Merck and Cardiome Pharma Corp. announced on September 1, 2010 that the intravenous (IV) formulation of BRINAVESS™ (vernakalant) has been granted marketing approval in the European Union (EU), Iceland and Norway.
The approved indication is: “Rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults:
• for non-surgery patients: atrial fibrillation ≤ 7 days duration;
• for post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration.”
Vernakalant hydrochloride is a novel anti-arrhythmic drug that acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow the impulse conduction. Vernakalant is the first product in a new class of pharmacologic agents for cardioversion of AF to launch in the EU.
Information on the clinical program for BRINAVESS
The approval of BRINAVESS is based on the results of three randomized, double-blind, placebo controlled studies (ACT I, ACT II, and ACT III) and an active comparator trial (AVRO).
In ACT I and III, the efficacy of BRINAVESS at converting patients from AF to sinus rhythm for a minimum duration of one minute with 90 minutes of initiating therapy was evaluated in 390 haemodynamically stable adult patients with short duration AF (3 hours to 7 days) versus placebo. In ACT I, vernakalant cardioverted 51.0 percent of patients versus 4.0 percent of patients taking placebo (n=74 and 3, respectively; p<0.0001). In ACT III, vernakalant cardioverted 51.2 percent of patients versus 3.6 percent of patients taking placebo (n=44 and 3, respectively; p<0.0001). Conversion of AF to sinus rhythm occurred rapidly; in responders, the median time to conversion was 10 minutes from start of first infusion, based on pooled results from the ACT I and ACT III studies. The efficacy of BRINAVESS was also studied in ACT II in 150 patients with sustained AF (3 hours to 72 hours duration) that occurred between 24 hours and 7 days post coronary artery bypass graft and/or valvular surgery. Treatment with BRINAVESS effectively converted 47.0 percent of patients from AF to sinus rhythm versus 14.0 percent placebo (p=0.0001).
In the AVRO, study BRINAVESS was significantly more effective than amiodarone IV in providing rapid conversion to sinus rhythm within the first 90 minutes of initiating therapy In the AVRO (Active-Controlled, Multi-Center Study of Vernakalant Injection versus Amiodarone in Subjects with Recent Onset Atrial Fibrillation) study, BRINAVESS was demonstrated to be significantly faster than amiodarone IV in converting AF patients to sinus rhythm. In the trial, BRINAVESS was studied in 116 patients with AF (3 hours to 48 hours) versus 116 patients on amiodarone. The amiodarone infusion was given over two hours (i.e., one hour loading dose of 5 mg/kg, followed by one hour maintenance infusion of 50 mg) with the objective to compare rapid conversion to sinus rhythm. The primary endpoint was the proportion of patients that achieved sinus rhythm for a minimum duration of one minute within 90 minutes of the first exposure of the study drug. In this study, treatment with BRINAVESS converted 51.7 percent of patients to sinus rhythm at 90 minutes versus 5.2 percent with amiodarone.
Contraindications:
1. Hypersensitivity to the active substance or to any of the excipients.
2. Severe aortic stenosis, SBP <100 mm Hg, and CHF class NYHA III and NYHA IV.
3. Prolonged QT at baseline (uncorrected >440 msec), severe bradycardia, sinus node dysfunction, or second-degree or third-degree heart block in the absence of a pacemaker.
4. Patients who use intravenous rhythm control antiarrhythmics (class I and class III) within four hours prior to administration of BRINAVESS and patients with acute coronary syndrome (including myocardial infarction) within the last 30 days.
ADVERSE EFFECTS: Hypotension (vernakalant 7.6%, placebo 5.1%), typically occurs early, either during the infusion or early after the end of the infusion. Patients with a history of CHF are at an increased risk of heaving hypotension and ventricular arrhythmias. A higher incidence of ventricular arrhythmia events has been reported in patients with valvular heart disease. Dysgeusia (taste disturbance) (20.1%), sneezing (14.6%), and paraesthesia (9.7%) are the other common adverse effects. Patients should be observed with assessment of vital signs and continuous cardiac rhythm monitoring during and after administration of BRINAVESS, until clinical and ECG parameters have stabilized.
It is preferable to avoid the use of BRINAVESS during pregnancy. It is unknown whether vernakalant/metabolites are excreted in human milk. Caution should be exercised when used in breast-feeding women.
http://www.merck.com/newsroom/news-release-archive/research-and-development/2010_0901.html?WT.svl=content&WT.pi=content+Views
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001215/smops/Positive/human_smop_000109.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d127&jsenabled=true
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