Regulatory Decision Summary for Brinavess

Benefit
Data and information provided by the sponsor in this submission has demonstrated convincingly that vernakalant infusion is efficacious in conversion of recent-onset atrial fibrillation (AF) of ≤ 7 days to sinus rhythm (SR). In several clinical trials, vernakalant infusion was shown to consistently convert about 50% of patients presenting with AF to SR within 90 minutes of initiation of treatment, compared to generally about 5% of placebo-treated patients. If patients converted within 90 minutes to SR, conversion occurred quickly, with a median time to conversion from initiation of Brinavess infusion of only about 11 minutes. Sinus rhythm was maintained through 24 hours in 97% of patients who converted to sinus rhythm. Current real-world conversion rates of recent-onset AF to SR, based on the most recent post-marketing study, are reported at 70% within 90 minutes of exposure to Brinavess infusion, in well-selected patients.

Data and information provided also demonstrated convincingly that vernakalant infusion is efficacious in conversion of recent-onset atrial fibrillation of ≤ 3 days to sinus rhythm (SR) in the immediate post-cardiac surgery setting.

Safety
Brinavess was generally well tolerated when used for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. Adverse events (AE) were typically peri-infusional, generally transient, and rarely treatment-limiting. Careful patient selection is important for Brinavess treatment to optimise benefit and minimise the risk of adverse events, including clinically-relevant hypotension, bradycardia, and ventricular arrhythmias.

The most common drug-related adverse events included dysgeusia (metallic taste in the mouth), sneezing and paresthesia, which generally occurred soon after initiation of Brinavess infusion. The incidence of serious adverse events (SAE) was increased by about 2.1%, over placebo, in the first two hours after initiation of Brinavess treatment, and included, hypotension, as an apparent direct drug effect, and sinus node dysfunction or sinus bradycardia, primarily in association with conversion to sinus rhythm. There was no observed increase in AE or SAE from 2-24 hours after Brinavess treatment, compared to placebo.

Patients with a history of congestive heart failure (CHF) have been identified as a population with a significantly increased incidence of hypotension events in the first 2 hours following Brinavess infusion. Use of Brinavess in patients with recent acute decompensated heart failure, or in advanced heart failure, the New York Heart Association (NYHA) Class III and IV, is contraindicated. Brinavess should be used with caution in patients with a history of CHF. In patients with a history of valvular heart disease, an increased incidence of bradycardia and ventricular arrhythmia has been observed in the first two hours after the start of vernakalant infusion. Caution is required in these patients.

Uncertainty
Brinavess was shown to be efficacious when used in carefully selected patients for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. The reproducibility of these findings, the large magnitude of effect, and the consistent and highly significant p values obtained showing statistical superiority over comparators used across all five Phase 3 trials, brings substantial evidence to support the efficacy of the product. However, it is important that these results are from carefully selected patients and limited to recent-onset atrial fibrillation.

The sponsor committed to conducting a post-authorisation non-interventional clinical study in Canada to confirm the established conversion rates in the real world clinical setting to document and better characterise the post-market safety of Brinavess.

Further, in an attempt to ensure that Brinavess use approximates closely the condition of use in pivotal trials, the sponsor has agreed to ensure that a Pre-Infusion Checklist be completed by the health care professional prior to administration of Brinavess. This Checklist will be supplied as a separate leaflet in the drug packaging.

Benefit-Risk Assessment
In carefully selected patients that meet eligibility criteria as outlined in the Brinavess Product Monograph, benefit-risk of Brinavess infusion is deemed favourable for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. Close monitoring of patients treated with Brinavess is required, as outlined in the Brinavess Pre-Infusion Checklist and in the Brinavess Product Monograph.