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Mechanism of Action
US Drug Names
NOTE: Relenza inhalation powder is not intended to be reconstituted in any liquid formulation and is not recommended for use in any nebulizer or mechanical ventilator.
General dosing information:
Seasonal influenza virus:
Novel influenza A viruses associated with severe human disease, including avian influenza virus:
10 mg by oral inhalation every 12 hours for 5 days. Administer 2 doses on the first day provided there are at least 2 hours between doses.   May consider extended courses for patients who remain severely ill after 5 days of treatment. 
10 mg by oral inhalation every 24 hours for 10 days. Protection occurs for as long as dosing is continued. High-risk patients may require prophylaxis during the entire influenza season. Guidelines recommend a 7-day course after the last known exposure. 
10 mg by oral inhalation every 24 hours for 28 days. Protection occurs for as long as dosing is continued. High-risk patients may require prophylaxis during the entire influenza season. For those vaccinated during an outbreak, guidelines recommend a 2-week course. For control of outbreaks in long-term care facilities and hospitals, chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case is recommended. 
10 mg by oral inhalation every 12 hours for 5 days for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset. 
10 mg by oral inhalation every 12 hours starting as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure if likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.  
10 mg (i.e., 2 oral inhalations of 5 mg) twice daily.
7 to 12 years: 10 mg (i.e., 2 oral inhalations of 5 mg) twice daily.
5 to 6 years: 10 mg (i.e., 2 oral inhalations of 5 mg) once daily.
1 to 4 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Zanamivir does not undergo hepatic metabolism. No dosage adjustments appear needed.
Due to the low systemic exposure after oral inhalation, no dosage adjustment is necessary in patients with renal impairment. However, consider the possibility for drug accumulation.
Zanamivir is a neuraminidase inhibitor antiviral agent that is administered via oral inhalation and indicated for the treatment of uncomplicated influenza A and B infection in patients 7 years and older and for seasonal influenza prophylaxis in patients 5 years and older. Zanamivir was chemically designed using knowledge of the crystal structure of influenza virus surface proteins. As opposed to amantadine and rimantadine that are only active against influenza A, zanamivir exhibits activity against both influenza A and B.  In clinical trials in otherwise healthy adults and children 7 years and older, zanamivir has been shown to decrease the symptoms of uncomplicated influenza by 1 day in the North American study and 1.5 to 2.5 days in other clinical trials. The modest benefit of zanamivir may be clinically significant since, typically, the illness lasts between 6 and 7.5 days in untreated individuals. Zanamivir treatment should be started as soon as possible after the onset of flu symptoms; ideally, begin zanamivir treatment within 48 hours of symptom onset. According to the Centers for Disease Control and Prevention (CDC), antiviral therapy is most effective when initiated within 48 hours of illness onset; however, specific patient populations (including those with severe, complicated, or progressive illness, pregnant women of any trimester, and hospitalized patients) may still receive benefit from antiviral treatment if initiated after 48 hours of illness onset. The safety and efficacy of zanamivir have not been established in individuals with underlying respiratory disease. Zanamivir has been studied as prophylaxis against influenza infection; however, zanamivir is not considered a substitute for influenza virus vaccination. Instead, antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main option for reducing the impact of influenza. In a study, prophylactic zanamivir administered once daily for 4 weeks to otherwise healthy adults was efficacious in preventing 31% of influenza infections during the 'flu season'. Studies have shown that zanamivir can prevent the spread of influenza among family members, decrease the overall incidence of complications due to influenza and decrease antibiotic use, and decrease the symptom duration in elderly patients vaccinated against influenza as compared to non-vaccinated patients. 
For storage information, see the specific product information within the How Supplied section.
NOTE: 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; a fatality has been reported in a mechanically ventilated patient with influenza who received zanamivir inhalation powder that was solubilized and administered by nebulizer for 3 days. The safety, effectiveness, and stability of zanamivir use via nebulization have not been established. 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.
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.
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.
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.
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.
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%).
Arrhythmia exacerbation and syncope have been noted during postmarketing use with zanamivir.
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.
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.
Muscle pain or myalgia (up to 8%), musculoskeletal pain (6%), and arthralgia or articular rheumatism (up to 2%) were reported during zanamivir clinical trials.
Malaise (up to 8%), fatigue (up to 8%), fever (up to 9%), and chills (5% to 9%) have been reported during zanamivir trials.
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.
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.
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.
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.
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.
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.
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. 
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.
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. 
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. 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.
Zanamivir is a neuraminidase (sialidase) inhibitor. Zanamivir selectively inhibits the neuraminidases of influenza A and B, and does not significantly inhibit human lysosomal neuraminidase. Zanamivir does not bind to non-influenza neuraminidase. Influenza virus neuraminidase is a surface glycoprotein that catalyzes the cleavage of the linkage between a terminal sialic acid and adjacent sugar residue. This action promotes the spread of virus in the respiratory tract by several mechanisms. Viral neuraminidase promotes the release of virions from infected cells; promotes the penetration of virus into respiratory epithelial cells; prevents the formation of viral aggregates; prevents viral inactivation by respiratory mucus; induces cellular apoptosis by activating transforming growth factor beta; and induces cytokines including interleukin-1 and tumor necrosis factor. Zanamivir acts extracellularly and binds to an unoccupied area of influenza neuraminidase that results in competitive inhibition of the enzyme. Topical application via inhalation of the powder into the lungs provides a high drug concentration at the site of infection and may potentiate its antiviral effects and reduce the risk of resistance.
Cell culture assays have identified the median EC50 (50% effective inhibitory concentration) of zanamivir against influenza A/H1N1, influenza A/H3N2, and influenza B viruses to be 210 nM (70 ng/mL; range, 1 to 16,000 nM), 14 nM (4.7 ng/mL; range, 1 to 1,700 nM), and 18 nM (6 ng/mL; range, 3 to 1,300 nM), respectively. A relationship between antiviral activity in cell culture and inhibition of influenza virus replication in humans has not been established. Zanamivir also reduces viral yields in human respiratory cells with EC90 values at 48 hours of less than 0.01 mg/L for influenza A strains and less than 0.25 mg/L for influenza B. Inhibition was comparable to ribavirin and superior to rimantadine. The combination of zanamivir with rimantadine, ribavirin, or deoxyfluoroguanosine has had additive effects in vivo. Resistance to neuraminidase inhibitors has been observed more often with oseltamivir compared with zanamivir. Due to differences in the way in which oseltamivir and zanamivir bind to the viral neuraminidase, most oseltamivir-resistant viruses will be susceptible to zanamivir. While zanamivir-resistant influenza strains have been developed in vitro, only 1 case of zanamivir resistance has been reported clinically. During prolonged treatment with zanamivir, a mutant strain of influenza B was isolated from an immunocompromised child.
Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.
Zanamivir is administered via oral inhalation. In clinical trials, it has been given intravenously and intranasally. Zanamivir has limited protein binding (less than 10%). It is renally excreted as unchanged drug with a half-life of 2.5 to 5.1 hours. Any unabsorbed drug is excreted in the feces. 
Affected cytochrome P450 isoenzymes and drug transporters: none
No pharmacokinetic drug interactions between zanamivir and other agents are predicted based on in vitro pharmacokinetic studies. Zanamivir is not a substrate for and does not affect any cytochrome P450 isoenzymes.
Zanamivir is not given orally due to poor bioavailability (1% to 5%).
After intravenous administration of zanamivir, high peak concentrations are reached but the drug is rapidly eliminated.
Peak serum concentrations range from 17 to 142 ng/mL within 1 to 2 hours after inhalation of a 10 mg dose. Systemic bioavailability after inhalation ranges from 10% to 20%. Zanamivir administered via a Diskhaler resulted in deposition of 13.2% of the dose in the lungs and 77.6% of the dose in the oropharynx in adults. The total inhaled dose is excreted within 24 hours.
The pharmacokinetics of zanamivir have not been studied in patients with hepatic dysfunction.
Zanamivir clearance appears to be reduced in renal impairment. After single intravenous doses of 2 or 4 mg in patients with mild/moderate renal impairment or severe renal impairment, respectively, significant decreases in Zanamivir renal clearance and increases in half-life and systemic exposure were noted. The elimination half-life increased to 4.7 hours in patients with moderate renal impairment and 18.5 hours in patients with severe renal impairment. Pharmacokinetic data for zanamivir are unavailable in pediatric patients with renal impairment. 
Pharmacokinetic data for zanamivir are limited in children; undetectable or low serum concentrations (8.32 to 10.38 ng/mL) were observed in 5 of 16 patients age 6 to 12 years after a single inhaled dose of 10 mg. The median Cmax in the remaining 11 patients was 43 ng/mL (range: 15 to 74 ng/mL). Undetectable or low concentrations were attributed to lack of measurable peak inspiratory flow rate. Children younger than 7 years of age do not produce proper peak inspiratory flow rates needed for use of the Diskhaler device, which limits the systemic absorption and clinical efficacy of zanamivir. Older children with poor inhalational technique experience similar problems with systemic absorption.
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