Zanamivir

Class: Neuraminidase Inhibitors
VA Class: AM800
Chemical Name: 5-Acetamido-2,6-anhydro-3,4,5-trideoxy-4-guanidino-d-glycero-d-g
CAS Number: 139110-80-8
Brands: Relenza

Medically reviewed by Drugs.com on Oct 4, 2021. Written by ASHP.

Introduction

Antiviral; neuraminidase inhibitor; sialic acid analog.

Uses for Zanamivir

Treatment of Seasonal Influenza A and B Virus Infections

Symptomatic treatment of uncomplicated acute illness caused by susceptible influenza A or B viruses in adults, adolescents, and children ≥7 years of age who have been symptomatic for ≤2 days.

Efficacy for treatment of influenza not established in patients with underlying airways disease (e.g., asthma, COPD). Because of risk of serious bronchospasm, not recommended in those with underlying airways disease. (See Individuals with Asthma or COPD under Cautions.) No evidence that zanamivir treatment reduces risk of transmission of influenza to others.

For treatment of suspected or confirmed acute, uncomplicated seasonal influenza in otherwise healthy outpatients, CDC, IDSA, and others state that any age-appropriate influenza antiviral (oral oseltamivir, inhaled zanamivir, oral baloxavir marboxil, IV peramivir) can be used if not contraindicated. CDC states may consider early empiric antiviral treatment in outpatients with suspected influenza (e.g., influenza-like illness such as fever with either cough or sore throat) based on clinical judgement if such treatment can be initiated within 48 hours of illness onset.

For treatment of suspected or confirmed seasonal influenza in hospitalized patients or outpatients with severe, complicated, or progressive illness (e.g., pneumonia, exacerbation of underlying chronic medical conditions), CDC states oseltamivir is the preferred influenza antiviral because of lack of data regarding use of other influenza antivirals in such patients. CDC states inhaled zanamivir not recommended for treatment of influenza in hospitalized patients.

Consider that influenza and coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have overlapping signs and symptoms and coinfection with influenza A or B viruses and SARS-CoV-2 can occur. Although laboratory testing can help distinguish between influenza virus infection and SARS-CoV-2 infection, CDC recommends initiating empiric influenza treatment in patients with suspected influenza who are hospitalized, have severe, complicated, or progressive illness, or are at high risk for influenza complication without waiting for results of influenza testing, SARS-CoV-2 testing, or multiplex molecular assays that detect influenza A and B viruses and SARS-CoV- 2.

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza. Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and emergence of resistant strains may decrease effectiveness of influenza antivirals. Although circulating influenza A and B viruses during recent years generally have been susceptible to zanamivir, consult most recent information on susceptibility of circulating viruses when selecting an antiviral for treatment of influenza.

CDC issues recommendations concerning use of antivirals for treatment of influenza, and these recommendations are updated as needed during each influenza season. Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at [Web].

Prevention of Seasonal Influenza A and B Virus Infections

Prophylaxis of influenza caused by seasonal influenza A or B viruses in adults, adolescents, and children ≥5 years of age.

Safety and efficacy established for prophylaxis of influenza in household settings and during community outbreaks; manufacturer states efficacy not established for prophylaxis of influenza in nursing home settings.

Because of risk of serious bronchospasm, not recommended in those with underlying airways disease (e.g., asthma, COPD). (See Individuals with Asthma or COPD under Cautions.)

Annual vaccination with seasonal influenza virus vaccine, as recommended by CDC's Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications. Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza in certain individuals.

Base decisions regarding use of antivirals for prophylaxis of seasonal influenza on the risk for influenza-related complications in the exposed individual, vaccination status, type and duration of contact, recommendations from local or public health authorities, and clinical judgment. In general, use antiviral postexposure prophylaxis only if it can be initiated within 48 hours after the most recent exposure.

CDC and others do not recommend routine use of influenza antivirals for postexposure prophylaxis in individuals exposed to influenza; may consider such prophylaxis in certain situations in exposed individuals at high risk for influenza-related complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals). Other possible candidates for antiviral prophylaxis include unvaccinated health care personnel, public health workers, and first responders with unprotected, close-contact exposure to a patient with confirmed, probable, or suspected influenza during the time when the patient was infectious. Also may be considered for controlling influenza outbreaks in nursing and long-term care facilities or other closed or semi-closed settings with large numbers of individuals at high risk for influenza-related complications.

CDC issues recommendations concerning use of antivirals for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season. Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at [Web].

Avian Influenza A Virus Infections

Treatment or prevention of infections caused by susceptible avian influenza A viruses†.

For treatment of uncomplicated avian influenza A infections in outpatients, CDC states oral oseltamivir, inhaled zanamivir, or IV peramivir may be used.

For treatment of severe, complicated, or progressive avian influenza A infections in hospitalized patients or outpatients, including infections caused by avian influenza A (H7N9), avian influenza A (H5N1), or novel avian influenza A H5 viruses, CDC recommends oseltamivir as antiviral of choice. In those with severe avian influenza A infections who cannot tolerate or absorb oseltamivir administered orally or enterically (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding), CDC states use of IV peramivir may be considered. Inhaled zanamivir not recommended because data insufficient regarding use for treatment of severe influenza in hospitalized patients or outpatients.

When antiviral prophylaxis indicated in close contacts of individuals with confirmed or probable infection with avian influenza A viruses that have caused or potentially may cause severe disease or indicated in individuals who have been exposed to birds infected with such avian influenza A viruses, CDC recommends oral oseltamivir or inhaled zanamivir.

Information regarding treatment and prevention of avian influenza A infections is available from CDC at [Web] and WHO at [Web].

Pandemic Influenza

Treatment or prevention of pandemic influenza† caused by susceptible strains of influenza virus.

Influenza viruses can cause pandemics, during which rates of illness and death from influenza-related complications can increase dramatically worldwide.

Most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09. In the US, the pandemic was characterized by a substantial increase in influenza activity that peaked in late October and early November 2009 and returned to seasonal baseline levels by January 2010. During that time, ≥99% of influenza viruses circulating in the US were influenza A (H1N1)pdm09. After the pandemic, influenza A (H1N1)pdm09 became a seasonal influenza virus and continues to circulate with other seasonal viruses.

The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asia and other countries that was first identified in 2003 represents a potential future pandemic threat. The novel avian influenza A (H7N9) virus first identified in China in March 2013 that has been causing sporadic human infections also has pandemic potential.

Information on pandemic influenza, including planning and preparedness resources if an influenza pandemic occurs, is available from CDC at [Web] and WHO at [Web].

Zanamivir Dosage and Administration

Administration

Administer commercially available powder for inhalation only by oral inhalation using the inhaler (Diskhaler) provided by the manufacturer.

Has been administered IV†; a parenteral dosage form not available in the US.

Do not use the powder for oral inhalation to prepare an extemporaneous solution; do not administer using a nebulizer or mechanical ventilator. (See Administration Precautions under Cautions.)

Oral Inhalation

Zanamivir powder for inhalation is commercially available in a disk containing 4 foil blisters of the drug (Rotadisk) and is provided with an inhaler (Diskhaler) that is used to deliver the drug to the respiratory tract.

Do not remove zanamivir powder for inhalation from its foil blister packaging.

Consult the manufacturer's instructions for information on how to load the Rotadisk onto the drug delivery system (Diskhaler) and how to use the Diskhaler to administer the drug.

Patients should be instructed in the safe and effective use of the Diskhaler; instructions should include a demonstration whenever possible.

Patients scheduled to use an inhaled bronchodilator at the same time as zanamivir should use the bronchodilator first.

Dosage

Pediatric Patients

Treatment of Seasonal Influenza A and B Virus Infections

Oral Inhalation

Adolescents and children ≥7 years of age: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days.

Whenever possible, first day of treatment should include 2 doses provided there is at least 2 hours between doses; on subsequent days, doses should be given about 12 hours apart (morning and evening) at approximately the same time each day.

Initiate treatment within 2 days after onset of symptoms. Although efficacy not established, there is some evidence that antiviral treatment initiated up to 4 or 5 days after onset of symptoms may still be beneficial in hospitalized patients and those with severe, complicated, or progressive influenza.

Recommended duration of antiviral treatment is 5 days, but hospitalized patients with severe or prolonged infections or individuals with immunosuppression may require >5 days of treatment.

Prevention of Seasonal Influenza A and B Virus Infections

Household Setting

Oral Inhalation

Adolescents and children ≥5 years of age: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 10 days. CDC recommends a duration of 7 days after last known exposure.

Administer at approximately same time each day. Efficacy in household settings not established if zanamivir prophylaxis initiated >1.5 days after onset of symptoms in index case.

Community Outbreaks

Oral Inhalation

Adolescents: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 28 days. Administer at approximately the same time each day. CDC recommends a duration of 7 days after last known exposure.

Efficacy in community outbreaks not established if zanamivir prophylaxis initiated >5 days after the outbreak is identified in the community. Safety and efficacy of prophylaxis given for >28 days not evaluated.

Outbreaks in Institutional Settings†

Oral Inhalation

Adolescents and children ≥5 years of age: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily. CDC recommends antiviral prophylaxis be given for minimum of 2 weeks and continued for up to 1 week after last known case of influenza is identified.

Avian Influenza A Virus Infections†

Treatment of Uncomplicated Avian Influenza A Virus Infections†

Oral Inhalation

Some experts state that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections should be given for 5 days. (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Not recommended for treatment of severe infections.

Prophylaxis of Avian Influenza A Virus Infections†

Oral Inhalation

Prophylaxis in close contacts of individuals with confirmed or probable infection or in individuals exposed to infected birds: CDC and WHO state that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections can be used. (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Continue antiviral prophylaxis for 5–10 days after last known exposure. If exposure was time-limited and not ongoing, continue for 5 days after last known exposure.

Adults

Treatment of Seasonal Influenza A and B Virus Infections

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days.

Whenever possible, first day of treatment should include 2 doses provided there is at least 2 hours between doses; on subsequent days, doses should be given about 12 hours apart (morning and evening) at approximately the same time each day.

Initiate zanamivir treatment within 2 days after onset of symptoms. Although efficacy not established, there is some evidence that antiviral treatment initiated up to 4 or 5 days after onset of symptoms may still be beneficial in hospitalized patients and those with severe, complicated, or progressive influenza.

Recommended duration of antiviral treatment is 5 days, but hospitalized patients with severe or prolonged infections or individuals with immunosuppression may require >5 days of treatment.

Prevention of Seasonal Influenza A and B Virus Infections

Household Setting

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 10 days. Administer at approximately same time each day. CDC recommends a duration of 7 days after last known exposure.

Efficacy in household settings not established if zanamivir prophylaxis initiated >1.5 days after onset of symptoms in index case.

Community Outbreaks

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 28 days. Administer at approximately same time each day. CDC recommends a duration of 7 days after last known exposure.

Efficacy in community outbreaks not established if zanamivir prophylaxis initiated >5 days after the outbreak is identified in the community. Safety and efficacy of prophylaxis given for >28 days not evaluated.

Outbreaks in Institutional Settings†

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily. CDC recommends antiviral prophylaxis be given for minimum of 2 weeks and continued for up to 1 week after last known case of influenza is identified.

Avian Influenza A Virus Infections†

Treatment of Uncomplicated Avian Influenza A Virus Infections†

Oral Inhalation

Some experts state that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections should be given for 5 days. (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Not recommended for treatment of severe infections.

Prophylaxis of Avian Influenza A Virus Infections†

Oral Inhalation

Prophylaxis in close contacts of individuals with confirmed or probable infection or in individuals exposed to infected birds: CDC and WHO state that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections can be used. (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Continue antiviral prophylaxis for 5–10 days after last known exposure. If exposure was time-limited and not ongoing, continue for 5 days after last known exposure.

Special Populations

Renal Impairment

Dosage adjustment not needed; consider potential for drug accumulation. (See Renal Impairment under Cautions.)

Cautions for Zanamivir

Contraindications

• History of hypersensitivity reaction to zanamivir or any ingredient in the formulation (e.g., milk protein contained in the lactose vehicle).

Warnings/Precautions

Respiratory Effects

Serious bronchospasm, including fatalities, reported when used in patients with or without underlying airways disease. (See Individuals with Asthma or COPD under Cautions.) Many such cases were reported during postmarketing surveillance and causality to the drug difficult to assess.

Some patients without prior respiratory disease also may have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase vulnerability to adverse drug reactions.

Discontinue use if bronchospasm develops or respiratory function declines; immediate treatment and hospitalization may be required.

Individuals with Asthma or COPD

Not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (e.g., asthma, COPD) because of risk of serious bronchospasm.

When tested in patients with mild or moderate asthma (but without acute influenza-like illness), bronchospasm documented in 1/13 patients. When used in patients with acute influenza-like illness superimposed on underlying asthma or COPD, a >20% decline in FEV₁ occurred in more patients receiving the drug than in those receiving placebo.

The benefits and risks should be considered carefully if use of zanamivir is considered in patients with underlying airways disease. If a decision is made to use the drug in such patients, monitor respiratory function carefully and have appropriate supportive care available, including short-acting β-adrenergic bronchodilators.

Sensitivity Reactions

Hypersensitivity Reactions

Allergic-like reactions (e.g., oropharyngeal edema, serious skin rash, anaphylaxis) reported.

Discontinue immediately and initiate appropriate treatment if an allergic reaction occurs or is suspected.

Neuropsychiatric and CNS Effects

Postmarketing reports of delirium and abnormal behavior leading to self-injury reported mainly in children receiving neuraminidase inhibitors, including zanamivir. Role of zanamivir not determined.

Influenza itself can be associated with a variety of neurologic and behavioral symptoms (e.g., seizures, hallucinations, delirium, abnormal behavior) and fatalities can occur. Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.

Closely monitor patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms develop, consider risks versus benefits of continued therapy.

Postmarketing reports of vasovagal-like episodes shortly after oral inhalation of zanamivir.

Concomitant Illness

Safety and efficacy for treatment or prophylaxis of influenza not established in patients with high-risk underlying medical conditions. (See Individuals with Asthma or COPD under Cautions.)

No data available regarding use in patients with severe or unstable medical conditions that may require inpatient care.

Differential Diagnosis

When making treatment decisions in patients with suspected influenza, consider the possibility of primary or concomitant bacterial infection for which zanamivir would be ineffective.

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza. No evidence that zanamivir prevents such complications.

No evidence of efficacy in illness caused by any organisms other than influenza A or B.

Administration Precautions

Administer zanamivir powder for inhalation using only the inhaler (Diskhaler) provided by the manufacturer. Do not remove the powder from its foil blister packaging (Rotadisk).

Must not be made into an extemporaneous solution for administration by nebulization or mechanical ventilation. Do not attempt to reconstitute or solubilize the powder in liquid; do not attempt to administer in a nebulizer or mechanical ventilator.

Safety and efficacy not established for administration by nebulization or mechanical ventilation. Lactose in the formulation may obstruct or interfere with proper functioning of mechanical ventilator equipment. There have been reports of hospitalized patients with influenza who received extemporaneous solutions made with the powder and administered by nebulization or mechanical ventilation; at least 1 death reported when lactose in the formulation apparently obstructed proper functioning of the equipment.

Instruct patients in the safe and effective use of the drug delivery system (Diskhaler) provided by the manufacturer. Instructions on use of the inhaler should include a demonstration whenever possible.

Some geriatric patients may need assistance with the inhaler.

Children should be under adult supervision with close attention to use of the inhaler. (See Pediatric Use under Cautions.)

Prior Use

No data available regarding safety and efficacy of repeated courses of zanamivir for treatment of influenza.

Influenza Vaccination

Not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine recombinant, influenza vaccine live intranasal).

Although antivirals used for treatment or prevention of influenza, including zanamivir, may be used concomitantly with or at any time before or after influenza virus vaccine inactivated or influenza vaccine recombinant, influenza antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal and decrease efficacy of the live vaccine. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Available data from published studies suggest use of zanamivir during pregnancy not associated with increased risk of birth defects or adverse maternal or fetal outcomes; however, these studies had several limitations (e.g., lack of specific analyses for zanamivir, possible exposure and outcome misclassifications, small sample sizes) which preclude a definitive assessment of the risk.

In animal reproduction studies, no adverse maternal or embryofetal effects observed in rats or rabbits treated with IV zanamivir at dosages resulting in systemic exposures approximately 300 times those in humans receiving 10 mg twice daily by oral inhalation.

Pregnant women are at increased risk for severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small size for gestational age.

Oseltamivir is the preferred antiviral for treatment of suspected or confirmed influenza or prevention of influenza in women who are pregnant or up to 2 weeks postpartum.

Lactation

Not known whether zanamivir distributes into human milk, affects milk production, or has any effects on breast-fed infants. Distributed into milk in rats.

Consider benefits of breast-feeding and importance of zanamivir to the woman; also consider potential adverse effects on breast-fed child from the drug or from underlying maternal condition.

Pediatric Use

Safety and efficacy for treatment of influenza not established in children <7 years of age.

Safety and efficacy for prophylaxis of influenza not established in children <5 years of age.

Safety and efficacy in adolescents and children ≥7 years of age for treatment of influenza and safety and efficacy in adolescents and children ≥5 years of age for prophylaxis of influenza similar to adults.

Some young children may have suboptimal inspiratory flow rates through the drug delivery system (Diskhaler). When considering use of zanamivir in pediatric patients, clinicians should carefully evaluate the ability of the child to use the inhaler.

Children should receive zanamivir only under adult supervision and with close attention to proper use of the inhaler. The supervising adult should be instructed on proper use of the inhaler.

Geriatric Use

Safety and efficacy for treatment of influenza in those ≥65 years of age similar to younger adults.

Safety and efficacy for prophylaxis of influenza in those ≥65 years of age in household or community settings similar to younger adults. Efficacy not established for prophylaxis in geriatric individuals in nursing home settings.

Possibility exists of greater sensitivity to the drug in some older individuals.

Some geriatric patients may need assistance with the drug delivery system (Diskhaler).

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.

Renal Impairment

Safety and efficacy not documented in patients with severe renal impairment. Although systemic exposure is limited after oral inhalation, consider potential for drug accumulation.

Common Adverse Effects

Diarrhea, nausea, vomiting, headache, dizziness, nasal signs and symptoms, bronchitis, sinusitis, cough, and ear, nose, and throat infections. Some adverse effects may be related to lactose vehicle (contains milk protein) used in the powder for oral inhalation.

Interactions for Zanamivir

Not metabolized by and does not affect CYP enzymes, including CYP1A1, 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4. Drug interactions with drugs that are substrates or inhibitors of these enzymes unlikely.

Not a substrate of P-glycoprotein (P-gp).

Does not inhibit organic anion transporter (OAT) 1, OAT2, OAT3, OAT4, organic cation transporter (OCT) 1, OCT2, OCT3, or urate transporter (URAT) 1.

Specific Drugs

Zanamivir Pharmacokinetics

Absorption

Bioavailability

Following oral inhalation of zanamivir, approximately 4–17% of the inhaled dose is absorbed systemically.

Absolute bioavailability averages 2% following oral inhalation; peak serum concentrations attained within 1–2 hours.

Special Populations

In pediatric patients <12 years of age with signs and symptoms of respiratory illness, zanamivir serum concentrations may be low or undetectable following oral inhalation because of inadequate or absent inspiratory flow rates. (See Pediatric Use under Cautions.)

In a limited number of individuals with renal impairment who received a single dose of IV zanamivir, systemic exposure was increased in those with creatinine clearances of ≤70 mL/minute.

Distribution

Extent

Delivered to epithelial lining of the respiratory tract following oral inhalation. Amount of drug in respiratory tract depends on patient factors such as inspiratory flow rate. May be present in sputum and nasal washings for at least 12 hours after a dose.

Crosses the placenta in animals.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

<10% bound to plasma proteins.

Elimination

Metabolism

Not metabolized.

Not a substrate for and does not affect CYP isoenzymes.

Elimination Route

Following oral inhalation, absorbed drug is excreted in urine within 24 hours; unabsorbed drug excreted in feces.

Half-life

Serum half-life following oral inhalation is 2.5–5.1 hours.

Special Populations

Pharmacokinetics not studied in patients with impaired hepatic function.

Stability

Storage

Oral Inhalation

Powder for Inhalation

25°C (may be exposed to 15–30°C).

Actions and Spectrum

• Zanamivir is a potent selective competitive inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication; possibly alters virus particle aggregation and release.

• Active in vitro in cell culture against influenza A and B viruses. Majority of seasonal influenza A (H1N1)pdm09, influenza A (H3N2), and influenza B viruses circulating during recent influenza seasons have been susceptible to zanamivir in vitro. May be active against some influenza strains, including some influenza A (H1N1)pdm09 strains, resistant to oseltamivir.

• Active in vitro against some avian influenza A viruses, including influenza A H5N1, H6N1, H7N7, H7N9, and H9N2.

• Major mechanisms of resistance to neuraminidase inhibitors are viral neuraminidase (NA) mutations that affect ability of the drugs to inhibit the enzyme and hemagglutinin (HA) mutations that reduce viral dependence on neuraminidase activity.

• Resistance to zanamivir has been produced in vitro by serial passage of influenza viruses in the presence of increasing concentrations of the drug. In addition, reduced in vitro susceptibility or resistance to zanamivir due to NA or HA mutations have been observed in some clinical isolates of seasonal influenza A and B viruses. Clinical importance of reduced in vitro susceptibility to zanamivir in these strains unknown.

• Avian influenza A (H5N1) and avian influenza A (H7N9) with reduced susceptibility to zanamivir reported. Clinical importance of reduced in vitro susceptibility to zanamivir in these avian influenza viruses unknown; the effects of specific substitutions on susceptibility may be strain-dependent.

• Cross-resistance between zanamivir and other neuraminidase inhibitors (e.g., oseltamivir, peramivir) in influenza A and influenza B viruses reported in cell culture and neuraminidase inhibition assays. However, because oseltamivir, peramivir, and zanamivir bind to different sites on the neuraminidase enzyme or interact differently with the binding sites, cross-resistance among the drugs is variable.

Advice to Patients

• Importance of understanding proper inhalation technique and use of the drug delivery system (Diskhaler); importance of reading patient instructions for use.

• Instruct patients that if they miss a dose of zanamivir, to take it as soon as they remember. If it is ≤2 hours before their next dose, instruct patients to skip the dose and take the next dose at the next scheduled time. Advise patients not to double their next dose or take more than the prescribed dose.

• Advise patients of the possible risk of bronchospasm, especially in those with underlying respiratory disease; importance of patients with asthma or COPD having a short-acting inhaled β-adrenergic bronchodilator readily available.

• Importance of discontinuing zanamivir and promptly contacting clinician if there is an increase in respiratory symptoms (e.g., wheezing, dyspnea, signs or symptoms of bronchospasm) or if symptoms of an allergic reaction occur.

• Advise patients using an inhaled bronchodilator at the same time as zanamivir of the importance of using the bronchodilator first.

• Importance of immediately contacting a clinician if patient demonstrates signs of unusual behavior. Influenza patients, particularly children and adolescents, may be at increased risk of seizures, confusion, or abnormal behavior early in their illness and should be closely observed for signs of unusual behavior. Such events are uncommon, but may occur after starting zanamivir treatment or when influenza is not treated and can result in accidental injury to the patient.

• Advise patients that zanamivir treatment does not reduce the risk of transmission of influenza virus to others.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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