Relenza Warnings, Precautions, Pregnancy, Nursing, Abuse - Zanamivir

Relenza Warnings, Precautions, Pregnancy, Nursing, Abuse - Zanamivir

WARNINGS

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.

General: Patients should be instructed in the use of the delivery system. Instructions should include a demonstration whenever possible. Patients should read and follow carefully the Patient Instructions for Use accompanying the product. Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. There is no evidence for efficacy of zanamivir in any illness caused by agents other than influenza virus A and B.

No data are available to support safety or efficacy in patients who begin treatment after 48 hours of symptoms.

Safety and efficacy of repeated treatment courses have not been studied.

Patients with Respiratory Disease: SAFETY AND EFFICACY OF RELENZA HAVE NOT BEEN DEMONSTRATED IN PATIENTS WITH UNDERLYING CHRONIC PULMONARY DISEASE (SEE WARNINGS). IN PARTICULAR, RELENZA HAS NOT BEEN SHOWN TO BE EFFECTIVE IN PATIENTS WITH SEVERE OR DECOMPENSATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE OR ASTHMA, AND SERIOUS ADVERSE EVENTS HAVE BEEN REPORTED IN SUCH PATIENTS. THEREFORE, RELENZA IS NOT GENERALLY RECOMMENDED FOR TREATMENT OF PATIENTS WITH UNDERLYING AIRWAYS DISEASE SUCH AS ASTHMA OR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (SEE WARNINGS).

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 1 study. In interim results from an ongoing treatment study in patients with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, more patients on zanamivir than on placebo experienced greater than 20% decline in FEV₁ or peak expiratory flow rate.

If treatment with 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 Reactions: Allergic-like reactions, including oropharyngeal edema and serious skin rashes, have been reported in post-marketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected.

Bacterial Infections: 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.

Prevention of Influenza: Use of zanamivir should not affect the evaluation of individuals for annual influenza vaccination in accordance with guidelines of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Safety and efficacy of zanamivir have not been established for prophylactic use of zanamivir to prevent influenza.

INFORMATION FOR PATIENTS

Patients should be instructed in use of the delivery system. Instructions should include a demonstration whenever possible.

For the proper use of RELENZA, the patient should read and follow carefully the accompanying Patient Instructions for Use. Patients should be advised that the use of RELENZA for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others.

Patients should be advised of the risk of bronchospasm, especially in the setting of underlying airways disease, and should stop RELENZA 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 (see WARNINGS). If a decision is made to prescribe RELENZA 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 scheduled to take inhaled bronchodilators at the same time as RELENZA should be advised to use their bronchodilators before taking RELENZA.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenesis: In 2-year carcinogenicity studies conducted in rats and mice using a powder formulation administered through inhalation, zanamivir induced no statistically significant increases in tumors over controls. The maximum daily exposures in rats and mice were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons.

Mutagenesis: Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood lymphocytes, and the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility: The effects of zanamivir on fertility and general reproductive performance were investigated in male (dosed for 10 weeks prior to mating, and throughout mating, gestation/lactation, and shortly after weaning) and female rats (dosed for 3 weeks prior to mating through day 19 of pregnancy, or day 21 post partum) at IV doses 1, 9, and 90 mg/kg/day. Zanamivir did not impair mating or fertility of male or female rats, and did not affect the sperm of treated male rats. The reproductive performance of the F1 generation born to female rats given zanamivir was not affected. Based on a subchronic study in rats at a 90-mg/kg/day IV dose, AUC values ranged between 142 and 199 mcg· hr/mL (>300 times the human exposure at the proposed clinical dose).

Pregnancy: Pregnancy Category C. 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. Pre- and post-natal developmental studies were performed in rats (dosed from day 16 of pregnancy until litter day 21 to 23). In all studies, intravenous (1, 9, and 90 mg/kg/day) instead of the inhalational route of drug administration was used. No malformations, maternal toxicity, or embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of insufficient blood sampling timepoints in both rat and rabbit reproductive toxicity studies, AUC values were not available. However, 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 high dose in the study produced an exposure greater than 1,000 times the human exposure at the proposed clinical dose. However, the individual incidence rate of each skeletal alteration or variant, in most instances, 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.

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.

Nursing Mothers: 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.

Pediatric Use: Safety and effectiveness of RELENZA have not been established in pediatric patients under 7 years of age.

The safety and effectiveness of RELENZA have been studied in a Phase 3 treatment study in pediatric patients, where 471 children 5 to 12 years of age received zanamivir or placebo (see INDICATIONS AND USAGE: Description of Clinical Studies, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). In a Phase 1 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 DESCRIPTION, CLINICAL PHARMACOLOGY: Pediatric Patients, and INDICATIONS AND USAGE: Description of Clinical Studies). Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered. When RELENZA is prescribed for children, it should be used only under adult supervision and with attention to proper use of the delivery system.

Adolescents were included in the 3 principal Phase 3 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.

Geriatric Use: Of the total number of patients in 6 clinical treatment studies of RELENZA, 59 were 65 and over, while 24 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects 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.