RELENZA® (zanamivir) Inhalation Powder, for oral inhalation

1 INDICATIONS AND USAGE

1.1 Treatment of Influenza

RELENZA 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.

1.2 Prophylaxis of Influenza

RELENZA is indicated for prophylaxis of influenza in adults and pediatric patients 5 years of age and older.

1.3 Important Limitations on Use of RELENZA

• RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) due to risk of serious bronchospasm [see Warnings and Precautions (5.1)].

• RELENZA has not been proven effective for treatment of influenza in individuals with underlying airways disease.
• RELENZA has not been proven effective for prophylaxis of influenza in the nursing home setting.
• RELENZA is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control's Immunization Practices Advisory Committee.
•  Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use RELENZA.
• There is no evidence for efficacy of zanamivir in any illness caused by agents other than influenza virus A and B.
• Patients should be advised that the use of RELENZA for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Considerations

• RELENZA is for administration to the respiratory tract by oral inhalation only, using the DISKHALER device provided.

• The 10 mg dose is provided by 2 inhalations (one 5 mg blister per inhalation).
• Patients should be instructed in the use of the delivery system. Instructions should include a demonstration whenever possible. If RELENZA is prescribed for children, it should be used only under adult supervision and instruction, and the supervising adult should first be instructed by a healthcare professional [see Patient Counseling Information (17.4)].
• Patients scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their bronchodilator before taking RELENZA [see Patient Counseling Information (17.2)].

2.2 Treatment of Influenza

• The recommended dose of RELENZA for treatment of influenza in adults and pediatric patients 7 years of age and older is 10 mg twice daily (approximately 12 hours apart) for 5 days.

• Two doses 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.
• The safety and efficacy of repeated treatment courses have not been studied.

2.3 Prophylaxis of Influenza

Household Setting:

• The recommended dose of RELENZA for prophylaxis of influenza in adults and pediatric patients 5 years of age and older in a household setting is 10 mg once daily for 10 days.
• 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.

Community Outbreaks:

• 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 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 eva luated for longer than 28 days’ duration.

3 DOSAGE FORMS AND STRENGTHS

Four 5 mg blisters of powder on a ROTADISK for oral inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses) and 1 DISKHALER inhalation device [see How Supplied/Storage and Handling (16)].

4 CONTRAINDICATIONS

Do not use in patients with history of allergic reaction to any ingredient of RELENZA including lactose (which contains milk proteins) [see Warnings and Precautions (5.2), Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Bronchospasm

RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease).

Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess.

RELENZA should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required.

Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions.

Bronchospasm was documented following administration of zanamivir in 1 of 13 patients with mild or moderate asthma (but without acute influenza-like illness) in a Phase I study. In a Phase III study in patients with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of patients on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in FEV1 following treatment for 5 days.

If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. 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.

5.2 Allergic Reactions

Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected.

 5.3 Neuropsychiatric Events

 Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behavior, 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.

 There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior 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 and rapid resolution. The contribution of RELENZA to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be eva luated for each patient.

5.4 Limitations of Populations Studied

Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management.

5.5 Bacterial Infections

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

5.6 Importance of Proper Use of DISKHALER

Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully eva luate the ability of young children to use the delivery system if use of RELENZA is considered [see Use in Specific Populations (8.4)].

6 ADVERSE REACTIONS

See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm (5.1) and allergic-like reactions (5.2), and for safety information in patients with underlying airways disease (5.1).

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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

Treatment of Influenza: Clinical Trials in Adults and Adolescents: Adverse events that occurred with an incidence ≥1.5% in treatment studies are listed in Table 1. This table shows adverse events occurring in patients ≥12 years of age receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA).

Additional adverse reactions occurring in less than 1.5% of patients receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.

The most frequent laboratory abnormalities in Phase III 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.

Clinical Trials in Pediatric Patients: Adverse events that occurred with an incidence ≥1.5% in children receiving treatment doses of RELENZA in 2 Phase III studies are listed in Table 2. This table shows adverse events occurring in pediatric patients 5 to 12 years old receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA).

In 1 of the 2 studies described in Table 2, some additional information is available from children (5 to 12 years old) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients.

Prophylaxis of Influenza: Family/Household Prophylaxis Studies: Adverse events that occurred with an incidence of ≥1.5% in the 2 prophylaxis studies are listed in Table 3. This table shows adverse events occurring in patients ≥5 years of age receiving RELENZA 10 mg inhaled once daily for 10 days.