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Zanamivir

Indications/Dosage

Labeled

  • influenza A virus infection
  • influenza B virus infection
  • seasonal influenza prophylaxis

Off-Label

  • avian influenza A virus infection
  • avian influenza prophylaxis
† Off-label indication

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†

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 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.[62315] [62336]

Intravenous dosage

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]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • 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.

Patients with Hepatic Impairment Dosing

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

Patients with Renal Impairment Dosing

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.[35421]

 

Intravenous Administration

Zanamivir is eliminated almost entirely through renal excretion; dosage adjustments are recommended in patients with renal impairment.[56679][56688][56689] The compassionate use program approved by the European Medicines Agency utilizes the following dosage adjustment protocol [56679]:

 

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.[56679]

 

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.[35421][56679]

† Off-label indication
Revision Date: 11/10/2020, 03:57:16 PM

References

35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.36918 - Food and Drug Administration MedWatch. Relenza (zanamivir) inhalation powder. Retrieved Oct. 12, 2009. Available on the World Wide Web http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186081.htm.56679 - Zanamivir solution for injection. European Medicines Agency product information for compassionate use. United Kingdom: GlaxoSmithKline; June 201156680 - Wijaya L, Chua YY, Cui L, et al. Intravenous zanamivir in critically ill patients due to pandemic 2009 (H1N1) influenza A virus. Singapore Med J 2011;52:481-485.56681 - Calfee DP, Peng AW, Cass LM, et al. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999;43:1616-1620.56683 - Ghosh S, Adams O, Schuster FR, et al. Efficient control of pandemic 2009 H1N1 virus infection with intravenous zanamivir despite the lack of immune function. Transpl Infect Dis 2012;14:657-659.56685 - Dohna-Schwake C, Schweiger B, Felderhoff-Muser U, et al. Severe H1N1 infection in a pediatric liver transplant recipient treated with intravenous zanamivir: Efficiency and complications. Transplantation 2010;90:223-224.56686 - Dulek DE, Williams JV, Creech CB, et al. Use of intravenous zanamivir after development of oseltamivir resistance in a critically ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin Infect Dis 2010;50:1493-1496.56687 - Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med 2010;362:88-89.56688 - Weller S, Jones LS, Lou Y, et al. Pharmacokinetics of zanamivir following intravenous administration to subjects with and without renal impairment. Antimicrob Agents Chemother 2013;57:2967-2971.56689 - Cass LM, Efthymiopoulos C, Marsh J, et al. Effect of renal impairment on the pharmacokinetics of intravenous zanamivir. Clin Pharmacokinet 1999;1:13-19.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62336 - Centers for Disease Control and Prevention (CDC). Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/novel-av-treatment-guidance.htm62337 - Centers for Disease Control and Prevention (CDC). Interim guidance on influenza antiviral chemoprophylaxis of persons exposed to birds with avian influenza A viruses associated with severe human disease or with the potential to cause severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm62338 - Centers for Disease Control and Prevention (CDC). Interim guidance on follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease and on the use of antiviral medications for chemoprophylaxis. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/novel-av-chemoprophylaxis-guidance.htm63866 - Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Management of Seasonal Influenza. Clin Infect Dis 2018 Dec 19 [Epub ahead of print].

How Supplied

Zanamivir Inhalation powder

Relenza 5mg Powder for Inhalation (00173-0681) (GlaxoSmithKline Group of Companies) null

Description/Classification

Description

Zanamivir is a neuraminidase inhibitor antiviral agent that is most commonly administered via oral inhalation and indicated for the treatment of uncomplicated influenza A and B infection in patients 7 years and older and for seasonal influenza prophylaxis in patients 5 years and older.[35421] Intravenous zanamivir is under investigation in clinical trials and has been used for compassionate use in hospitalized patients with severe influenza. Zanamivir was chemically designed using knowledge of the crystal structure of influenza virus surface proteins. As opposed to amantadine and rimantadine that are only active against influenza A, zanamivir exhibits activity against both influenza A and B.[56756] [56679] [62315] In clinical trials in otherwise healthy adults and children 7 years and older, zanamivir has been shown to decrease the symptoms of uncomplicated influenza by 1 day in the North American study and 1.5 to 2.5 days in other clinical trials. The modest benefit of zanamivir may be clinically significant since, typically, the illness lasts between 6 to 7.5 days in untreated individuals. Zanamivir treatment should be started as soon as possible after the onset of flu symptoms; ideally, begin zanamivir treatment within 48 hours of symptom onset. According to the Centers for Disease Control and Prevention (CDC), antiviral therapy is most effective when initiated within 48 hours of illness onset; however, specific patient populations (including those with severe, complicated, or progressive illness, pregnant women of any trimester, and hospitalized patients) may still receive benefit from antiviral treatment if initiated after 48 hours of illness onset. The safety and efficacy of zanamivir have not been established in individuals with underlying respiratory disease. Zanamivir has been studied as prophylaxis against influenza infection; however, zanamivir is not considered a substitute for influenza virus vaccination. Instead, antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main option for reducing the impact of influenza.[62315] In a study, prophylactic zanamivir administered once daily for 4 weeks to otherwise healthy adults was efficacious in preventing 31% of influenza infections during the 'flu season'.[25973] Studies have shown that zanamivir can prevent the spread of influenza among family members, decrease the overall incidence of complications due to influenza and decrease antibiotic use, and decrease the symptom duration in elderly patients vaccinated against influenza as compared to non-vaccinated patients.[25974] [25975]

Classifications

  • General Anti-infectives Systemic
    • Antivirals For Systemic Use
      • Neuraminidase Inhibitor Antivirals
Revision Date: 04/05/2019, 11:15:56 AM

References

25973 - Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999;282:31-35.25974 - Hayden FG, et al. Inhaled zanamivir for the prevention of influenza in families. N Engl J Med 2000; 343:1282-1289.25975 - Gravenstein S, Freund BM, McElhaney JE, et al. Greater effectiveness from zanamivir treatment of influenza with antecedent influenza vaccine in older adults (abstract 1902). 39th Annual Interscience Conference on Animicrobial Agents and Chemotherapy; September 26-29, 1999. San Francisco, CA.35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.56679 - Zanamivir solution for injection. European Medicines Agency product information for compassionate use. United Kingdom: GlaxoSmithKline; June 201156756 - Colman PM. Zanamivir: an influenza virus neuraminidase inhibitor. Expert Rev Anti Infect Ther 2005;3:191-199.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Route-Specific 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.[56679] 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.[56679]

 

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.[56679]

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]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 04/03/2019, 05:21:54 PM

    References

    35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.56679 - Zanamivir solution for injection. European Medicines Agency product information for compassionate use. United Kingdom: GlaxoSmithKline; June 201162315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

    Adverse Reactions

    Mild

    • abdominal pain
    • agitation
    • anorexia
    • anxiety
    • appetite stimulation
    • arthralgia
    • chills
    • cough
    • diarrhea
    • dizziness
    • emotional lability
    • fatigue
    • headache
    • infection
    • malaise
    • musculoskeletal pain
    • myalgia
    • nausea
    • nightmares
    • rash
    • sinusitis
    • syncope
    • urticaria
    • vomiting

    Severe

    • anaphylactoid reactions
    • angioedema
    • arrhythmia exacerbation
    • bronchospasm
    • erythema multiforme
    • laryngeal edema
    • seizures
    • Stevens-Johnson syndrome
    • toxic epidermal necrolysis

    Moderate

    • confusion
    • delirium
    • dyspnea
    • elevated hepatic enzymes
    • hallucinations
    • lymphopenia
    • neutropenia
    • psychosis

    0

    • fever

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

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

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

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

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

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

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

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

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

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

    Revision Date: 09/19/2019, 02:19:07 PM

    References

    35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • milk protein hypersensitivity
    • administration via nebulizer
    • angioedema
    • asthma
    • breast-feeding
    • bronchitis
    • cardiac disease
    • children
    • chronic obstructive pulmonary disease (COPD)
    • emphysema
    • geriatric
    • pregnancy
    • psychosis
    • pulmonary disease
    • renal failure
    • renal impairment
    • serious rash
    • vaccination
    • viral infection

    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.[56679] Intravenous zanamivir is only available as part of an ongoing clinical trial or through participation in a compassionate use program.

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

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

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

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

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

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

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

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

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

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

    Revision Date: 11/10/2020, 11:44:16 AM

    References

    35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.46967 - Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ. 2009;181(1-2):55-58.56679 - Zanamivir solution for injection. European Medicines Agency product information for compassionate use. United Kingdom: GlaxoSmithKline; June 201162315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

    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.[35421][52875][56756]

     

    In vitro studies show that zanamivir has a lower EC50 (50% effective inhibitory concentration) than amantadine, rimantadine, and ribavirin for both influenza A and B. Zanamivir is active against influenza isolates resistant to amantadine, rimantadine, and ribavirin. 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. 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.[25977]

     

    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.[36906][62337]

    Revision Date: 09/25/2017, 05:36:08 PM

    References

    25977 - Ubareva LV, Matrosovich MN, Brenner MK, et al. Evidence of zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998;178:1257-1262.35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.36906 - Treanor JJ. Influenza viruses (including avian influenza and swine influenza). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 8th ed. New York: Churchhill Livingstone; 2015:2000-2024.52875 - Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363-1373.56756 - Colman PM. Zanamivir: an influenza virus neuraminidase inhibitor. Expert Rev Anti Infect Ther 2005;3:191-199.62337 - Centers for Disease Control and Prevention (CDC). Interim guidance on influenza antiviral chemoprophylaxis of persons exposed to birds with avian influenza A viruses associated with severe human disease or with the potential to cause severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm

    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.[35421] [56754]

     

    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.[35421]

    Route-Specific Pharmacokinetics

    Oral Route

    Zanamivir is not given orally due to poor bioavailability (1% to 5%).[56754]

    Intravenous Route

    After intravenous administration of zanamivir, high peak concentrations are reached but the drug is rapidly eliminated.[56754]

    Inhalation Route

    Peak serum concentrations range from 17 to 142 ng/mL within 1 to 2 hours after inhalation of a 10 mg dose.[35421] Systemic bioavailability after inhalation ranges from 10% to 20%.[56754] 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.[56755] The total inhaled dose is excreted within 24 hours.[35421]

    Special Populations

    Hepatic Impairment

    The pharmacokinetics of zanamivir have not been studied in patients with hepatic dysfunction.[35421]

    Renal Impairment

    Zanamivir clearance appears to be reduced in renal impairment. After single intravenous doses of 2 or 4 mg in patients with mild/moderate renal impairment or severe renal impairment, respectively, significant decreases in Zanamivir renal clearance and increases in half-life and systemic exposure were noted. The elimination half-life increased to 4.7 hours in patients with moderate renal impairment and 18.5 hours in patients with severe renal impairment. Pharmacokinetic data for zanamivir are unavailable in pediatric patients with renal impairment. [35421]

    Pediatrics

    Children

    Pharmacokinetic data for zanamivir are limited in children; undetectable or low serum concentrations (8.32 to 10.38 ng/mL) were observed in 5 of 16 patients age 6 to 12 years after a single inhaled dose of 10 mg. The median Cmax in the remaining 11 patients was 43 ng/mL (range: 15 to 74 ng/mL). Undetectable or low concentrations were attributed to lack of measurable peak inspiratory flow rate. Children younger than 7 years of age do not produce proper peak inspiratory flow rates needed for use of the Diskhaler device, which limits the systemic absorption and clinical efficacy of zanamivir. Older children with poor inhalational technique experience similar problems with systemic absorption.[35421]

    Revision Date: 11/10/2020, 03:52:58 PM

    References

    35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.56754 - Cass LM, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 1999;36 Suppl 1:1-11.56755 - Cass LM, Brown J, Pickford M, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet 1999;36 Suppl 1: 21-31.

    Pregnancy/Breast-feeding

    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.[46967] If an infant is exposed to zanamivir through breast-feeding, significant serum concentrations are not expected because it is poorly absorbed via the oral route. Limited data from postmarketing case reports have not suggested a safety concern in infants exposed to breast milk of mothers using zanamivir. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for zanamivir and any potential adverse effects on the breastfed child from zanamivir or the underlying maternal condition.[35421]

    Revision Date: 11/10/2020, 11:44:16 AM

    References

    35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.46967 - Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ. 2009;181(1-2):55-58.56679 - Zanamivir solution for injection. European Medicines Agency product information for compassionate use. United Kingdom: GlaxoSmithKline; June 201162315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

    Interactions

    Level 2 (Major)

    • Live Attenuated Influenza Vaccine (intranasal)
    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. [35421] [63436]
    Revision Date: 10/14/2020, 02:50:00 AM

    References

    35421 - Relenza (zanamivir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Jun.63436 - Grohskopf LA, Alyanak E, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-2021 Influenza Season. MMWR 2020;69(No. RR-8):1-24.

    Monitoring Parameters

    • laboratory monitoring not necessary

    US Drug Names

    • Relenza