Relenza Information
Relenza (Zanamivir) Dosage And Administration
Household Setting:
Community Outbreaks:
Relenza (Zanamivir) Dosage Forms And Strengths
Blister for oral inhalation: 5 mg. Four 5-mg blisters of powder on a ROTADISK for oral inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses) and 1 DISKHALER inhalation device .
Relenza (Zanamivir) Contraindications
Do not use in patients with history of allergic reaction to any ingredient of Relenza (Zanamivir) including milk proteins.
Relenza (Zanamivir) Warnings And Precautions
Relenza (Zanamivir) is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease).
Serious cases of bronchospasm, including fatalities, have been reported during treatment with Relenza (Zanamivir) in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess.
Relenza (Zanamivir) should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required.
Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions.
Bronchospasm was documented following administration of zanamivir in 1 of 13 patients with mild or moderate asthma (but without acute influenza-like illness) in a Phase I study. In a Phase III study in patients with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of patients on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in FEV following treatment for 5 days.
If use of Relenza (Zanamivir) is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. If a decision is made to prescribe Relenza (Zanamivir) for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation, and appropriate supportive care including availability of fast-acting bronchodilators.
Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.
There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including Relenza (Zanamivir) . Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon based on usage data for Relenza (Zanamivir) . These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Relenza (Zanamivir) to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.
Relenza (Zanamivir) Adverse Reactions
See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm (5.1) and allergic-like reactions (5.2), and for safety information in patients with underlying airways disease (5.1).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The placebo used in clinical studies consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation.
Additional adverse reactions occurring in less than 1.5% of patients receiving Relenza (Zanamivir) included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.
The most frequent laboratory abnormalities in Phase III treatment studies included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.
Clinical Trials in Pediatric Patients:
In 1 of the 2 studies described in Table 2, some additional information is available from children (aged 5 to 12 years) without acute influenza-like illness who received an investigational prophylaxis regimen of Relenza (Zanamivir) ; 132 children received Relenza (Zanamivir) and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with Relenza (Zanamivir) than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients.
Community Prophylaxis Studies:
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of zanamivir (Relenza (Zanamivir) ). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zanamivir (Relenza (Zanamivir) ).
Cardiac:
Neurologic:
Relenza (Zanamivir) Drug Interactions
Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes. No clinically significant pharmacokinetic drug interactions are predicted based on data from in vitro studies.
The concurrent use of Relenza (Zanamivir) with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of potential interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of Relenza (Zanamivir) , unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus.
Trivalent inactivated influenza vaccine can be administered at any time relative to use of Relenza (Zanamivir) .
Relenza (Zanamivir) Use In Specific Populations
Pregnancy Category C. There are no adequate and well-controlled studies of zanamivir in pregnant women. Zanamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Embryo/fetal development studies were conducted in rats (dosed from days 6 to 15 of pregnancy) and rabbits (dosed from days 7 to 19 of pregnancy) using the same IV doses (1, 9, and 90 mg/kg/day). Pre- and post-natal developmental studies were performed in rats (dosed from day 16 of pregnancy until litter day 21 to 23). No malformations, maternal toxicity, or embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of insufficient blood sampling timepoints in rat and rabbit reproductive toxicity studies, AUC values were not available. In a subchronic study in rats at the 90 mg/kg/day IV dose, the AUC values were greater than 300 times the human exposure at the proposed clinical dose.
An additional embryo/fetal study, in a different strain of rat, was conducted using subcutaneous administration of zanamivir, 3 times daily, at doses of 1, 9, or 80 mg/kg during days 7 to 17 of pregnancy. There was an increase in the incidence rates of a variety of minor skeleton alterations and variants in the exposed offspring in this study. Based on AUC measurements, the 80 mg/kg dose produced an exposure greater than 1,000 times the human exposure at the proposed clinical dose. However, in most instances, the individual incidence rate of each skeletal alteration or variant remained within the background rates of the historical occurrence in the strain studied.
Zanamivir has been shown to cross the placenta in rats and rabbits. In these animals, fetal blood concentrations of zanamivir were significantly lower than zanamivir concentrations in the maternal blood.
In a Phase I study of 16 children aged 6 to 12 years with signs and symptoms of respiratory disease, 4 did not produce a measurable peak inspiratory flow rate (PIFR) through the DISKHALER (3 with no adequate inhalation on request, 1 with missing data), 9 had measurable PIFR on each of 2 inhalations, and 3 achieved measurable PIFR on only 1 of 2 inhalations. Neither of two 6-year-olds and one of two 7-year-olds produced measurable PIFR. Overall, 8 of the 16 children (including all those younger than 8 years) either did not produce measurable inspiratory flow through the DISKHALER or produced peak inspiratory flow rates below the 60 L/min considered optimal for the device under standardized in vitro testing; lack of measurable flow rate was related to low or undetectable serum concentrations . Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of Relenza (Zanamivir) is considered.
Of the total number of patients in 6 clinical studies of Relenza (Zanamivir) for treatment of influenza, 59 patients were aged 65 years and older, while 24 patients were aged 75 years and older. Of the total number of patients in 4 clinical studies of Relenza (Zanamivir) for prophylaxis of influenza in households and community settings, 954 patients were aged 65 years and older, while 347 patients were aged 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may need assistance with use of the device.
In 2 additional studies of Relenza (Zanamivir) for prophylaxis of influenza in the nursing home setting, efficacy was not demonstrated .
Relenza (Zanamivir) Overdosage
There have been no reports of overdosage from administration of Relenza (Zanamivir) .
Relenza (Zanamivir) Description
The active component of Relenza (Zanamivir) 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 CHNOand a molecular weight of 332.3. It has the following structural formula:
Zanamivir is a white to off-white powder for oral inhalation with a solubility of approximately 18 mg/mL in water at 20°C.
Relenza (Zanamivir) is for administration to the respiratory tract by oral inhalation only. Each Relenza (Zanamivir) ROTADISK 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 (Zanamivir) 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 (Zanamivir) 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.
Relenza (Zanamivir) Clinical Pharmacology
Absorption and Bioavailability:
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Distribution:
Metabolism:
Elimination:
Impaired Hepatic Function:
Impaired Renal Function:
Gender, Race, and Weight:
Mechanism of Action:
Antiviral Activity:
Resistance:
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 substitution (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:
Influenza Vaccine Interaction Study:
Influenza Challenge Studies:
Relenza (Zanamivir) Clinical Studies
Adults and Adolescents:
Populations Studied:
Principal Results:
Other Findings:
In general, patients with lower temperature (e.g., 38.2°C or less) or investigator-rated as having less severe symptoms at entry derived less benefit from therapy.
No consistent treatment effect was demonstrated in patients with underlying chronic medical conditions, including respiratory or cardiovascular disease
No consistent differences in rate of development of complications were observed between treatment groups.
Some fluctuation of symptoms was observed after the primary study endpoint in both treatment groups.
Pediatric Patients:
Although this study was designed to enroll children aged 5 to 12 years, the product is indicated only for children aged 7 years and older. This evaluation is based on the combination of lower estimates of treatment effect in 5- and 6-year-olds compared with the overall study population, and evidence of inadequate inhalation through the DISKHALER in a pharmacokinetic study .
The efficacy of Relenza (Zanamivir) in preventing naturally occurring influenza illness has been demonstrated in 2 post-exposure prophylaxis studies in households and 2 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 2 or more of the following symptoms: oral temperature ≥100°F/37.8°C or feverishness, cough, headache, sore throat, and myalgia; and laboratory confirmation of influenza A or B by culture, PCR, or seroconversion (defined as a 4-fold increase in convalescent antibody titer from baseline).
Household Prophylaxis Studies:
In the second study, index cases were not treated. The incidence of symptomatic laboratory-confirmed influenza was reduced from 19.0% (46 of 242 households) for the placebo group to 4.1% (10 of 245 households) for the group receiving Relenza (Zanamivir) .
Seasonal Prophylaxis Studies:
The second seasonal prophylaxis study enrolled subjects aged 12 to 94 years (mean age 60 years) with 56% of them older than 65 years. Sixty-seven percent of the subjects were vaccinated. In this study, the incidence of symptomatic laboratory-confirmed influenza was reduced from 1.4% (23 of 1,685) for the placebo group to 0.2% (4 of 1,678) for the group receiving Relenza (Zanamivir) .
Relenza (Zanamivir) How Supplied/storage And Handling
Relenza (Zanamivir) is supplied in a circular double-foil pack (a ROTADISK) containing 4 blisters of the drug. Five ROTADISKs are packaged in a white polypropylene tube. The tube is packaged in a carton with 1 blue and gray DISKHALER inhalation device (NDC 0173-0681-01).
Relenza (Zanamivir) Patient Counseling Information
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Patients should be advised of the risk of bronchospasm, especially in the setting of underlying airways disease, and should stop Relenza (Zanamivir) and contact their physician if they experience increased respiratory symptoms during treatment such as worsening wheezing, shortness of breath, or other signs or symptoms of bronchospasm
. If a decision is made to prescribe Relenza (Zanamivir) for a patient with asthma or chronic obstructive pulmonary disease, the patient should be made aware of the risks and should have a fast-acting bronchodilator available.
Patients should be instructed in use of the delivery system. Instructions should include a demonstration whenever possible. For the proper use of Relenza (Zanamivir) , the patient should read and follow carefully the accompanying Instructions for Use.
Patients should be advised that the use of Relenza (Zanamivir) for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others.
Relenza (Zanamivir) , DISKHALER, and ROTADISK are registered trademarks of GlaxoSmithKline.
GlaxoSmithKlineResearch Triangle Park, NC 27709
©2011, GlaxoSmithKline. All rights reserved.
December 2011
RLZ:9PI
Relenza (Zanamivir)
Relenza (Zanamivir)
