BRINAVESS™ (vernakalant) For Infusion Approved In The European Union For Rapid Conversion Of Recent Onset Atrial Fibrillation

Main Category: Cardiovascular / Cardiology
Also Included In: Regulatory Affairs / Drug Approvals
Article Date: 03 Sep 2010 - 2:00 PST

email to a friend   printer friendly   opinions  

MSD (known in the US and Canada as Merck) (NYSE:MRK) and Cardiome Pharma Corp. (NASDAQ: CRME/ TSX: COM) announced that the intravenous (IV) formulation of BRINAVESS™ (vernakalant) has been granted marketing approval in the European Union (EU), Iceland and Norway for the conversion of recent onset atrial fibrillation (AF) to sinus rhythm in adults.

The full indication is for the rapid conversion of recent onset AF to sinus rhythm in adults: for non-surgery patients with AF of seven days or less and for post-cardiac surgery patients with AF of three days or less.

The new treatment has a unique mechanism of action from other AF medicines and is the first product in a new class of pharmacologic agents for cardioversion of AF to launch in the EU.

"BRINAVESS is the first and only agent that acts preferentially in the atria. This medicine offers physicians, patients and hospitals an important new therapy option to use for the rapid treatment of recent-onset AF, and we are pleased to add this to our strong portfolio of medicines for cardiovascular disease," said Patrick Magri, senior vice president, general manager, Cardiovascular Franchise, Merck. "We welcome this important milestone in our collaboration with Cardiome and we are planning to make the product available in the EU by the end of the year."

"BRINAVESS is the first pharmacologic innovation for recent onset of AF in over ten years, and European approval is an exciting juncture for Cardiome." said Doug Janzen, president and chief executive officer of Cardiome. This success was made possible through the commitment and hard work of our employees and our partner Merck, the support of our shareholders, and the efforts of many dedicated medical professionals and patients who have taken part in the clinical program."

Information on the clinical program for vernakalant

The approval of vernakalant 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 vernakalant at converting patients from AF to sinus rhythm for a minimum duration of one minute within 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 vernakalant also was 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 vernakalant effectively converted 47.0 percent of patients from AF to sinus rhythm versus 14.0 percent with placebo (p=0.0001).

In the AVRO study, vernakalant was significantly more effective than amiodarone IV in providing rapid conversion to sinus rhythm within 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, vernakalant was demonstrated to be significantly faster than amiodarone IV in restoring AF patients to sinus rhythm. In the trial, vernakalant 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 first exposure of the study drug. In this study, treatment with vernakalant converted 51.7 percent of patients to sinus rhythm at 90 minutes versus 5.2 percent with amiodarone.

Important Safety Information

Vernkalant is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients. Vernakalant also is contraindicated in patients with severe aortic stenosis, systolic blood pressure <100 mm Hg, and heart failure class NYHA III and NYHA IV. Furthermore, vernakalant is contraindicated in patients with 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. Vernakalant is also contraindictated in patients who use intravenous rhythm control antiarrhythmics (class I and class III) within four hours prior to administration of vernakalant and patients with acute coronary syndrome (including myocardial infarction) within the last 30 days.

Vernakalant is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients; patients with severe aortic stenosis, patients with systolic blood pressure <100 mm Hg, and patients with heart failure class NYHA III and NYHA IV and patients with 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. Vernakalant is also contraindicated in 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.

Patients should be observed with assessment of vital signs and continuous cardiac rhythm monitoring during and after administration of vernakalant, until clinical and ECG parameters have stabilised.

Hypotension can occur in a small number of patients (vernakalant 7.6%, compared to placebo 5.1%). Hypotension typically occurs early, either during the infusion or early after the end of the infusion, and can usually be corrected by standard supportive measures. Patients with congestive heart failure (CHF) have been identified as a population at higher risk for hypotension.

Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first 2 hours post dose (7.3% for vernakalant compared to 1.6% for placebo). These arrhythmias typically presented as asymptomatic, monomorphic, non-sustained (average 3 to 4 beats) ventricular tachycardias. By contrast, ventricular arrhythmias were reported with similar frequencies in patients without a history of CHF who were treated with either vernakalant or placebo (3.2% for vernakalant versus 3.6% for placebo).

In patients with valvular heart disease, there was a higher incidence of ventricular arrhythmia events in patients on BRINAVESS. These patients should be monitored closely.

As a precautionary measure, 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.

In clinical studies, the most commonly reported adverse reactions (greater than 5%) seen in the first 24 hours after receiving BRINAVESS were dysgeusia (taste disturbance 20.1%), sneezing (14.6 percent), and paraesthesia (9.7%).

Clinically significant adverse reactions observed in clinical trials included hypotension and ventricular arrhythmia.

Before initiating therapy, the full prescribing information should be consulted.

Merck-Cardiome Agreement

In April 2009, Cardiome and Merck announced a collaboration and license agreement for the development and commercialization of vernakalant. The agreement provides Merck, Sharp and Dohme Corp. (formerly known as Merck & Co., Inc.) with exclusive global rights to vernakalant oral formulation for the maintenance of normal heart rhythm in patients with AF, and provides another Merck affiliate, Merck Sharp & Dohme (Switzerland) GmbH, with exclusive rights outside of the United States, Canada and Mexico to vernakalant IV formulation for rapid conversion of recent onset AF to sinus rhythm in adults.

Source:
Cardiome Pharma Corp.
Merck

• Additional
• References
• Citations