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Central nervous system adverse reactions occurring in patients receiving zanamivir treatment patients include headache (2%) and dizziness (up to 2%). Headache was reported in 13% of all patients receiving a 10-day prophylaxis course and in 24% of patients receiving a 28-day prophylaxis course in clinical trials. Seizures and vasovagal-like episodes were noted in postmarketing reports.[35421]

Urticaria has been reported in less than 1.5% of adult treatment patients during zanamivir clinical trials. Postmarketing allergic or allergic-like reactions included anaphylactoid reactions, facial edema (angioedema) or oropharyngeal edema (laryngeal edema), and rash. Some skin rashes have been serious, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.[35421]

Serious cases of bronchospasm, including fatalities, have been reported during zanamivir treatment in patients with and without underlying airway disease. Due to the risk of serious bronchospasm, the drug is not indicated for use in patients with underlying airway disease, such as asthma or chronic obstructive pulmonary disease. In a phase I study, zanamivir-associated bronchospasm was documented in 1 of 13 patients with mild or moderate asthma (but without acute influenza-like illness). In a phase III study, more patients with underlying asthma or chronic obstructive pulmonary disease treated with zanamivir experienced a greater than 20% decline in FEV1 than those treated with placebo. If the decision is made to use the drug in a patient with underlying respiratory disease, the patient should be instructed to have a fast-acting inhaled bronchodilator available during treatment, and respiratory function should be closely monitored. Serious side effects warrant drug discontinuation. Other respiratory adverse events noted with zanamivir use include nasal signs and symptoms (2% to 20%), bronchitis (2%), cough (up to 17%), sinusitis (up to 3%), ear/nose/throat infection (2% to 5%), ear/nose/throat hemorrhage (less than 1%), throat or tonsil discomfort and pain (8% to 19%), asthma (less than 1%), viral respiratory infections (3% to 13%), and nasal inflammation (1%). In a subset of pediatric patients with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, and viral respiratory infections or influenza-like symptoms) were reported in 7 of 7 zanamivir patients. Dyspnea has been noted in postmarketing reports.[35421]

Cases of self-injury and delirium (psychosis) have been reported during postmarketing use of neuraminidase inhibitors, including zanamivir. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. Additional psychiatric adverse events that have been reported during postmarketing use include altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, and nightmares. Patients should report any emotional lability while taking zanamivir. Influenza may also be associated with a variety of neurologic and behavioral symptoms.[35421]

Gastrointestinal adverse reactions occurring in patients receiving zanamivir include diarrhea (2% to 3%), nausea (up to 3%), vomiting (1% to 2%), abdominal pain (less than 1.5%), and feeding problems including appetite stimulation, decreased appetite, or anorexia (2% to 4%).[35421]

Arrhythmia exacerbation and syncope have been noted during postmarketing use with zanamivir.[35421]

Elevated hepatic enzymes and creatine phosphokinase (CPK) have been noted in adults during zanamivir treatment trials. These laboratory abnormalities were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.[35421]

Lymphopenia and neutropenia have been reported in adult patients in zanamivir treatment trials. These laboratory abnormalities were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.[35421]

Muscle pain or myalgia (up to 8%), musculoskeletal pain (6%), and arthralgia or articular rheumatism (up to 2%) were reported during zanamivir clinical trials.[35421]

Malaise (up to 8%), fatigue (up to 8%), fever (up to 9%), and chills (5% to 9%) have been reported during zanamivir trials.[35421]

Zanamivir is contraindicated in any patient who is hypersensitive to the drug or to any component of the formulation, including patients with milk protein hypersensitivity; zanamivir oral inhalation contains the milk protein lactose as a vehicle. Serious adverse reactions, including angioedema, serious rash, and anaphylaxis, have been reported during postmarketing use of the drug. Stop zanamivir and initiate appropriate treatment if an allergic reaction occurs or is suspected.[35421]

There is no evidence of efficacy of zanamivir in viral infection caused by agents other than influenza virus A and B. Data on the treatment of influenza B are limited as only 11% of patients in the clinical trials were infected with this virus. There are no data available to support the safety or efficacy of zanamivir therapy in patients who begin treatment after 48 hours of symptoms.[35421]

Zanamivir has only been studied in limited populations. Use with caution in any patient with high-risk underlying medical conditions (e.g., geriatric patients, severe metabolic disease, lung or cardiac disease); safety and efficacy have not been established in these patients. No information is available regarding zanamivir treatment in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management.[35421] Intravenous zanamivir requires a dosage adjustment for patients with renal dysfunction; because elderly patients are at higher risk for impaired renal function, careful consideration should be given when determining the dosage.[56679]

Safety and efficacy of zanamivir oral inhalation have not been established in patients with significant renal impairment or renal failure. Drug accumulation may occur; however, because oral inhalation results in low systemic bioavailability, no dosage adjustments are needed.[35421] Dose adjustments are recommended for patients with renal impairment receiving intravenous zanamivir as part of the compassionate use protocol.[56679]

The safety and efficacy of zanamivir have not been established in patients with chronic pulmonary disease, and use is not generally recommended in these patients. In particular, this product has not been shown to be effective and may carry safety risks in patients with severe or decompensated asthma or chronic obstructive pulmonary disease (COPD) (i.e., chronic bronchitis or emphysema). Some patients with underlying respiratory diseases treated with zanamivir may be at increased risk for bronchospasm and/or a decline in lung function (i.e., decreased FEV1). Advise any patient who develops bronchospasm or a decline in lung function to stop treatment with zanamivir; also, health care professionals should assess if hospitalization or immediate medical treatment is required. Instruct patients with underlying pulmonary disease to have a fast-acting inhaled bronchodilator available during treatment with zanamivir.[35421]

Avoid zanamivir administration via nebulizer; do not administer to patients on mechanical ventilation. The safety, effectiveness, and stability of zanamivir via nebulization have not been established. Additionally, a death has been reported of a mechanically ventilated patient with influenza who received zanamivir inhalation powder that was solubilized and administered by nebulizer for 3 days. Zanamivir inhalation powder is not intended to be reconstituted in any liquid formulation and is not recommended for use in any nebulizer or mechanical ventilator. Zanamivir inhalation powder is a mixture of active drug substance and lactose drug carrier. There is a risk that the lactose in this formulation can obstruct proper functioning of mechanical ventilator equipment.[35421]

Concurrent administration of zanamivir with live attenuated influenza vaccine (LAIV) may inhibit viral replication of LAIV and decrease the efficacy of LAIV vaccination. Therefore, administer LAIV at least 2 weeks before zanamivir treatment or 48 hours after cessation of therapy, unless medically indicated. Inactivated influenza virus vaccine can be administered as indicated.[35421] [62315]

The safety and efficacy of zanamivir have not been established in children younger than 7 years for the treatment of influenza and children younger than 5 years for the prophylaxis of influenza. Although zanamivir has been studied in 471 children 5 to 12 years of age, clinical trials estimated a lower treatment effect in children younger than 7 years compared to the overall population. Also, young children exhibit evidence of inadequate inhalational technique from the Diskhaler device; carefully evaluate the ability of young children to use the delivery system. When zanamivir is prescribed to any child, the system should be used under adult supervision and an adult should help ensure the proper use of the delivery system by the child. Neuropsychiatric adverse reactions of self-injury and delirium (psychosis) have also been reported during postmarketing use of zanamivir; some cases resulted in fatal outcomes. These reactions were primarily reported in pediatric patients and often occurred abruptly and resolved rapidly. Since influenza infection itself is associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior), the role of zanamivir in causing these reactions is unclear. Patients with influenza who are receiving zanamivir, particularly children and adolescents, should be closely monitored for signs of abnormal behavior. The risks and benefits of continuing zanamivir should be evaluated if neuropsychiatric events occur.[35421]

Although zanamivir crosses the placenta, data from published studies suggest use of the drug during pregnancy is not associated with an increased risk of birth defects or adverse maternal or fetal outcomes; however, these studies are limited in size (i.e., power), which precludes a definitive assessment of risk. When deciding on treatment, health care providers are advised to consider that pregnant women are at higher risk of severe complications from influenza, which may result in adverse pregnancy or fetal outcomes (i.e., maternal death, stillbirth, birth defects, preterm delivery, low birth weight, small gestational age). The CDC states that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use.[35421] [62315]

There are no data on the presence of zanamivir in human milk or the effects on milk production; however, one study estimated the exposure of an exclusively breast-fed 5 kg infant at 0.075 mg/day based on peak maternal serum concentrations of 34 to 96 ng/mL, a milk-to-plasma ratio of 1, and an assumed milk ingestion of 150 mL/kg/day.[46967] If an infant is exposed to zanamivir through breast-feeding, significant serum concentrations are not expected because it is poorly absorbed via the oral route. Limited data from postmarketing case reports have not suggested a safety concern in infants exposed to breast milk of mothers using zanamivir. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for zanamivir and any potential adverse effects on the breastfed child from zanamivir or the underlying maternal condition.[35421]