Relenza 5 mg

Interactions with herbal products have not been established.

Interactions with food have not been established.

Zanamivir is less than 15% protein bound. There is no evidence of hepatic metabolism, and zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes. Therefore, based on data from in-vitro studies, clinically significant drug interactions are unlikely. RELENZA (zanamivir), when given for 28 days (10 mg once daily), did not impair the immune response to the influenza vaccine.

Interactions with laboratory tests have not been established.

The recommended dose of RELENZA for prophylaxis of influenza in adults and adolescents in a community setting is 10 mg once daily for 28 days. The 10 mg dose is provided by 2 inhalations (one 5 mg blister per inhalation). The dose should be administered at approximately the same time each day. There are no data on the effectiveness of prophylaxis with RELENZA in a community outbreak when initiated more than 5 days after the outbreak was identified in the community. The safety and effectiveness of prophylaxis with RELENZA have not been evaluated for longer than 28 days duration.

The recommended dose of RELENZA for prophylaxis of influenza in adults and pediatric patients 7 years of age and older in a household setting is 10 mg once daily for 10 days. The 10 mg dose is provided by 2 inhalations (one 5 mg blister per inhalation). The dose should be administered at approximately the same time each day. There are no data on the effectiveness of prophylaxis with RELENZA in a household setting when initiated more than 1.5 days after the onset of signs or symptoms in the index case.

The recommended dose of RELENZA (zanamivir) for treatment of influenza in adults and pediatric patients ≥7 years of age is 2 inhalations (one 5 mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days. A second dose should be taken on the first day of treatment whenever possible, provided there is at least 2 hours between doses. On subsequent days, doses should be about 12 hours apart (e.g., morning and evening) at approximately the same time each day. There are no data on the effectiveness of treatment with RELENZA when initiated more than 2 days after the onset of signs or symptoms. For maximum benefit, treatment must begin within two days, after the onset of symptoms.

RELENZA is for administration to the respiratory tract by oral inhalation only. The contents of each blister are inhaled using a specially designed breath-activated plastic device for inhaling powder called the DISKHALER inhalation device.

Patients scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their bronchodilator before taking RELENZA (see Warnings and Precautions, Respiratory).

In case of a missed dose, RELENZA should be taken immediately, except if it is near the next dose (within 2 hours). Then, RELENZA should be continued at the usual times.

Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments.

The following adverse events have been reported spontaneously during post-marketing experience with RELENZA. However, a causal relationship to RELENZA cannot be clearly established for spontaneously reported events.

The most frequent laboratory abnormalities in Phase 3 treatment studies included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Because the placebo consisted of inhaled lactose powder which is also the vehicle for the active drug, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation.

diarrhea, nausea, vomiting.

bronchospasm, dyspnea (see Warnings and Precautions).

delirium, including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares (see Warnings and Precautions).

allergic or allergic-like reactions, including facial and oropharyngeal oedema, laryngospasm (see Warnings and Precautions).

dizziness, headaches, insomnia, seizures.

See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm and allergic-like reactions, and for safety information in patients with underlying respiratory disease.

rash, urticaria, and severe skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (see Warnings and Precautions).

arrhythmias, syncope, tachycardia.

Summary of Adverse Events ≥1% Incidence During 28 Day Prophylaxis Studies in Adults and Adolescents^a

RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease [see Warnings and Precautions]) due to risk of serious bronchospasm.

RELENZA has not been proven effective for prophylaxis of influenza in the nursing home setting.

RELENZA is not a substitute for influenza vaccination on an annual basis as recommended by the National Advisory Committee on Immunization (NACI).

RELENZA (zanamivir) is indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients 7 years of age and older, who have been symptomatic for no more than 2 days. No data are available to support zanamivir safety and efficacy in patients who receive treatment after 48 hours of symptoms.

This indication is based on placebo-controlled studies conducted in North America, the Southern Hemisphere, and Europe during their respective influenza seasons. The magnitude of treatment effect varied between studies, with possible relationships to population-related factors including amount of symptomatic relief medication used.

RELENZA, when taken as recommended for treatment of influenza, alleviates the symptoms and reduces their duration.

Safety and effectiveness of RELENZA for treatment of influenza have not been established in pediatric patients under 7 years of age. Safety and effectiveness of RELENZA for prophylaxis of influenza have not been assessed in pediatric patients under 5 years of age. Efficacy data from the age of 5 to 7 years are limited.

In clinical trials, the safety profile of RELENZA did not appear to vary with increasing age and no overall differences in the safety and efficacy were observed between the elderly and younger patients. A brief discussion can be found in Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age).

RELENZA is indicated in adults and pediatric patients 7 years of age and older for prophylaxis of influenza.

At the therapeutic daily dose of 20 mg, bioavailability is low (10-20%), and as a result, systemic exposure of patients to RELENZA is limited. However, after a single IV dose of 4 mg or 2 mg of zanamivir in volunteers with mild or moderate, or severe renal impairment, respectively, significant decreases in renal clearance (and hence total clearance: normals 5.3 L/h, mild/moderate 2.7 L/h, and severe 0.8 L/h; median values) and significant increases in half-life (normals 3.1 h, mild/moderate 4.7 h, and severe 18.5 h; median values) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency after repeated dosing.

The pharmacokinetics of zanamivir have not been investigated in patients with impaired hepatic function; doses of up to 1200 mg IV in healthy adults did not show evidence of hepatic metabolism.

Serious bacterial infections may begin with influenza-like symptoms or may co-exist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications.

Allergic-like reactions, including facial and oropharyngeal edema, bronchospasm, laryngospasm, dyspnea, urticaria, serious skin rashes and anaphylaxis have been reported in post-marketing experience. RELENZA should be discontinued and immediate medical attention sought by any patient who develops an allergic reaction or if one is suspected.

There have been post-marketing reports (mostly from Japan) of delirium and abnormal behaviour leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including RELENZA. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon based on usage data for RELENZA. These events were reported primarily among pediatric patients and often had an abrupt onset. The contribution of RELENZA to these events has not been established. Patients with influenza receiving RELENZA should be closely monitored for signs of abnormal behaviour. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.

It should be noted that influenza infection itself can be complicated with a variety of neurologic and behavioural symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.

Due to the limited number of patients with severe asthma or other severe chronic respiratory diseases, patients with chronic illnesses or immunocompromised patients who have been treated, it has not been possible to demonstrate the efficacy and safety of RELENZA in these groups.

Vaccination of persons at high risk each year before the influenza season is currently recognized as the most effective measure for reducing the impact of influenza. The use of zanamivir should not affect the evaluation of individuals for annual influenza vaccination, in accordance to “Health Canada, An Advisory Committee Statement, National Advisory Committee on Immunization (NACI), Statement on Influenza Vaccination for the current Year/Season”.

Patients should be instructed in the use of the DISKHALER inhalation device and instructions should include a demonstration wherever possible. Patients should be advised to read and follow carefully the patient instructions to ensure safe and effective use. Patients should be advised to finish the full course of treatment or prophylaxis therapy as prescribed.

Severe skin reactions including erythema multiforme, Stevens-Johnnson syndrome and toxic epidermal necrolysis have been reported in post-marketing experience.

Safety and efficacy of RELENZA have not been demonstrated in patients with severe underlying chronic pulmonary disease or severe asthma due to limited number of patients treated. Therefore, RELENZA is not generally recommended for treatment in such patients. Serious adverse events have been reported in patients with underlying chronic pulmonary disease and in patients with severe or decompensated chronic obstructive pulmonary disease or asthma (see Serious Warnings and Precautions).

If treatment with RELENZA is considered for a patient with an underlying airway disease, the potential risks and benefits should be carefully weighed. The patients should be advised of the risk of bronchospasm. If a decision is made to prescribe RELENZA for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation and appropriate supportive care including availability of fast-acting bronchodilators. Patients should be instructed to contact their physician if they experience increased respiratory symptoms during treatment such as worsening wheezing, shortness of breath, or other signs or symptoms of bronchospasm (see Serious Warnings and Precautions) and to discontinue RELENZA. Patients scheduled to take inhaled bronchodilators at the same time as RELENZA should be advised to use their bronchodilators before taking RELENZA.

In a placebo controlled study in patients with predominantly mild/moderate asthma and/or Chronic Obstructive Pulmonary Disease (COPD), RELENZA was shown to be effective and well tolerated for the treatment of influenza. There was no evidence of a difference between RELENZA and placebo in forced expiratory volume in one second (FEV₁) or peak expiratory flow rate (PEFR) measured after the end of treatment.

At the therapeutic daily dose of 20 mg, bioavailability of zanamivir in young healthy adults is low (10-20%), and as a result systemic exposure of patients to zanamivir is limited. The bioavailability of zanamivir in elderly individuals has not been determined. However, a total of 83 elderly patients (aged ≥65 years old) received inhaled zanamivir at a dose of 10 mg twice daily, or greater, for the treatment of symptomatic influenza in completed clinical trials. Of the total number of patients who received zanamivir 10 mg once daily for prophylaxis of influenza in households and community settings in 4 clinical studies of RELENZA, 954 were aged 65 and over. The safety profile did not appear to vary with increasing age and no overall differences in the safety and efficacy were observed between the elderly and younger patients. However, greater sensitivity of some older patients to medications in general, cannot be ruled out. In 2 additional studies of RELENZA for prophylaxis of influenza in the nursing home setting, efficacy was not demonstrated. Elderly subjects may need assistance with use of the device.

Safety and effectiveness of RELENZA for treatment of influenza have not been established in pediatric patients under 7 years of age. Safety and effectiveness of RELENZA for prophylaxis of influenza have not been assessed in pediatric patients under 5 years of age. Efficacy data from the age of 5 to 7 years are limited. Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered. When RELENZA is prescribed for children, it should be used only under adult supervision and with attention to proper use of the delivery system.

The safe use of zanamivir during pregnancy has not been established. There are no adequate and well controlled studies of zanamivir in pregnant women. There is no information on placental transfer in humans. Reproductive studies performed in rats and rabbits indicated that placental transfer of zanamivir occurs. In these animals, fetal blood concentrations of zanamivir were significantly lower than zanamivir concentrations in the maternal blood. Studies in rats did not show any evidence of teratogenicity, impairment of fertility or malformations. One embryo/fetal study, was conducted using subcutaneous administration of zanamivir, 3 times daily at doses of 1, 9 or 80 mg/kg during days 7 to 17 of pregnancy. Based on AUC measurements, the high dose in the study produced an exposure greater than 1000 times the human exposure at the proposed clinical dose. There was an increase in the incidence rates of a variety of minor skeleton alterations and variants in the exposed offspring in this study. The individual incidence rates of each skeletal alteration or variant, in many but not in all cases, remained within the range of background rates of the historical occurrence in the rat strain studied.

RELENZA should not be used in pregnancy, especially during the first trimester, unless the possible benefit to the patient is thought to outweigh any possible risk to the fetus.

Studies in rats have demonstrated that zanamivir is excreted in milk. Nursing mothers, however, should be instructed that it is not known whether zanamivir is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELENZA is administered to a nursing mother.

The pharmacokinetics of zanamivir have not been investigated in patients with impaired hepatic function; doses of up to 1200 mg IV in healthy adults did not show evidence of hepatic metabolism.

The bioavailability of zanamivir in elderly individuals has not been determined (see Warnings and Precautions).

In healthy adults, after oral inhalation, RELENZA is widely deposited at high concentrations throughout the respiratory tract, thus delivering the drug to the site of influenza infection. The high concentrations of RELENZA in the respiratory tract will result in the rapid onset of inhibition of the viral neuraminidase. The two major sites of deposition are the oropharynx and the lungs (mean 77.6% and 13.2 %, respectively), from where zanamivir is eliminated via the gastrointestinal tract.

Pharmacokinetic studies in humans have shown that the absolute oral absorption of zanamivir, as compared to IV administration of the drug, was low (mean 2%). Similar studies of orally inhaled RELENZA (zanamivir) indicate that approximately 10-20% of the dose is systemically absorbed, with serum concentrations generally peaking within 1-2 hours. The peak serum concentrations ranged from 17 to 142 ng/mL following a 10 mg dose. The area under the serum concentration versus time curve (AUC to infinity) ranged from 111 to 1364 ng·hr/mL.

RELENZA (zanamivir) is a selective inhibitor of neuraminidase, the influenza virus surface enzyme. It is believed that viral neuraminidase aids the release of newly formed virus particles from infected cells and may facilitate access of virus through mucus to epithelial cell surfaces, to allow viral infection of other cells. It is believed that the inhibition of this enzyme is reflected in both in vitro and in vivo (in animals) activity against influenza A and B virus replication, and encompasses all of the known neuraminidase subtypes of influenza A viruses.

It is believed that the activity of zanamivir is extracellular. It reduces the propagation of both influenza A and B viruses by inhibiting the release of infectious influenza virions from the epithelial cells of the respiratory tract. Influenza viral replication is primarily confined to the superficial epithelium of the respiratory tract. The efficacy of topical administration of zanamivir to this site has been confirmed in clinical studies.

The serum half-life of zanamivir following administration by oral inhalation ranges from 2.6 to 5.05 hours. It is entirely excreted unchanged in the urine. Total clearance ranges from 2.5 to 10.9 L/h as approximated by urinary clearance. Renal elimination is completed within 24 hours. The unabsorbed drug is excreted in the feces.

At the therapeutic daily dose of 20 mg, bioavailability is low (10-20%), and as a result systemic exposure of patients to RELENZA is limited. However, after a single IV dose of 4 mg or 2 mg of zanamivir in volunteers with mild or moderate, or severe renal impairment, respectively, significant decreases in renal clearance (and hence total clearance: normal 5.3 L/h, mild/moderate 2.7 L/h, and severe 0.8 L/h; median values) and significant increases in half-life (normal 3.1 h, mild/moderate 4.7 h, and severe 18.5 h; median values) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency after repeated dosing.

Zanamivir has been shown to be renally excreted as unchanged drug. There is no evidence of metabolism of orally inhaled drug.

The pharmacokinetics of zanamivir were evaluated in pediatric patients with signs and symptoms of respiratory illness. Sixteen patients, 6 to 12 years of age, received a single dose of 10 mg zanamivir dry powder via the DISKHALER inhalation device. Five patients had either undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to 10.38 ng/mL) that were not detectable after 1.5 hours. Eleven patients had C_max median values of 43 ng/mL (range 15 to 74) and AUC_∞ median values of 167 ng·hr/mL (range 58 to 279). Low or undetectable serum concentrations were related to lack of measurable peak inspiratory flow rates (PIFR) in individual patients (see Warnings and Precautions, Special Populations, Pediatrics).