Ultibro Breezhaler Adverse Reactions

The presentation of the safety profile of Ultibro Breezhaler is based on the experience with Ultibro Breezhaler and the individual monotherapy components.
Summary of the safety profile: The safety experience with Ultibro Breezhaler was comprised of exposure of up to 15 months at the recommended therapeutic dose (110/50 microgram).
The Ultibro Breezhaler Phase III clinical development program consisted of 11 key studies and enrolled over 10000 patients with a clinical diagnosis of moderate to very severe COPD. Safety data from 9 of these studies with treatment durations of 4 weeks or longer were pooled from 4352 patients exposed to Ultibro Breezhaler 110/50 microgram once-daily.
The safety profile was characterised by typical anticholinergic and beta-adrenergic symptoms related to the individual monotherapy components of the combination. Other most common adverse drug reactions related to the drug product (≥3% and greater than placebo) were headache, cough and nasopharyngitis.
At the recommended dose, the adverse drug reaction profile of Ultibro Breezhaler in patients with COPD showed clinically insignificant systemic effects of beta₂-adrenergic stimulation. Mean heart rate changes were less than one beat per min, and tachycardia was infrequent and reported at a lower rate than with placebo. Relevant prolongations of QTcF were not detectable in comparison to placebo. The frequency of notable QTcF intervals [i.e., >450 ms] and reports of hypokalemia were similar to placebo.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions (ADR) are listed by MedDRA system organ class (Table 4). The frequency of adverse drug reactions was based on a pool of 3 Phase III placebo-controlled trials of 6 and 12 months in duration. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000, <1/1,000); and very rare (<1/10,000).
ULTIBRO BREEZHALER 110/50 showed similar adverse drug reactions as the individual monotherapy components. As Ultibro Breezhaler contains indacaterol and glycopyrronium, the type and severity of adverse reactions associated with each of the monotherapy components may be expected in the combination. (See Table 4.)

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Study 2307: For the 12-month trial A2307 comparing Ultibro Breezhaler (n=226) and placebo (n=113), the most commonly reported AE was COPD (Ultibro Breezhaler 28.0% vs. placebo 25.7%). Cough, lower respiratory tract infections, pyrexia and pneumonia were reported for a slightly higher percentage of patients in the Ultibro Breezhaler group compared with placebo.
Five deaths were reported in this study, four in the Ultibro Breezhaler 110/50 group (1.8%) and 1 in the placebo group (0.9%). In the Ultibro Breezhaler 110/50 group 1 sudden death was adjudicated to cardiovascular cause. Three deaths were adjudicated to respiratory cause (COPD exacerbations, including 1 with pneumonia). The cause of the 1 death observed in the placebo group was accidental.
A higher proportion of patients in the Ultibro Breezhaler group had severe COPD (31.1%) compared to placebo (18.6%) at baseline. Inhaled corticosteroid use was also higher in the Ultibro Breezhaler group compared with placebo (45.8% vs. 38.9%) at baseline, whereas more patients had a history of cardiovascular disease in the placebo group than in the Ultibro Breezhaler group.
Post-marketing experience: Adverse drug reactions from spontaneous reports and literature cases: The following adverse drug reactions have been reported with Ultibro Breezhaler in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.
Adverse drug reactions from spontaneous reports and literature cases (frequency not known): Immune system disorders: Angioedema.
Respiratory, thoracic and mediastinal disorders: Dysphonia.
Description of selected adverse drug reactions: The most common anticholinergic adverse event was dry mouth (0.64% versus 0.45% for placebo); however, this adverse event was reported at a lower frequency with Ultibro Breezhaler than with glycopyrronium monotherapy. The majority of the reports of dry mouth were suspected to be drug related and of mild degree, none was severe. Cough was common, but usually of mild intensity.
Some serious adverse events, including hypersensitivity and ischaemic heart disease, have been reported as ADRs for indacaterol administered as monotherapy. The reported frequencies for Ultibro Breezhaler for hypersensitivity and ischaemic heart disease were 2.06% versus 1.9% for placebo and 0.67% versus 0.78% for placebo, respectively.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.