WARNINGS AND PRECAUTIONS
RELENZA 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 in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess.
RELENZA 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 FEV1 following treatment for 5 days.
If use of RELENZA 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 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.
Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected.
5.3 Neuropsychiatric Events
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. 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. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RELENZA 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.
Limitations of Populations Studied
Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications.
Importance of Proper Use of DISKHALER
Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully evaluate the ability of young children to use the delivery system if use of RELENZA is considered [see Use in Specific Populations].
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.
Studies in rats have demonstrated that zanamivir is excreted in milk. However, nursing mothers should be instructed that it is not known whether zanamivir is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELENZA is administered to a nursing mother.
Treatment of Influenza: Safety and effectiveness of RELENZA for treatment of influenza have not been assessed in pediatric patients less than 7 years of age, but were studied in a Phase III treatment study in pediatric patients, where 471 children 5 to 12 years of age received zanamivir or placebo [see Clinical Studies 14.1)]. Adolescents were included in the 3 principal Phase III adult treatment studies. In these studies, 67 patients were 12 to 16 years of age. No definite differences in safety and efficacy were observed between these adolescent patients and young adults.
In a Phase I study of 16 children ages 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 under 8 years old) 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 [see Clinical Pharmacology Clinical Studies]. Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered.
Prophylaxis of Influenza: The safety and effectiveness of RELENZA for prophylaxis of influenza have been studied in 4 Phase III studies where 273 children 5 to 11 years of age and 239 adolescents 12 to 16 years of age received RELENZA. No differences in safety and effectiveness were observed between pediatric and adult subjects [see Clinical Studies (14.2)].
Of the total number of patients in 6 clinical studies of RELENZA for treatment of influenza, 59 patients were 65 years of age and older, while 24 patients were 75 years of age and older. Of the total number of patients in 4 clinical studies of RELENZA for prophylaxis of influenza in households and community settings, 954 patients were 65 years of age and older, while 347 patients were 75 years of age 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 for prophylaxis of influenza in the nursing home setting, efficacy was not demonstrated [see Indications and Usage].