The active component of RELENZA is zanamivir. The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid. It has a molecular formula of C12H20N4O7 and a molecular weight of 332.3. It has the following structural formula:
Zanamivir is a white to off-white powder with a solubility of approximately 18 mg/mL in water at 20¡ãC.
RELENZA is for administration to the respiratory tract by oral inhalation only. Each RELENZA ROTADISKÒ contains 4 regularly spaced double-foil blisters with each blister containing a powder mixture of 5 mg of zanamivir and 20 mg of lactose (which contains milk proteins). The contents of each blister are inhaled using a specially designed breath-activated plastic device for inhaling powder called the DISKHALER. After a RELENZA ROTADISK is loaded into the DISKHALER, a blister that contains medication is pierced and the zanamivir is dispersed into the air stream created when the patient inhales through the mouthpiece. The amount of drug delivered to the respiratory tract will depend on patient factors such as inspiratory flow. Under standardized in vitro testing, RELENZA ROTADISK delivers 4 mg of zanamivir from the DISKHALER device when tested at a pressure drop of 3 kPa (corresponding to a flow rate of about 62 to 65 L/min) for 3 seconds. In a study of 5 adult and 5 adolescent patients with obstructive airway diseases, the combined peak inspiratory flow rates (PIFR) ranged from 66 to 140 L/min. In a separate study of 16 pediatric patients, PIFR results were more variable; 4 did not achieve measurable flow rates, and PIFR for measurable inhalations by 12 children ranged from 30.5 to 122.4 L/min. Only 1 of 4 children under age 8 had a measurable flow rate (see CLINICAL PHARMACOLOGY: Pediatric Patients, INDICATIONS AND USAGE: Description of Clinical Studies, and PRECAUTIONS: Pediatric Use).
MICROBIOLOGY
Mechanism of Action: The mechanism of action of zanamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.
Antiviral Activity: The antiviral activity of zanamivir against laboratory and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of zanamivir required for inhibition of influenza virus were highly variable depending on the assay method used and virus isolate tested. The 50% and 90% effective concentrations (EC50 and EC90) of zanamivir were in the range of 0.005 to 16.0 mM and 0.05 to >100 mM, respectively (1 mM = 0.33 mcg/mL). The relationship between the in vitro inhibition of influenza virus by zanamivir and the inhibition of influenza virus replication in humans has not been established.
Resistance: Influenza viruses with reduced susceptibility to zanamivir have been recovered in vitro by multiple passages of the virus in the presence of increasing concentrations of the drug. Genetic analysis of these viruses showed that the reduced susceptibility in vitro to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance mutations selected in vitro which result in neuraminidase amino acid substitutions include E119G/A/D and R292K.Mutations selected in vitro in hemagglutinin include: K68R, G75E, E114K, N145S, S165N, S186F, N199S, and K222T.
In an immunocompromised patient infected with influenza B virus, a variant virus emerged after treatment with an investigational nebulized solution of zanamivir for 2 weeks. Analysis of this variant showed a hemagglutinin mutation (T198I) which resulted in a reduced affinity for human cell receptors, and a substitution in the neuraminidase active site (R152K) which reduced the enzyme¡¯s activity to zanamivir by 1,000-fold. Insufficient information is available to characterize the risk of emergence of zanamivir resistance in clinical use.
Cross-Resistance: Cross-resistance has been observed between some zanamivir-resistant and some oseltamivir-resistant influenza virus mutants generated in vitro. However, some of the in vitro zanamivir-induced resistance mutations, E119G/A/D and R292K, occurred at the same neuraminidase amino acid positions as in the clinical isolates resistant to oseltamivir, E119V and R292K. No studies have been performed to assess risk of emergence of cross-resistance during clinical use.
Influenza Vaccine Interaction Study: An interaction study (n = 138) was conducted to evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers. There was no clear difference in hemagglutination inhibition antibody titers at 2 weeks and 4 weeks after vaccine administration between zanamivir and placebo recipients.
Influenza Challenge Studies: Antiviral activity of zanamivir was supported for infection with influenza A virus, and to a more limited extent for infection with influenza B virus, by Phase 1 studies in volunteers who received intranasal inoculations of challenge strains of influenza virus, and received an intranasal formulation of zanamivir or placebo starting before or shortly after viral inoculation.
