TRANSFORM HOW YOU USE DRUG INFORMATION

NOTE: Relenza inhalation powder is not intended to be reconstituted in any liquid formulation and is not recommended for use in any nebulizer or mechanical ventilator.[36918]

General dosing information:

• Because antiviral resistance patterns can change over time, monitor local antiviral resistance surveillance data. If patients become symptomatic or have worsening symptoms after or during the use of an antiviral agent, a resistant organism is possible.[62315] [62336] [63866]

Seasonal influenza virus:

• Antiviral treatment with zanamivir is recommended for outpatients with acute uncomplicated influenza infection who are at higher risk for influenza complications (e.g., adults 65 years and older; patients with chronic conditions; immunosuppressed patients; females who are pregnant or postpartum (less than 2 weeks since delivery); children on long-term aspirin therapy; American Indians/Alaska Natives; morbidly obese patients; and residents of long-term care facilities). Treatment may also be considered for previously healthy, symptomatic patients that are not considered high risk based on clinical judgment if treatment can be initiated within 48 hours of symptom onset.
• When indicated, antiviral therapy should be started as soon as possible after illness onset, ideally within 48 hours of symptom onset.
• Widespread or routine use of zanamivir for influenza prevention is discouraged. Preexposure chemoprophylaxis is only recommended for patients at very high risk for influenza-related complications (i.e., immunosuppressed patients). In general, postexposure chemoprophylaxis is only recommended when antivirals can be initiated within 48 hours of exposure. The decision regarding who should receive postexposure prophylaxis is dependent on patient risk factors, type and duration of exposure, clinical judgment, and product availability. Chemoprophylaxis lowers but does not eliminate the risk for influenza infection.
• The 2009 H1N1 influenza virus (swine influenza) is included in seasonal influenza A viruses.[62315] [63866]

Novel influenza A viruses associated with severe human disease, including avian influenza virus:

• Antiviral therapy is recommended as early as possible for patients with suspected or confirmed cases, even if more than 48 hours have elapsed since illness onset. Treatment is recommended for any patient with recent or close contact with a confirmed or probable case.
• Postexposure chemoprophylaxis of exposed persons: Postexposure prophylaxis can be considered in all persons in contact with infected sick or dead birds or infected flocks in the past 10 days. Decisions to initiate prophylaxis should be based on clinical judgment, with consideration given to type of exposure and whether the exposed person is at high risk for influenza complications.
• Postexposure chemoprophylaxis of asymptomatic close contacts: Postexposure chemoprophylaxis of asymptomatic close contacts is recommended for high-risk exposure groups (i.e., household or close family member contacts of a confirmed or probable case) and may be considered for moderate-risk exposure groups (i.e., health care personnel with unprotected contact with a confirmed or probable case). Chemoprophylaxis is not routinely recommended for low-risk exposure groups (i.e., persons with social contact of short duration with a confirmed or probable case in a non-hospital setting). Decisions to initiate therapy in moderate- and low-risk exposure should be based on clinical judgment, with consideration given to type of exposure and whether the exposed person is at high risk for influenza complications.[62336] [62337] [62338]

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

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]

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]

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

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 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]

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.[35421] 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.[56762][56763] 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]

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]