIA3002, and NAIB3002 | n=558 6.5 | n=609 5.0 | 1.5 | <0.001 |
| Asthma/COPD study | ||||
| NAI30008 | n=153 7.0 | n=160 5.5 | 1.5 | 0.009 |
| Elderly study | ||||
| NAI30012 | n=114 7.5 | n=120 7.25 | 0.25 | 0.609 |
| Paediatric study | ||||
| NAI30009 | n=182 5.0 | n=164 4.0 | 1.0 | <0.001 |
In the Intent to Treat (ITT) population the difference in time to alleviation of symptoms was 1.0 day (95% CI: 0.5 to 1.5) in the combined analysis of NAIB3001, NAIA3002 and NAIB3002, 1.0 day (95% CI: 0 to 2) in study NAI30008, 1.0 day (95% CI –1.0 to 3.0) in study NAI30012 and 0.5 days (95% CI: 0 to 1.5) in study NAI30009. There are limited data in high risk children.
In a combined analysis of patients with influenza B (n=163), including 79 treated with zanamivir, a 2.0 day treatment benefit was observed (95%CI: 0.50 to 3.50).
In the pooled analysis of 3 phase III studies in influenza positive, predominantly healthy adults, the incidence of complications was 152/558 (27%) in placebo recipients and 119/609 (20%) in zanamivir recipients (relative risk zanamivir:placebo 0.73; 95% CI 0.59 to 0.90, p=0.004). In study NAI30008 enrolling patients with asthma and COPD the incidence of complications was 56/153 (37%) in influenza-positive placebo recipients and 52/160 (33%) in influenza positive zanamivir recipients (relative risk zanamivir:placebo 0.89; 95% CI: 0.65 to 1.21, p=0.520). In study NAI30012 enrolling elderly patients the incidence of complications was 46/114 (40%) in influenza positive placebo recipients and 39/120 (33%) in influenza positive zanamivir recipients (relative risk zanamivir:placebo 0.80, 95% CI: 0.57 to 1.13, p=0.256). In the paediatric study NAI30009, the incidence of complications was 41/182 (23%) in influenza-positive placebo recipients and 26/164 (16%) in influenza-positive zanamivir recipients (relative risk zanamivir:placebo 0.70; 95% CI: 0.45 to 1.10, p=0.151).
In a placebo controlled study in patients with predominantly mild/moderate asthma and/or Chronic Obstructive Pulmonary Disease (COPD) there was no clinically significant difference between zanamivir and placebo in forced expiratory volume in one second (FEV1) or peak expiratory flow rate (PEFR) measured during treatment or after the end of treatment.
The efficacy of Relenza in preventing naturally occurring influenza illness has been demonstrated in two post-exposure prophylaxis studies in households and two seasonal prophylaxis studies during community outbreaks of influenza. The primary efficacy endpoint in these studies was the incidence of symptomatic, laboratory-confirmed influenza, defined as the presence of two or more of the following symptoms: oral temperature 37.8C or feverishness, cough, headache, sore throat, and myalgia; and laboratory confirmation of influenza by culture, PCR, or seroconversion (defined as a 4-fold increase in convalescent antibody titer from baseline).
Two studies assessed post-exposure prophylaxis in household contacts of an index case. Within 1.5 days of onset of symptoms in an index case, each household (including all family members ≥5 years of age) was randomized to Relenza 10 mg or placebo inhaled once daily for 10 days. In the first study only, each index case was randomized to the same treatment (Relenza or placebo) as the other household members. In this study, the proportion of households with at least one new case of symptomatic influenza was reduced from 19% (32 of 168 households) with placebo to 4% (7 of 169 households) with Relenza (79% protective efficacy ; 95% CI: 57% to 89%, p<0.001). In the second study, index cases were not treated and the incidence of symptomatic influenza was reduced from 19% (46 of 242 households) with placebo to 4% (10 of 245 households) with Relenza (81% protective efficacy; 95% CI: 64% to 90%, p<0.001). Results were similar in the subgroups with influenza A or B. In these studies, which included a total of 2128 contact cases, 553 children were aged 5-11 years, of which 123 children were 5-6 years. The incidence of symptomatic laboratory confirmed influenza in the 5- to 6-year-old group (placebo vs. zanamivir) was 4/33 (12%) vs. 1/28 (4%) in the first study and 4/26 (15%) vs. 1/36 (3%) in the second study, which seems to be consistent with older age categories. However, as the studies were not powered to establish protective efficacy in individual age categories, a formal subgroup analysis has not been performed.
Two seasonal prophylaxis studies assessed Relenza 10 mg versus placebo inhaled once daily for 28 days during community outbreaks. In the first study, which involved unvaccinated, otherwise healthy adults aged ≥18 years, the incidence of symptomatic influenza was reduced from 6.1% (34 of 554) with placebo to 2.0% (11 of 553) with Relenza (67% protective efficacy; 95% CI: 39% to 83%, p<0.001). The second study involved community-dwelling subjects aged ≥12 years at high risk of complications from influenza, where 67% of participants had received vaccine in the season of the study. High risk was defined as subjects ≥65 years of age and subjects with chronic disorders of the pulmonary or cardiovascular systems or with diabetes mellitus. In this study, the incidence of symptomatic influenza was reduced from 1.4% (23 of 1,685) with placebo to 0.2% (4 of 1,678) with Relenza (83% protective efficacy; 95% CI: 56% to 93%, p<0.001).
Due to limited and inconclusive data, the efficacy of Relenza in the prevention of influenza in the nursing home setting has not been established.
Pharmacokinetic studies in humans have shown that the absolute oral bioavailability of the drug is low (mean (min, max) is 2%(1%, 5%)). Similar studies of orally inhaled zanamivir indicate that approximately 4-17% of the dose is systemically absorbed, with serum concentrations generally peaking within 1-2 hours. The poor absorption of the drug results in low systemic concentrations and therefore there is no significant systemic exposure to zanamivir after oral inhalation. There is no evidence of modification in the kinetics after repeated dosing with oral inhaled administration.
Zanamivir is not protein bound (<10%). The volume of distribution of zanamivir in adults is approximately 16 L, which approximates to the volume of extracellular water. After oral inhalation, zanamivir is widely deposited at high concentrations throughout the respiratory tract, thus delivering the drug to the site of influenza infection.
Zanamivir has been shown to be renally excreted as unchanged drug, and does not undergo metabolism.
The serum half-life of zanamivir following administration by oral inhalation ranges from 2.6 to 5.05 hours. It is eliminated entirely through renal filtration. Total clearance ranges from 2.5 to 10.9 L/h as approximated by urinary clearance. Renal elimination is completed within 24 hours.
Inhaled zanamivir results in approximately 4-17% of the inhaled dose being absorbed. In the severe renal impairment group from the single IV zanamivir dose trial subjects were sampled after a dose of 2 mg or twice to four times the expected exposure from inhalation. Using the normal dosing regimen (10 mg bid), the predicted exposure at Day 5 is 40-fold lower than what was tolerated in healthy subjects after repeated iv administration. Given the importance of local concentrations, the low systemic exposure, and the previous tolerance of much higher exposures no dose adjustment is advised.
Zanamivir is not metabolised, therefore dose adjustment in patients with hepatic impairment is not required.
At the therapeutic daily dose of 20mg, bioavailability is low (4-17%), and as a result there is no significant systemic exposure of patients to zanamivir. Any alteration of pharmacokinetics that may occur with age is unlikely to be of clinical consequence and no dose modification is recommended.
In an open-label single-dose study the pharmacokinetics of zanamivir was evaluated in 16 paediatric subjects, aged 6 to 12 years, using dry powder (10 mg) inhalation formulation (Diskhaler device). The systemic exposure was similar to 10 mg of inhaled powder in adults, but the variability was large in all age groups and more pronounced in the youngest children. Five patients were excluded due to undetectable serum concentrations at all time points or 1.5 hours post-dose, suggesting inadequate drug delivery.
General toxicity studies did not indicate any significant toxicity of zanamivir. Zanamivir was not genotoxic and no clinically relevant findings were observed in long term carcinogenicity studies in rats and mice.
No drug-related malformations, maternal toxicity or embryotoxicity were observed in pregnant rats or rabbits or their foetuses following intravenous administration of zanamivir at doses up to 90 mg/kg/day. Following subcutaneous administration of zanamivir in an additional rat embryofoetal development study, there was an increase in the incidence rates of a variety of minor skeletal and visceral alterations and variants in the exposed offspring at the highest dose 80 mg/kg, three times daily (240 mg/kg/day; total daily dose), most of which remained within the background rates of the historical occurrence in the strain studied. Based on AUC measurements, the 80 mg/kg dose (240 mg/kg/day) produced an exposure approximately 1000 times the human exposure at the clinical inhaled dose. In the peri- and post-natal developmental study conducted in rats, there was no clinically meaningful impairment of development of offspring.
Intravenous doses of up to 90mg/kg/day zanamivir produced no effect on fertility and reproductive function of the treated or subsequent generation in male and female rats.
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