Summary Basis of Decision for Brinavess

Clinical Pharmacology

Vernakalant hydrochloride, the medicinal ingredient in Brinavess, is an antiarrhythmic drug that acts preferentially in the atria by prolonging atrial refractoriness and slowing impulse conduction in a rate-dependent fashion. These actions are thought to suppress atrial re-entry, and are likely the predominant electrophysiological properties underlying the antiarrhythmic effects of vernakalant. The relative atrial-selective activity of vernakalant results in significantly prolonged atrial refractoriness without significant effects on ventricular refractoriness at clinically relevant plasma levels in clinical electrophysiologic studies.

Vernakalant has unique potassium channel and sodium channel blocking properties which are enhanced under conditions of increased frequency depolarisations, as seen in recent-onset atrial fibrillation. Brinavess has a short pharmacokinetic half-life, which results in a rapid onset and relatively rapid offset of action.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Brinavess for the specified indication.

For further details, please refer to the Brinavess Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical development program, which included 1,018 patients in eight Phase II and Phase III clinical trials, consistently demonstrated that Brinavess provides rapid conversion of recent-onset atrial fibrillation (less than 7 days) to sinus rhythm within 90 minutes in approximately 50% of patients. In atrial fibrillation patients who converted to sinus rhythm within 90 minutes, median time to conversion was only 11 minutes. In the non-post-cardiac surgery patients who converted from atrial fibrillation to sinus rhythm, approximately 97% maintained sinus rhythm through 24 hours, and 93% through 7 days. Brinavess was also effective and generally well-tolerated in the post-cardiac surgery patients with recent-onset atrial fibrillation (less than 3 days).

The reproducibility of the findings across five Phase III clinical trials (ACT I, ACT II, ACT III, ACT V, AVRO), the large magnitude of effect, and the consistent statistical superiority over comparators used (placebo or amiodarone) bring substantial evidence to support the efficacy of Brinavess. Notably, however, these results are obtained from a carefully selected patient population and limited to recent-onset atrial fibrillation.

Brinavess was found to be ineffective for conversion of atrial flutter to sinus rhythm. Less than 5% of such patients converted to rhythm within 90 minutes of initiation of Brinavess. Accordingly, Brinavess is not indicated for conversion of atrial flutter to sinus rhythm. Furthermore, in patients with longer (7 to 45 days) duration of atrial fibrillation, Brinavess was not effective in conversion to sinus rhythm. Less than 10% of such patients converted to sinus rhythm in the clinical development program.

Indication

The original New Drug Submission (NDS) for Brinavess was filed with the following proposed indication:

• Brinavess (vernakalant hydrochloride) is indicated for rapid conversion of recent onset atrial fibrillation (AF) to sinus rhythm in adults:
  • for non-surgery patients: AF ≤7 days duration;
  • for post-cardiac surgery patients: AF ≤3 days duration.

Given that Brinavess was found to be ineffective for conversion of atrial flutter to sinus rhythm, Health Canada revised the proposed indication by including a relevant statement, and approved the following indication:

• Brinavess (vernakalant hydrochloride) is indicated for rapid conversion of recent onset atrial fibrillation to sinus rhythm, for:
  • non-surgery patients, with duration of AF ≤7 days;
  • post-cardiac surgery patients, with duration of AF ≤3 days.
  Brinavess is not recommended for conversion of atrial flutter to sinus rhythm.

For more information, refer to the Brinavess Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Brinavess has been evaluated in clinical trials involving 1,148 subjects, including patients and healthy volunteers, who were exposed to Brinavess. Based on data from 1,018 patients in eight Phase II and Phase III trials, the most commonly reported adverse reactions (>5%) seen in the first 24 hours after receiving Brinavess were dysgeusia (taste disturbance) (18.2%), sneezing (12.9%), and paresthesia (7.4%). These reactions occurred around the time of infusion, were transient, and were rarely treatment limiting.

The incidence of serious adverse events was higher in Brinavess-treated patients (2.8%) compared to placebo-treated patients (0.7%), in the first two hours after initiation of Brinavess infusion. However, no difference in the incidence of serious adverse events over the entire first 24-hour time period was seen between Brinavess (4.7%) and placebo (4.5%). In the first two hours post-dose, serious adverse events occurring in more than one Brinavess-treated patient and more frequent for Brinavess than placebo included hypotension (0.8%), sinus arrest (0.2%), sinus bradycardia (0.2%), and ventricular fibrillation (0.2%). None of these serious adverse events were reported in placebo-treated patients.

Seven fatalities were reported in patients who received Brinavess infusion in the clinical development program, two of which were considered as possibly or likely related to Brinavess treatment. One death occurred within 24 hours of two infusions of Brinavess. It was determined that the patient should have been excluded from the study due to a history of severe aortic stenosis, and due to experiencing acute coronary syndrome at the time of admission. Another patient died on Day 29 following Brinavess infusion likely due to complications of an earlier cardiogenic shock determined to be related to the administration of Brinavess. The patient had pre-existing comorbidities.

Careful patient selection is required before initiation of Brinavess infusion to ensure optimal benefit/risk ratio and prevention of unwanted or unnecessary adverse reactions, such as clinically relevant hypotension, bradycardia, arrhythmias or cardiac conduction defects. In patients with a history of congestive heart failure who received Brinavess, there was a significantly increased incidence of hypotension in the first two hours post-dose compared to patients receiving placebo (13.4% vs. 4.7%, respectively). Caution is required in these patients, as specified in the Warnings and Precautions section of the Brinavess Product Monograph. Furthermore, Brinavess is contraindicated in patients with advanced heart failure, Class III or IV patients as per the New York Heart Association (NYHA) Functional Classification, or in those with acute decompensated heart failure in the previous 30 days. Brinavess is also contraindicated in patients with significant prolongation of the QT interval at baseline, or in those with congenital or acquired Long QT syndrome. Patients with a baseline systolic blood pressure lower than 100 mmHg, those with underlying severe aortic stenosis, or those who have experienced an acute coronary syndrome within 30 days of intended treatment with Brinavess, are at increased risk of clinically relevant hypotensive adverse events or potentially life-threatening ventricular arrhythmias. Therefore, Brinavess is contraindicated in these patients.

In order to help ensure optimal patient selection before administration of Brinavess, a pre-infusion checklist is required to be completed by health care professionals who will administer Brinavess infusion. The pre-infusion checklist will be supplied as a separate leaflet in the drug packaging, and will also be available on a dedicated website, as specified in the Dosage and Administration section of the Brinavess Product Monograph. Furthermore, the sponsor has committed to conducting a post-authorisation non-interventional clinical study in Canada to document drug utilization, conversion rates, and safety in actual clinical settings.

Appropriate warnings and precautions are in place in the approved Brinavess Product Monograph to address the identified safety concerns.

Interim data from the European post-marketing safety study, SPECTRUM, with a cut-off date of June 17, 2016, confirm the clinical efficacy and safety profile of Brinavess in real-world clinical practice. In this registry, follow-up data for 1,143 patients with a total of 1,256 Brinavess treatment episodes were reported, following which 70% of patients converted from atrial fibrillation to sinus rhythm within 90 minutes of initiation of Brinavess infusion.

The incidence rates of events of interest in the SPECTRUM study remained relatively constant from the previous interim report and consistent with adverse events reported in the clinical trial database. A total of 15 predefined events of interest of medically significant hypotension, significant ventricular arrhythmia (defined as sustained ventricular tachycardia, torsades de pointes, ventricular fibrillation), significant atrial flutter, significant bradycardia, were reported. Fourteen of these events occurred within two hours from the start of first Brinavess infusion, one at three hours. Twelve of the 15 events of interest recorded were significant bradycardia events, with a cumulative incidence of 1.0%. Significant bradycardia may be expected in association with any attempt at cardioversion that successfully induces sinus rhythm, unmasking underlying sinus node dysfunction. Two of the significant bradycardia events of interest occurred simultaneously with significant hypotension. The cumulative incidence of hypotension events of interest was 0.2%. Three additional serious adverse events of hypotension were seen, amounting to a total incidence of 0.4%. In addition, rare cases of hemodynamically significant atrial flutter with 1:1 atrioventricular conduction have been observed, with a cumulative incidence of 0.1%.

For more information, refer to the Brinavess Product Monograph, approved by Health Canada and available through the Drug Product Database.