Relenza Drug Information

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. • Patients scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their bronchodilator before taking RELENZA.

Treatment of Influenza •

The recommended dose of RELENZA for treatment of influenza in adults and pediatric patients aged 7 years 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.

Prophylaxis of Influenza Household Setting •

The recommended dose of RELENZA for prophylaxis of influenza in adults and pediatric patients aged 5 years 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 evaluated for longer than 28 days’ duration.

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 trials 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 greater than or equal to 1.5% in treatment trials are listed in Table 1.

This table shows adverse events occurring in subjects aged 12 years and older 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). Table 1. Summary of Adverse Events ≥1.5% Incidence during Treatment in Adults and Adolescents Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.

The most frequent laboratory abnormalities in Phase 3 treatment trials included elevations of liver enzymes and creatine phosphokinase (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 Subjects: Adverse events that occurred with an incidence greater than or equal to 1.5% in children receiving treatment doses of RELENZA in 2 Phase 3 trials are listed in Table 2.

Table 2. 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 Trials: Adverse events that occurred with an incidence of greater than or equal to 1.5% in the 2 prophylaxis trials are listed in Table 3.

This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 10 days. Table 3. Summary of Adverse Events ≥1.5% Incidence during 10-Day Prophylaxis Trials in Adults, Adolescents, and Children a Community Prophylaxis Trials: Adverse events that occurred with an incidence of greater than or equal to 1.5% in 2 prophylaxis trials are listed in Table 4.

Table 4.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of RELENZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic Reactions Allergic or allergic-like reaction, including oropharyngeal edema.

Psychiatric Delirium, including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares. Cardiac Arrhythmias, syncope. Neurologic Seizures.

Vasovagal-like episodes have been reported shortly following inhalation of zanamivir. Respiratory Bronchospasm, dyspnea. Skin Facial edema; rash, including serious cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria.

• The concurrent use of RELENZA with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of potential interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of RELENZA, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of RELENZA. Live attenuated influenza vaccine, intranasal:
• Do not administer until 48 hours following cessation of RELENZA.
• Do not administer RELENZA until 2 weeks following administration of the live attenuated influenza vaccine, unless medically indicated.

Pregnancy Risk Summary Available data from published studies suggest that use of RELENZA during pregnancy is not associated with an increased risk of birth defects or adverse maternal or fetal outcomes. However, these studies are limited by their small sample sizes, which preclude a definitive assessment of the risk (see Data). There are risks to the mother and fetus associated with influenza infection in pregnancy (see Clinical Considerations).

In animal reproduction studies, no adverse developmental effects were observed with intravenous or subcutaneous administration of zanamivir at exposures 300 and 150 times, respectively, the systemic exposure at the maximum recommended human inhalation dose (MRHID) of 10 mg twice daily (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes, including maternal death, stillbirths, birth defects, preterm delivery, low birth weight, and small for gestational age. Data Human Data: A study of population-based registers from Denmark, Norway, Sweden, and France reported outcomes of 5,824 pregnant women who filled a prescription for an NAI compared with outcomes in unexposed pregnant women in the general population.

This study included 1,560 women who filled a prescription for zanamivir (including 321 first trimester exposures). Although no specific analyses were conducted for zanamivir, exposure to the NAI class in utero was not associated with major birth defects, preterm birth, low birth weight, small for gestational age, still birth, neonatal morbidity, or neonatal mortality. A few published studies compared outcomes of pregnant women exposed to zanamivir with outcomes in various comparator cohorts.

These studies suggested no increased risk of major birth defects, preterm birth, or low birth weight. Limitations of available studies include the lack of specific analyses for zanamivir, possible exposure and outcome misclassification, and small sample sizes. These limitations preclude a definitive assessment of the risk.

Animal Data: Zanamivir was administered intravenously to pregnant rats and rabbits at 1, 9, or 90 mg/kg/day during organogenesis (gestation Day ). No adverse maternal or embryo-fetal effects were observed up to the highest intravenous dose of zanamivir (90 mg/kg/day), resulting in systemic drug exposure (AUC) estimated from both rats and rabbits, 300 times the exposure at the MRHID. An increased incidence of skeletal and visceral alterations and variants was observed at the high dose (240 mg/kg/day).

No adverse maternal or embryo-fetal effects were observed at the middle dose (27 mg/kg/day), resulting in systemic drug exposure (AUC) 150 times the exposure at the MRHID. No significant effects were observed in the offspring at systemic drug exposures (AUC) estimated to be 300 times the exposure at the MRHID. Zanamivir distributed across the placenta in pregnant rats and rabbits, with less than 0.04% of the administered maternal dose being recovered from the fetus on gestation Day 12.

Pediatric Use Treatment of Influenza Safety and effectiveness of RELENZA for treatment of influenza have not been assessed in pediatric patients younger than 7 years, but were studied in a Phase 3 treatment trial in pediatric subjects, where 471 children aged 5 to 12 years received zanamivir or placebo. Adolescents were included in the 3 principal Phase 3 adult treatment trials. In these trials, 67 patients were aged 12 to 16 years.

No definite differences in safety and efficacy were observed between these adolescent patients and young adults. Neither of two 6-year-olds and one of two 7-year-olds produced measurable PIFR. Overall, 8 of the 16 children (including all those younger than 8 years) either did not produce measurable inspiratory flow through the DISKHALER or produced peak inspiratory flow rates below the 60 L/minute considered optimal for the device under standardized in vitro testing; lack of measurable flow rate was related to low or undetectable serum concentrations.

Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered. No differences in safety and effectiveness were observed between pediatric and adult subjects.

RELENZA is contraindicated in patients with history of allergic reaction to any ingredient of RELENZA, including milk proteins. Do not use in patients with history of allergic reaction to any ingredient of RELENZA, including milk proteins.

Reports of overdosage from administration of RELENZA have been received during postmarketing experience. The reported clinical signs or symptoms were similar to those observed with therapeutic doses of RELENZA and the underlying disease. As zanamivir has a low molecular weight, low protein binding, and small volume of distribution, it is expected to be removed by hemodialysis.