Relenza

Neuraminidase Inhibitor Antivirals

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]

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

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

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

Relenza

Rx

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

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]

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]

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]

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]

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]

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]

10 mg by oral inhalation every 12 hours for 5 days for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset.[62315] [62336]

10 mg by oral inhalation every 12 hours for 5 days for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset.

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]

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

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.

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.

Relenza Respiratory (Inhalation) Pwd: 5mg

10 mg (i.e., 2 oral inhalations of 5 mg) twice daily.

10 mg (i.e., 2 oral inhalations of 5 mg) twice daily.

10 mg (i.e., 2 oral inhalations of 5 mg) twice daily.

7 to 12 years: 10 mg (i.e., 2 oral inhalations of 5 mg) twice daily.
5 to 6 years: 10 mg (i.e., 2 oral inhalations of 5 mg) once daily.
1 to 4 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.

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.

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

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

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.

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.