PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Neuraminidase Inhibitor Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Neuraminidase inhibitor given via oral inhalation
    Used for the treatment and prophylaxis of influenza virus A and B infection
    When used for treatment, most effective when started within 48 hours of symptom onset

    COMMON BRAND NAMES

    Relenza

    HOW SUPPLIED

    Relenza Respiratory (Inhalation) Pwd: 5mg

    DOSAGE & INDICATIONS

    For the treatment of uncomplicated acute influenza A virus infection or influenza B virus infection.
    Oral inhalation dosage
    Adults

    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.[35421] [62315] [63866] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

    Children and Adolescents 7 to 17 years

    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.[35421] [62315] [63866] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

    Intravenous dosage†

    NOTE: Intravenous zanamivir is only available through enrollment in an ongoing clinical trial or through a compassionate use program; follow dosage recommendations from the clinical trial or provided by the manufacturer.

    Adults

    600 mg IV every 12 hours for 5 days.[56679] [56680] [56681] May consider treatment beyond 5 days depending on the clinical situation.[56679]

    Children and Adolescents 6 to 17 years

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days.[56679] [56683] [56685] [56686] [56687] May consider treatment beyond 5 days depending on the clinical situation. The European Medicines Agency compassionate use program approved 12 mg/kg/dose (Max: 600 mg/dose) IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Infants and Children 6 months to 5 years

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days.[56679] [56683] [56685] [56686] [56687] May consider treatment beyond 5 days depending on the clinical situation. The European Medicines Agency compassionate use program approved 14 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Infants 3 to 5 months

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days.[56679] [56683] [56685] [56686] [56687] May consider treatment beyond 5 days depending on the clinical situation. The European Medicines Agency compassionate use program approved 12 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Infants 1 to 2 months

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days.[56679] [56683] [56685] [56686] [56687] May consider treatment beyond 5 days depending on the clinical situation. The European Medicines Agency compassionate use program approved 10 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Term Neonates

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days.[56679] [56683] [56685] [56686] [56687] May consider treatment beyond 5 days depending on the clinical situation. The European Medicines Agency compassionate use program approved 8 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    For seasonal influenza prophylaxis for infections due to influenza A or influenza B virus.
    For seasonal influenza prophylaxis for infections due to influenza A or influenza B virus in the household setting.
    Oral inhalation dosage
    Adults

    10 mg by oral inhalation every 24 hours for 10 days.[35421] 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.[62315] [63866]

    Children and Adolescents 5 to 17 years

    10 mg by oral inhalation every 24 hours for 10 days.[35421] 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.[62315] [63866]

    For seasonal influenza prophylaxis for infections due to influenza A or influenza B virus in community outbreaks.
    Oral inhalation dosage
    Adults

    10 mg by oral inhalation every 24 hours for 28 days.[35421] 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.[62315] [63866]

    Children and Adolescents 5 to 17 years

    10 mg by oral inhalation every 24 hours for 28 days.[35421] 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.[62315] [63866]

    For the treatment of novel influenza A viruses associated with severe human disease†, including avian influenza A virus infection†.
    Oral inhalation dosage
    Adults

    10 mg by oral inhalation every 12 hours for 5 days for outpatients with uncomplicated disease.[62315] [62336]

    Children and Adolescents 7 to 17 years

    10 mg by oral inhalation every 12 hours for 5 days for outpatients with uncomplicated disease.

    Intravenous dosage

    NOTE: Intravenous zanamivir is only available through enrollment in an ongoing clinical trial or through a compassionate use program; follow dosage recommendations from the clinical trial or provided by the manufacturer.

    Adults

    600 mg IV every 12 hours for 5 days in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir.[56679] [56680] [56681] [62336] Consider longer courses of treatment (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.[62336]

    Children and Adolescents 6 to 17 years

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir.[56683] [56685] [56686] [56687] [62336] Consider longer courses of treatment (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.[62336] The European Medicines Agency compassionate use program approved 12 mg/kg/dose (Max: 600 mg/dose) IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Infants and Children 6 months to 5 years

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir.[56683] [56685] [56686] [56687] [62336] Consider longer courses of treatment (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.[62336] The European Medicines Agency compassionate use program approved 14 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Infants 3 to 5 months

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir.[56683] [56685] [56686] [56687] [62336] Consider longer courses of treatment (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.[62336] The European Medicines Agency compassionate use program approved 12 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Infants 1 to 2 months

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir.[56683] [56685] [56686] [56687] [62336] Consider longer courses of treatment (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.[62336] The European Medicines Agency compassionate use program approved 10 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    Term Neonates

    Limited data are available. 10 to 20 mg/kg/dose IV every 12 hours for 5 days in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir.[56683] [56685] [56686] [56687] [62336] Consider longer courses of treatment (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.[62336] The European Medicines Agency compassionate use program approved 8 mg/kg/dose IV every 12 hours in this population, which was derived from a modeling approach based on renal function for age and body size. This dose is expected to provide comparable exposure to 600 mg IV every 12 hours in adults.[56679]

    For prophylaxis of novel influenza A viruses associated with severe human disease†, including avian influenza prophylaxis†.
    Oral inhalation dosage
    Adults

    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.[62315] [62337] [62338]

    Children and Adolescents 7 to 17 years

    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.[62315] [62337] [62338]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    10 mg (i.e., 2 oral inhalations of 5 mg) twice daily for 5 days. Safety and efficacy of the IV formulation have not been established; however, doses up to 600 mg IV twice daily have been used in clinical trials and compassionate use programs.

    Geriatric

    10 mg (i.e., 2 oral inhalations of 5 mg) twice daily for 5 days. Safety and efficacy of the IV formulation have not been established; however, doses up to 600 mg IV twice daily have been used in clinical trials and compassionate use programs.

    Adolescents

    10 mg (i.e., 2 oral inhalations of 5 mg) twice daily for 5 days. Safety and efficacy of the IV formulation have not been established; however, doses up to 12 mg/kg/dose (Max: 600 mg/dose) IV twice daily have been used in clinical trials and compassionate use programs.

    Children

    6 to 12 years: 10 mg (i.e., 2 oral inhalations of 5 mg) twice daily for 5 days. Safety and efficacy of the IV formulation have not been established; however, doses up to 12 mg/kg/dose IV every 12 hours (Max: 600 mg/dose) have been used in clinical trials and compassionate use programs.
    5 years: 10 mg (i.e., 2 oral inhalations of 5 mg) once daily for up to 28 days. Safety and efficacy of the IV formulation have not been established; however, doses up to 14 mg/kg/dose IV every 12 hours have been used in clinical trials and compassionate use programs.
    1 to 4 years: Safety and efficacy have not been established; however, doses up to 14 mg/kg/dose IV every 12 hours have been used in clinical trials and compassionate use programs.

    Infants

    6 to 11 months: Safety and efficacy have not been established; however, doses up to 14 mg/kg/dose IV every 12 hours have been used in clinical trials and compassionate use programs.
    3 to 5 months: Safety and efficacy have not been established; however, doses up to 12 mg/kg/dose IV every 12 hours have been used in clinical trials and compassionate use programs.
    1 to 2 months: Safety and efficacy have not been established; however, doses up to 10 mg/kg/dose IV every 12 hours have been used in clinical trials and compassionate use programs.

    Neonates

    Term Neonates: Safety and efficacy have not been established; however, doses up to 8 mg/kg/dose IV twice daily have been used in clinical trials and compassionate use programs.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Zanamivir does not undergo hepatic metabolism. No dosage adjustments appear needed.

    Renal Impairment

    Oral Inhalation
    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.
     
    Intravenous Administration
    Zanamivir is eliminated almost entirely through renal excretion; dosage adjustments are recommended in patients with renal impairment. The compassionate use program approved by the European Medicines Agency utilizes the following dosage adjustment protocol :
     
    Adults and Pediatric Patients weighing 50 kg or more
    CrCl or Cl CRRT 80 mL/minute or more: No dosage adjustment required.
    CrCl or Cl CRRT 50 to 79 mL/minute: 600 mg IV x 1 dose, followed by maintenance dose of 400 mg IV every 12 hours.
    CrCl or Cl CRRT 30 to 49 mL/minute: 600 mg IV x 1 dose, followed by maintenance dose of 250 mg IV every 12 hours.
    CrCl or Cl CRRT 15 to 29 mL/minute: 600 mg IV x 1 dose, followed by maintenance dose of 150 mg IV every 12 hours; maintenance dose should be initiated 24 hours after the initial dose.
    CrCl or Cl CRRT less than 15 mL/minute: 600 mg IV x 1 dose, followed by maintenance dose of 60 mg IV every 12 hours; maintenance dose should be initiated 48 hours after the initial dose.
     
    Children and Adolescents 6 years and older (less than 50 kg)
    CrCl or Cl CRRT 80 mL/minute/1.73 m2 or more: No dosage adjustment required.
    CrCl or Cl CRRT 50 to 79 mL/minute/1.73 m2: 12 mg/kg IV x 1 dose, followed by maintenance dose of 8 mg/kg/dose IV every 12 hours.
    CrCl or Cl CRRT 30 to 49 mL/minute/1.73 m2: 12 mg/kg IV x 1 dose, followed by maintenance dose of 5 mg/kg/dose IV every 12 hours.
    CrCl or Cl CRRT 15 to 29 mL/minute/1.73 m2: 12 mg/kg IV x 1 dose, followed by maintenance dose of 3 mg/kg/dose IV every 12 hours; maintenance dose should be initiated 24 hours after the initial dose.
    CrCl or Cl CRRT less than 15 mL/minute/1.73 m2: 12 mg/kg IV x 1 dose, followed by maintenance dose of 1.2 mg/kg/dose IV every 12 hours; maintenance dose should be initiated 48 hours after the initial dose.
     
    Infants and Children 6 months to younger than 6 years
    CrCl or Cl CRRT 80 mL/minute/1.73 m2 or more: No dosage adjustment required.
    CrCl or Cl CRRT 50 to 79 mL/minute/1.73 m2: 14 mg/kg IV x 1 dose, followed by maintenance dose of 9.3 mg/kg/dose IV every 12 hours.
    CrCl or Cl CRRT 30 to 49 mL/minute/1.73 m2: 14 mg/kg IV x 1 dose, followed by maintenance dose of 5.8 mg/kg/dose IV every 12 hours.
    CrCl or Cl CRRT 15 to 29 mL/minute/1.73 m2: 14 mg/kg IV x 1 dose, followed by maintenance dose of 3.5 mg/kg/dose IV every 12 hours; maintenance dose should be initiated 24 hours after the initial dose.
    CrCl or Cl CRRT less than 15 mL/minute/1.73 m2: 14 mg/kg IV x 1 dose, followed by maintenance dose of 1.4 mg/kg/dose IV every 12 hours; maintenance dose should be initiated 48 hours after the initial dose.
     
    Dosage adjustment recommendations are not available for infants younger than 6 months of age with renal impairment.
     
    Intermittent hemodialysis or peritoneal dialysis
    Due to a low molecular weight, low protein binding, and small volume of distribution, zanamivir is expected to be removed by hemodialysis. The zanamivir dosage, as determined by calculated creatinine clearance, should be administered after the completion of dialysis.

    ADMINISTRATION

    Injectable Administration
    Intravenous Administration

    NOTE: Zanamivir is not FDA-approved for IV administration and is not available in the US for clinical trial or compassionate use.[62315] The following is based on product information from the IV zanamivir product approved for compassionate use by the European Medicines Agency. Consult accompanying information for the specific product being administered to ensure proper preparation, administration, and storage.
     
    Dilution
    May administer undiluted (supplied as 10 mg/mL) or diluted in 0.9% NaCl Injection to a concentration of 0.2 mg/mL or more.
    Each vial is for single use only; discard any remaining solution.
    Refrigerate infusion bag if not used immediately after preparation; warm infusion bag to room temperature prior to use.
    Storage: Diluted solution is stable for up to 24 hours refrigerated at 2 to 8 degrees C.
     
    Intermittent IV Infusion
    Infuse over 30 minutes.
    If the infusion is to be given through a port containing heparin (e.g., heparin lock), flush the catheter with 3 to 5 mL of sterile 0.9% NaCl Injection before and after zanamivir administration.

    Inhalation Administration
    Oral Inhalation Administration

    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.[35421]
    Zanamivir is administered via oral inhalation using the Diskhaler device provided. Do not use the Diskhaler device with other inhaled agents that use this device and do not use zanamivir with another product's Diskhaler.
    Advise patients who also use an inhaled bronchodilator at the same time as zanamivir to use their bronchodilator before using zanamivir.
    Instruct patients in the use of the delivery. Instructions should include a demonstration whenever possible.
    Always check the inside of the mouthpiece to make sure it is free of foreign objects before use. Always replace the cover after each use.
    Do not puncture any zanamivir Rotadisk blister until taking a dose using the Diskhaler.
    Instruct patient to open and prepare mouthpiece of Diskhaler device, load zanamivir Rotadisk medication blister pack, and activate the first dose (see package instructions provided with product). Holding the Diskhaler mouthpiece level to, but away from the mouth, exhale. Then, put the mouthpiece to the lips and breathe in the dose deeply and slowly. Remove mouthpiece from the mouth, hold breath for at least 10 seconds, and then exhale slowly.
    Keep the Diskhaler device dry while it contains the Rotadisk medication blister disk; do not wash. The Diskhaler may be washed once the medication disk is removed.
    To avoid the spread of infection, do not use the inhaler for more than 1 person.[35421]

    STORAGE

    Relenza:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Use intravenous zanamivir with caution in patients with hepatic disease. Hepatic events, some severe, have been reported in patients receiving intravenous zanamivir. However, these reports are confounded by the severity of influenza-related illness and underlying medical conditions and causality with zanamivir cannot be established. Patients with elevated hepatic enzymes should be closely monitored and the potential benefit of continued treatment should be weighed against the potential risks. Intravenous zanamivir is only available as part of an ongoing clinical trial or through participation in a compassionate use program.

    Angioedema, milk protein hypersensitivity, serious rash

    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.

    Viral infection

    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.

    Cardiac disease, geriatric

    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. 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.

    Renal failure, renal impairment

    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. Dose adjustments are recommended for patients with renal impairment receiving intravenous zanamivir as part of the compassionate use protocol.

    Asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary disease

    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.

    Administration via nebulizer

    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.

    Vaccination

    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]

    Children, psychosis

    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.

    Pregnancy

    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]

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    laryngeal edema / Rapid / 0-1.0
    seizures / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known

    Moderate

    dyspnea / Early / Incidence not known
    psychosis / Early / Incidence not known
    delirium / Early / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known

    Mild

    headache / Early / 2.0-24.0
    cough / Delayed / 0-17.0
    infection / Delayed / 2.0-13.0
    fever / Early / 0-9.0
    chills / Rapid / 5.0-9.0
    myalgia / Early / 0-8.0
    malaise / Early / 0-8.0
    fatigue / Early / 0-8.0
    musculoskeletal pain / Early / 6.0-6.0
    anorexia / Delayed / 2.0-4.0
    appetite stimulation / Delayed / 2.0-4.0
    sinusitis / Delayed / 0-3.0
    diarrhea / Early / 2.0-3.0
    nausea / Early / 0-3.0
    dizziness / Early / 0-2.0
    vomiting / Early / 1.0-2.0
    arthralgia / Delayed / 0-2.0
    urticaria / Rapid / 0-1.5
    abdominal pain / Early / 0-1.5
    rash / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    nightmares / Early / Incidence not known
    agitation / Early / Incidence not known
    emotional lability / Early / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Live Attenuated Influenza Vaccine (intranasal): (Major) Do not administer the intranasal live attenuated influenza vaccine (LAIV) 2 weeks before or 48 hours after administration of zanamivir, unless medically indicated. Inactivated influenza vaccines may be used, as appropriate. Because of its antiviral properties, zanamivir may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live influenza virus vaccines are not recommended during treatment with zanamivir. Consult currently recommended guidance on the use of antiviral drugs against influenza.

    PREGNANCY AND LACTATION

    Pregnancy

    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. 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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Oral Route

    Zanamivir is not given orally due to poor bioavailability (1% to 5%).

    Intravenous Route

    After intravenous administration of zanamivir, high peak concentrations are reached but the drug is rapidly eliminated.

    Inhalation Route

    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.