Regulatory Decision Summary for Baca Respiclick

The Sponsor has developed a multi-dose dry powder inhaler (MDPI) containing salbutamol for the treatment and/or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease, as well as for the prevention of exercise-induced bronchospasm (EIB) in patients 4 years of age and older.

The metabolism and excretion of salbutamol have been well described in the published literature and in the labelling for approved inhaled salbutamol products. Therefore, the Sponsor did not perform any additional studies to investigate metabolism or elimination, and no studies were performed in any special populations.

Baca Respiclick was shown to be effective and safe in the treatment of asthma in adults/adolescents, with demonstrated efficacy versus Placebo in 2 pivotal double-blind Phase 3 studies and safety in 3 double-blind studies and several other clinical studies involving 1378 patients. Safety and efficacy have been demonstrated in children aged 4 years and older across 3 studies in the pediatric population.

The pivotal studies in adults, both met their primary endpoints demonstrating that subjects treated with Baca Respiclick, 194 mcg experienced clinically meaningful and statistically significant increases in Area Under Curve 0-6 h of Forced Expiratory Volume-one second FEV₁ AUC_0-6h compared to placebo-treated subjects over the 12-weeks of the controlled period of the studies. The primary efficacy variable in the paediatric pivotal study, the baseline-adjusted Percent Predicted (PP) FEV₁ AUC_0-6h over the 3-week treatment period, confirmed these results.

Analyses of the secondary endpoints of the pivotal studies were supportive. Onset of action for Baca Respiclick was seen within 5-6 minutes with duration of effect that is consistent with that of other salbutamol containing products. Despite some attenuation of the effect, which suggests development of tachyphylaxis, clinically relevant bronchodilatory effect was maintained after 12 weeks of chronic dosing in adults/adolescents and 3 weeks in pediatric patients. The data confirm the known effectiveness of salbutamol in subjects 4 years of age and older with asthma.

Efficacy in preventing EIB was demonstrated in a dedicated Phase 3 study in adults and adolescents. Treatment with Baca Respiclick prior to exercise reduced the post-exercise percentage fall in FEV₁ to 6% compared to 22% for placebo treated subjects, suggesting that 84% of the patients pre-treated with Baca Respiclick experienced a <10% decrease in FEV₁ compared to only 16% of placebo-pretreated subjects, which translates into a clinically significant benefit. The EIB indication was extrapolated to pediatric patients based on the results from the adult/adolescent EIB study and the demonstration of bronchodilation in children 4 to 11 years of age.

The two studies that assessed the performance of the new MDPI device demonstrated that the total number of device-related complaints was low and that the proposed MDPI device with integrated counter performed adequately and in a reliable manner.

The safety database for Baca Respiclick consists of 8 clinical studies in adult and adolescent patients and 3 clinical trials in children 4-11. Overall, 1456 adult/adolescent patients were included in the clinical program of whom 1120 received treatment with Salbutamol MDPI. Among patients treated with Salbutamol MDPI, 840 were treated with the inhaler proposed for marketing. No major safety concerns were identified during the clinical development program for Salbutamol MDPI. No deaths occurred and the safety profile observed was similar to that seen with other inhaled Salbutamol products or inhaled products containing lactose. Upper respiratory tract infection, urinary tract infection, gastroenteritis, nasopharyngitis, and back pain were the most commonly reported adverse events. Less common adverse events included palpitations, dry mouth, tremor, migraine, headache, dysphonia and oropharyngeal pain. There was no evidence observed for a change in the reporting pattern of adverse events when Salbutamol MDPI was administered for up to 52 weeks. There was no apparent evidence for an effect of sex, age, or race on the adverse event profile.

A total of 261 pediatric patients were treated in 3 Salbutamol MDPI studies in the pediatric development program; this included 169 patients treated with at least 1 dose of Baca Respiclick 194 mcg. All patients were treated with the inhaler proposed for commercialization. These clinical studies continue to support the profile of Salbutamol MDPI as a safe and well tolerated treatment for asthma.

Salbutamol MDPI, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Appropriate warnings and precautions have been included in the Product Monograph.

Appropriate cautions (including contraindications) have been incorporated in the product labelling to prevent use of Salbutamol MDPI by patients with severe milk protein allergy or hypersensitivity to Salbutamol. Specific risks related to the device have been identified and mitigated by appropriate labelling.

The clinical program conducted by the Sponsor has demonstrated that therapy with Baca Respiclick 194 mcg effectively treats or prevents bronchospasm in patients 4 years of age and older who are diagnosed with persistent asthma and/or exercise-induced bronchospasm. Analysis of the safety data did not demonstrate an important safety signal with the use of Baca Respiclick and the results support the safety of Baca Respiclick for use in the proposed patient population.

For treatment of bronchospasm or prevention of symptoms associated with bronchospasm, the proposed dosage for adults and children 4 years and older is 2 inhalations repeated every 4 to 6 hours. In some patients, 1 inhalation every 4 hours may be sufficient. For prevention of exercise-induced bronchospasm in adults and children 4 years of age or older, the proposed dosage is 2 inhalations 15 to 30 minutes before exercise.

A notice of compliance, pursuant to section C.08.004 of the Food and Drug Regulations, was issued.