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

Introduction

Antiviral; neuraminidase inhibitor; sialic acid analog.^{1 144}

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.^{1 3 4 5 6 14 105 112 116 144}

Efficacy for treatment of influenza not established in patients with underlying airways disease (e.g., asthma, COPD).¹ Because of risk of serious bronchospasm, not recommended in those with underlying airways disease.¹ (See Individuals with Asthma or COPD under Cautions.) No evidence that treatment with the drug reduces risk of transmission of influenza to others.¹

CDC, US Public Health Service Advisory Committee on Immunization Practices (ACIP), AAP, and others recommend antiviral treatment initiated as soon as possible in all individuals with suspected or confirmed influenza who require hospitalization or have severe, complicated, or progressive illness (regardless of vaccination status or underlying illness).^{105 112 116 137 144} Early empiric antiviral treatment also recommended in individuals with suspected or confirmed influenza of any severity if they are at high risk of developing influenza-related complications because of age or underlying medical conditions.^{112 116 137 144} This includes children <2 years of age, adults ≥65 years of age, individuals of any age with certain chronic medical or immunosuppressive conditions, women who are pregnant or up to 2 weeks postpartum, individuals <19 years of age who are receiving long-term aspirin therapy, American Indians or Alaskan natives, morbidly obese individuals with body mass index (BMI) ≥40, and residents of any age in nursing homes or other long-term care facilities.^{112 116 137}

CDC, ACIP, and AAP also state empiric antiviral treatment can be considered in previously healthy, symptomatic individuals with suspected or confirmed influenza who are not known to be at increased risk of developing severe or complicated illness if such treatment can be initiated within 48 hours of illness onset.^{105 112 137 144} Although these individuals typically do not require treatment, early empiric antiviral treatment might provide some benefit (e.g., shortened duration of illness).¹⁴⁴

If indicated, initiate treatment with an appropriate antiviral as early as possible since benefit is greatest if started within 48 hours of symptom onset.^{105 112 137 144} Because there is some evidence that antiviral treatment initiated up to 96 hours after illness onset might still be beneficial in reducing morbidity and mortality in hospitalized patients and in those with severe, complicated, or progressive illness, some experts state that antiviral treatment can be initiated >48 hours after illness onset in such patients.^{137 144} Do not delay initiation of treatment while waiting for laboratory confirmation.^{112 137 144}

When treatment of seasonal influenza indicated, oseltamivir or zanamivir usually recommended.^{112 137 144} Oseltamivir usually preferred for hospitalized patients and patients with severe or complicated influenza since data are lacking regarding use of inhaled zanamivir in such patients.¹⁶¹

CDC states that use of investigational IV zanamivir† may be considered for hospitalized patients with severe influenza if they cannot tolerate or absorb oral oseltamivir (e.g., because of suspected or known gastric stasis, malabsorption, GI bleeding) or have infections caused by oseltamivir-resistant strains.¹⁶¹ Although safety and efficacy of IV zanamivir not established, an investigational aqueous solution for IV administration may be available either by enrollment in an ongoing clinical trial or under an emergency investigational new drug (EIND) protocol.¹⁶¹ (See Administration under Dosage and Administration.)

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.^{112 137 144} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;¹⁴⁴ emergence of zanamivir-resistant influenza virus may decrease effectiveness of the drug.¹ Although influenza A and B viruses circulating in US during last few years generally have been susceptible to zanamivir, consult most recent information.^{137 144}

CDC issues recommendations concerning use of antivirals for treatment of influenza, and these recommendations are updated as needed during each influenza season.^{137 144} Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .

Prevention of Seasonal Influenza A and B Virus Infections

Prophylaxis of influenza caused by influenza A or B viruses in adults, adolescents, and children ≥5 years of age.^{1 2 17 18 105 112 116 137 144}

Safety and efficacy established for prophylaxis of influenza in household settings and during community outbreaks;^{1 2 17 18} manufacturer states efficacy not established for prophylaxis of influenza in nursing home settings.¹

Because of risk of serious bronchospasm, not recommended in those with underlying airways disease (e.g., asthma, COPD).¹ (See Individuals with Asthma or COPD under Cautions.)

Annual vaccination with seasonal influenza virus vaccine, as recommended by ACIP, is the primary means of preventing seasonal influenza and its severe complications.^{100 105 112 116 144 488} Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza.^{1 105 112 116 137 144 488}

Indiscriminate use of antivirals for prophylaxis may promote resistance or reduce availability of antivirals for treatment.^{137 144} Base decisions regarding use of antivirals for prophylaxis of influenza on exposed person's risk for influenza complications, vaccination status, type and duration of contact, recommendations from local or public health authorities, and clinical judgment.¹⁴⁴ Generally use postexposure prophylaxis only if it can be initiated within 48 hours of most recent exposure.^{137 144}

When seasonal influenza viruses are circulating in the community, postexposure prophylaxis with oseltamivir or zanamivir can be considered for certain individuals, including those at high risk of developing influenza complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals).^{112 116 137 144} 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.^{112 137 144} Also consider antiviral prophylaxis 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 complications.^{112 116 137 144} In individuals at high risk of influenza complications who receive parenteral inactivated influenza vaccine, prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.^{112 116} (See Influenza Virus Vaccines under Interactions.)

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for prophylaxis of influenza.^{112 137} The most appropriate antiviral for prevention of influenza is based on the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.^{137 144} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;^{137 144} emergence of zanamivir-resistant influenza virus may decrease effectiveness of the drug.¹

CDC issues recommendations concerning use of antivirals for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.^{137 144} Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .

Avian Influenza A Virus Infections

Treatment or prevention of infections caused by susceptible avian influenza A viruses†.^{50 94 104}

CDC and WHO state that oseltamivir is drug of choice for treatment or prophylaxis of infections caused by highly pathogenic avian influenza A (H5N1);^{50 68 94 104} zanamivir is an alternative.^{50 94}

Oseltamivir also is drug of choice for treatment of infections caused by avian influenza A (H7N9), especially in hospitalized patients and patients with severe or complicated illness.⁵⁰ Because of limited data, zanamivir not recommended for treatment of severe avian influenza A (H7N9) infections, but may be considered in uncomplicated infections.⁵⁰ Either oseltamivir or zanamivir can be used for prophylaxis in close contacts of patients with confirmed or probable avian influenza A (H7N9) infection.⁵⁰

Consider use of investigational IV zanamivir† for hospitalized patients with severe influenza A (H7N9) infection who cannot tolerate or absorb oral oseltamivir (e.g., because of suspected or known gastric stasis, malabsorption, GI bleeding) or have infections caused by oseltamivir-resistant strains.⁵⁰ (See Administration under Dosage and Administration.)

Pandemic Influenza

Treatment or prevention of pandemic influenza† caused by susceptible strains of influenza virus.^{52 151}

Influenza viruses can cause pandemics, during which rates of illness and death from influenza-related complications can increase dramatically worldwide.^{52 104 488}

Most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09.^{52 100 134 144 151 488} 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.^{123 488} During that time, >99% of influenza viruses circulating in the US were influenza A (H1N1)pdm09.^{123 488} In August 2010, the WHO declared that the world was in a post-pandemic period;¹⁴⁸ since that time, influenza A (H1N1)pdm09 has become a seasonal influenza virus and continues to circulate with other seasonal viruses.^{144 551 553}

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.^{28 50 54 55 56 104 147}

Zanamivir Dosage and Administration

Administration

Administer commercially available powder for inhalation only by oral inhalation using the inhaler (Diskhaler) provided by the manufacturer.¹

Zanamivir has been administered IV†;^{158 159 160 161} a parenteral dosage form not commercially available in the US.¹⁶¹ An investigational aqueous solution for IV administration may be available for use in hospitalized patients with severe or complicated influenza (see Treatment of Seasonal Influenza A and B Virus Infections under Uses).¹⁶¹ Contact manufacturer's clinical support help desk by email (gskclinicalsupportHD@gsk.com) or phone (877-626-8019 or 866-341-9160) to determine patient's eligibility for enrollment in an ongoing clinical trial of IV zanamivir or to request use of IV zanamivir under an EIND protocol.¹⁶¹

Do not use the powder for oral inhalation to prepare an extemporaneous solution;^{1 141} do not administer using a nebulizer or mechanical ventilator.^{1 141} (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.¹

Do not remove zanamivir powder for inhalation from its foil blister packaging.¹⁴¹

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.¹

Patients should be instructed in the safe and effective use of the Diskhaler;¹ instructions should include a demonstration whenever possible.¹

Patients scheduled to use an inhaled bronchodilator at the same time as zanamivir should use the bronchodilator first.¹

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.¹

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.¹

Initiate treatment within 2 days after onset of symptoms.¹ Although efficacy not established,¹ there is some evidence that antiviral treatment initiated up to 96 hours after onset of symptoms may still be beneficial in hospitalized patients and those with severe, complicated, or progressive influenza.^{112 116 137 144} Although usual duration of antiviral treatment is 5 days, patients hospitalized with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) or immunosuppressed individuals may require >5 days of treatment.^{137 144}

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.¹

Administer at approximately same time each day.¹ Efficacy in household settings not established if zanamivir prophylaxis initiated >1.5 days after onset of symptoms in index case.¹

Community Outbreak

Oral Inhalation

Adolescents: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 28 days.¹ Administer at approximately the same time each day.¹

Efficacy in community outbreaks not established if zanamivir prophylaxis initiated >5 days after the outbreak is identified in the community.¹ Safety and efficacy of prophylaxis given for >28 days not evaluated.¹

Avian Influenza A Virus Infections†

Treatment of Uncomplicated Avian Influenza A Virus Infections†

Oral Inhalation

Some experts recommend the twice-daily regimen usually recommended for treatment of seasonal influenza A and B virus infections.⁹⁴ (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Not recommended for treatment of severe infections.⁵⁰ (See Avian Influenza A Virus Infections under Uses.)

Prophylaxis of Avian Influenza A Virus Infections†

Oral Inhalation

Prophylaxis of highly pathogenic avian influenza virus A (H5N1) infection in close contacts†: CDC and WHO state that the once-daily dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections can be used.^{50 94} (See Prevention of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Continue prophylaxis for 7–10 days after last known exposure.^{50 94}

Prophylaxis of avian influenza virus A (H7N9) infection in close contacts†: CDC recommends that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections be given for 5–10 days.⁵⁰ (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

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.¹

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.¹

Initiate zanamivir treatment within 2 days after onset of symptoms.¹ Although efficacy not established,¹ there is some evidence that antiviral treatment initiated up to 96 hours after onset of symptoms may still be beneficial in hospitalized patients and those with severe, complicated, or progressive influenza.^{112 116 137 144} Although usual duration of antiviral treatment is 5 days, patients hospitalized with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) or immunosuppressed individuals may require >5 days of treatment.^{137 144}

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.¹ Administer at approximately same time each day.¹

Efficacy in household settings not established if zanamivir prophylaxis initiated >1.5 days after onset of symptoms in index case.¹

Community Outbreak

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 28 days.¹ Administer at approximately same time each day.¹

Efficacy in community outbreaks not established if zanamivir prophylaxis initiated >5 days after the outbreak is identified in the community.¹ Safety and efficacy of prophylaxis given for >28 days not evaluated.¹

Outbreaks in Long-term Care Facilities or Hospitals

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily.¹³⁷ CDC recommends antiviral prophylaxis be continued for minimum of 2 weeks and up to 7 days after last known case of influenza is identified.¹³⁷

Avian Influenza A Virus Infections†

Treatment of Uncomplicated Avian Influenza A Virus Infections†

Oral Inhalation

Some experts recommend the twice-daily regimen usually recommended for treatment of seasonal influenza A and B virus infections.⁹⁴ (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Not recommended for treatment of severe infections.⁵⁰ (See Avian Influenza A Virus Infections under Uses.)

Prophylaxis of Avian Influenza A Virus Infections†

Oral Inhalation

Prophylaxis of highly pathogenic avian influenza virus A (H5N1) infection in close contacts†: CDC and WHO state that the once-daily dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections can be used.^{50 94} (See Prevention of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Continue prophylaxis for 7–10 days after last known exposure.^{50 94}

Prophylaxis of avian influenza virus A (H7N9) infection in close contacts†: CDC recommends that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections be given for 5–10 days.⁵⁰ (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Special Populations

Renal Impairment

Dosage adjustment not needed;¹ consider potential for drug accumulation.¹ (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).¹

Warnings/Precautions

Respiratory Effects

Serious bronchospasm, including fatalities, reported when used in patients with or without underlying airways disease.¹ (See Individuals with Asthma or COPD under Cautions.) Many such cases were reported during postmarketing surveillance and causality to the drug difficult to assess.¹

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.¹

Discontinue use if bronchospasm develops or respiratory function declines;¹ immediate treatment and hospitalization may be required.¹

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.¹

When tested in patients with mild or moderate asthma (but without acute influenza-like illness), bronchospasm documented in 1/13 patients.¹ 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.¹

The benefits and risks should be considered carefully if use of zanamivir is considered in patients with underlying airways disease.¹ 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.¹

Sensitivity Reactions

Hypersensitivity Reactions

Allergic-like reactions (e.g., oropharyngeal edema, serious skin rash, anaphylaxis) reported.¹

Discontinue immediately and initiate appropriate treatment if an allergic reaction occurs or is suspected.¹

Neuropsychiatric and CNS Effects

Postmarketing reports of delirium and abnormal behavior leading to self-injury reported mainly in Japanese children receiving neuraminidase inhibitors, including zanamivir.¹ Role of zanamivir not determined.¹

Influenza itself can be associated with a variety of neurologic and behavioral symptoms (e.g., seizures, hallucinations, delirium, abnormal behavior) and fatalities can occur.¹ Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.¹

Closely monitor patients with influenza for signs of abnormal behavior.¹ If neuropsychiatric symptoms develop, consider risks versus benefits of continued therapy.¹

Postmarketing reports of vasovagal-like episodes shortly after oral inhalation of zanamivir.¹

Concomitant Illness

Safety and efficacy for treatment or prophylaxis of influenza not established in patients with high-risk underlying medical conditions.¹ (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.¹

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.¹

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.¹ No evidence that zanamivir prevents such complications.¹

No evidence of efficacy in illness caused by any organisms other than influenza A or B.¹

Administration Precautions

Administer zanamivir powder for inhalation using only the inhaler (Diskhaler) provided by the manufacturer.^{1 141} Do not remove the powder from its foil blister packaging (Rotadisk).¹⁴¹

Mustnot be made into an extemporaneous solution for administration by nebulization or mechanical ventilation.¹ Do not attempt to reconstitute or solubilize the powder in liquid;¹⁴¹ do not attempt to administer in a nebulizer or mechanical ventilator.¹⁴¹

Safety and efficacy not established for administration by nebulization or mechanical ventilation.¹⁴¹ Lactose in the formulation may obstruct or interfere with proper functioning of mechanical ventilator equipment.^{140 141} 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.^{1 140 141}

Instruct patients in the safe and effective use of the drug delivery system (Diskhaler) provided by the manufacturer.¹ Instructions on use of the inhaler should include a demonstration whenever possible.¹

Some geriatric patients may need assistance with the inhaler.¹

Children should be under adult supervision with close attention to use of the inhaler.¹ (See Pediatric Use under Cautions.)

Prior Use

No data available regarding safety and efficacy of repeated courses of zanamivir for treatment of influenza.¹

Influenza Vaccination

Not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine recombinant, influenza vaccine live intranasal).^{1 144}

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,^{1 100} these antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal.^{1 100} (See Specific Drugs.)

Specific Populations

Pregnancy

Category C.¹

Pregnant women are at increased risk for severe complications and death from influenza.^{142 144}

CDC and ACIP state that pregnancy is not a contraindication to use of zanamivir for treatment or prevention of influenza; zanamivir regimens recommended in pregnant women are the same as those for other adults.^{142 144}

CDC and ACIP state that oseltamivir may be preferred when a neuraminidase inhibitor indicated for treatment of influenza in women who are pregnant or up to 2 weeks postpartum,^{142 144} but the drug of choice for prophylaxis of influenza is less clear.¹⁴² Zanamivir may be preferred by some clinicians for prophylaxis in pregnant women because of its limited systemic absorption; however, consider respiratory complications that may be associated with zanamivir because of its route of administration, especially in women at risk for respiratory problems.^{142 144}

Lactation

Use with caution.¹

Distributed into milk in rats; not known whether distributed into human milk.¹

Pediatric Use

Safety and efficacy for treatment of influenza not established in children <7 years of age.^{1 14}

Safety and efficacy for prophylaxis of influenza not established in children <5 years of age.¹

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.¹

Some young children may have suboptimal inspiratory flow rates through the drug delivery system (Diskhaler).¹ When considering use of zanamivir in pediatric patients, clinicians should carefully evaluate the ability of the child to use the inhaler.¹

Children should receive zanamivir only under adult supervision and with close attention to proper use of the inhaler.¹ The supervising adult should be instructed on proper use of the inhaler.¹

Geriatric Use

Safety and efficacy for treatment of influenza in those ≥65 years of age similar to younger adults.¹

Safety and efficacy for prophylaxis of influenza in those ≥65 years of age in household or community settings similar to younger adults.¹ Efficacy not established for prophylaxis in geriatric individuals in nursing home settings.¹

Possibility exists of greater sensitivity to the drug in some older individuals.¹

Some geriatric patients may need assistance with the drug delivery system (Diskhaler).¹

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.¹

Renal Impairment

Safety and efficacy not documented in patients with severe renal impairment.¹ Although systemic exposure is limited after oral inhalation, consider potential for drug accumulation.¹

Common Adverse Effects

Diarrhea, nausea, vomiting, headache, dizziness, nasal signs and symptoms, bronchitis, sinusitis, cough, and ear, nose, and throat infections.¹ Some adverse effects may be related to lactose vehicle (contains milk protein) used in the powder for oral inhalation.¹

Interactions for Zanamivir

Zanamivir not metabolized by and does not affect CYP enzymes, including CYP1A1, 1A2, 2A6, 2C9, 2C18, 2D6, 2E1, or 3A4.¹ Drug interactions with drugs that are substrates or inhibitors of these enzymes unlikely.¹

Specific Drugs

Zanamivir Pharmacokinetics

Absorption

Bioavailability

Following oral inhalation of zanamivir, approximately 4–17% of the inhaled dose is absorbed systemically.¹

Absolute bioavailability averages 2% following oral inhalation;³ peak serum concentrations attained within 1–2 hours.^{1 3}

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.¹ (See Pediatric Use under Cautions.)

Distribution

Extent

Delivered to epithelial lining of the respiratory tract following oral inhalation.²² Amount of drug in respiratory tract depends on patient factors such as inspiratory flow rate.¹ May be present in sputum and nasal washings for at least 12 hours after a dose.²²

Crosses the placenta in animals.¹

Distributed into milk in animals;¹ not known whether distributed into human milk.¹

Plasma Protein Binding

<10% bound to plasma proteins.¹

Elimination

Metabolism

Not metabolized.¹

Not a substrate for and does not affect CYP isoenzymes.¹

Elimination Route

Following oral inhalation, absorbed drug is excreted unchanged in urine within 24 hours;¹ unabsorbed drug excreted in feces.¹

Half-life

Serum half-life following oral inhalation is 2.5–5.1 hours.^{1 23}

Special Populations

Half-life prolonged in those with renal impairment;¹ studies using IV zanamivir indicate half-life is 4.7 hours if mild to moderate impairment and 18.5 hours if severe impairment.¹

Stability

Storage

Oral Inhalation

Powder for Inhalation

25°C (may be exposed to 15–30°C).¹

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.^{1 2 3 4 5 6}

• Active against influenza A and B viruses, including amantadine- and rimantadine-resistant isolates.^{1 2 3 4 5 6} Almost all seasonal influenza A (H3N2), influenza A (H1N1)pdm09, and influenza B viruses circulating during recent influenza seasons have been susceptible to zanamivir.^{551 552}

• Active in vitro against some avian influenza A viruses, including influenza A H5N1, H6N1, H7N7, H7N9, and H9N2.^{24 30 31 50 555}

• Active against some influenza strains, including some influenza A (H1N1)pdm09 strains, resistant to oseltamivir.^{52 113 124 144 153 162 551 552}

• Influenza viruses with reduced susceptibility to zanamivir have been produced in vitro.^{1 7 10} Risk of emergence of resistant isolates with clinical use not quantified;¹ seasonal influenza A (H1N1) and seasonal influenza A (H3N2) resistant to zanamivir reported rarely.^{153 551}

• Influenza strains cross-resistant to zanamivir and oseltamivir have been generated in cell culture;^{1 21} only limited data available regarding possible emergence of clinical isolates with cross-resistance to both drugs.^{1 21} To date, influenza A (H1N1)pdm09 isolates with the H275Y mutation¹⁴⁴ and avian influenza A (H5N1) with the H274Y mutation⁹⁴ that are resistant to oseltamivir have been susceptible to zanamivir in vitro.^{94 144}

Advice to Patients

• Importance of understanding proper inhalation technique and use of the drug delivery system (Diskhaler);¹ importance of reading patient instructions for use.¹

• Importance of initiating zanamivir treatment as soon as possible after appearance of influenza symptoms (within 2 days after symptom onset);^{1 11} efficacy not established if treatment begins after 48 hours of symptoms.¹

• Advise patients that zanamivir treatment does not reduce the risk of transmission of influenza virus to others.¹

• 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.¹

• Advise patients using an inhaled bronchodilator at the same time as zanamivir of the importance of using the bronchodilator first.¹

• 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.¹

• Importance of immediately contacting a clinician if patient demonstrates signs of unusual behavior.¹ 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.¹ 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.¹

• 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.¹

• Importance of advising patients of other important precautionary information.¹ (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.