Brivaness

1.

NAME OF THE MEDICINAL PRODUCT

BRINAVESS 20 mg/ml, concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate contains 20 mg of vernakalant hydrochloride which is equivalent to 18.1 mg of

vernakalant free base.

Each 10 ml vial of 200 mg of vernakalant hydrochloride is equivalent to 181 mg of vernakalant free

base.

Each 25 ml vial of 500 mg of vernakalant hydrochloride is equivalent to 452.5 mg of vernakalant free

base.

After dilution the concentration of the solution is 4 mg/ml vernakalant hydrochloride

Excipient: Each vial of 200 mg contains approximately 1.4 mmol (32 mg) sodium. Each vial of

500 mg contains approximately 3.5 mmol (80 mg) of sodium.

Each administered millilitre of the diluted solution contains approximately 3.5 mg of sodium (sodium

chloride 9 mg/ml (0.9%) solution for injection), 0.64 mg sodium (Glucose injection 5%) or 3.2 mg

sodium (Lactated Ringers for Injection).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear and colourless to pale yellow solution with a pH of approximately 5.5.

The osmolality of the medicinal product is controlled between the following range: 270-

320 mOsmol/kg

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

BRINAVESS should be administered by intravenous infusion, by qualified medical personnel in a

monitored clinical setting appropriate for cardioversion.

Posology

BRINAVESS is dosed by patient body weight, with a maximum calculated dose based upon 113 kgs.

The recommended initial infusion is 3 mg/kg to be infused over a 10 minute period. For patients

weighing ≥ 113 kg, do not exceed the maximum initial dose of 339 mg (84.7 ml of 4 mg/ml solution).

If conversion to sinus rhythm does not occur within 15 minutes after the end of the initial infusion, a

second 10 minute infusion of 2 mg/kg may be administered. For patients weighing ≥ 113 kg, do not

exceed the maximum second infusion of 226 mg (56.5 ml of 4 mg/ml solution). Cumulative doses of

greater than 5 mg/kg should not be administered within 24 hours. There are no clinical data on repeat

2

doses after the initial and second infusions. By 24 hours there appears to be insignificant levels of

vernakalant.

If conversion to sinus rhythm occurs during either the initial or second infusion, that infusion should

be continued to completion. If haemodynamically stable atrial flutter is observed after the initial

infusion, the second infusion of BRINAVESS may be administered as patients may convert to sinus

rhythm. (See sections 4.4 and 4.8.)

An infusion pump is the preferred delivery device. However, a syringe pump is acceptable provided

that the calculated volume can be accurately given within the specified infusion time.

Do not administer as an intravenous push or bolus.

Recommended diluents are 0.9% Sodium Chloride for Injection, Lactated Ringers for Injection, or 5%

Glucose for Injection.

Read all steps before administration.

Preparation of BRINAVESS for infusion

Step 1: Visually inspect BRINAVESS vials for particulate matter and discolouration before

administration. Do not use any vials exhibiting particulate matter or discolouration. Note:

BRINAVESS concentrate for solution for infusion ranges from colourless to pale yellow. Variations

of colour within this range do not affect potency.

Step 2: Dilution of concentrate

To ensure proper administration, a sufficient amount of BRINAVESS 20 mg/ml should be prepared at

the outset of therapy to deliver the initial and second infusion should it be warranted.

Create a solution with a concentration of 4mg/ml following the dilution guidelines below:

Patients ≤ 100 kg: 25 ml of BRINAVESS 20 mg/ml is added to 100 ml of diluent.

Patients > 100 kg: 30 ml of BRINAVESS 20 mg/ml is added to 120 ml of diluent.

Step 3: Inspect solution

The diluted sterile solution should be clear, colourless to pale yellow. Visually re-inspect the solution

for particulate matter and discolouration before administering.

Method of administration

BRINAVESS vials are for single use only and must be diluted prior to administration.

Step 4: Administration of the initial infusion

The initial infusion of BRINAVESS is administered as a 3 mg/kg dose over 10 minutes.

Step 5: Patient observation

If conversion to sinus rhythm has not occurred, observe the patient’s vital signs and cardiac rhythm for

an additional 15 minutes.

Step 6: Administration of second infusion

If conversion to sinus rhythm did not occur with the initial infusion or within the 15 minute

observation period, administer a 2 mg/kg second infusion over 10 minutes.

Cumulative doses above 565 mg have not been evaluated.

Post-cardiac surgery patients :

No dose adjustment necessary.

Renal impairment:

No dose adjustment necessary (see section 5.2).

3

Hepatic impairment:

No dose adjustment necessary (see sections 4.4 and 5.2).

Elderly (≥ 6 years) :

No dose adjustment necessary.

Paediatric population :

There is no relevant use of BRINAVESS in children and adolescents < 18 years of age in the current

indication and therefore should not be used in this population.

4.3 Contraindications

•

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

•

Patients with severe aortic stenosis, patients with systolic blood pressure <100 mm Hg, and

patients with heart failure class NYHA III and NYHA IV.

•

Patients with prolonged QT at baseline (uncorrected > 440 msec), or severe bradycardia, sinus

node dysfunction or second degree and third degree heart block in the absence of a pacemaker.

•

Use of intravenous rhythm control anti-arrhythmics (class I and class III) within 4 hours prior to

BRINAVESS administration.

•

Acute coronary syndrome (including myocardial infarction) within the last 30 days.

4.4 Special warnings and precautions for use

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 stabilised.

Direct-current cardioversion may be considered for patients who do not respond to therapy. There is

no clinical experience with direct-current cardioversion under two hours postdose.

Prior to attempting pharmacological cardioversion, ensure that patients are adequately hydrated and

haemodynamically optimized and if necessary patients should be anticoagulated in accordance with

treatment guidelines. In patients with uncorrected hypokalemia (serum potassium of less than

3.5 mmol/l), potassium levels should be corrected prior to use of BRINAVESS.

During infusion of BRINAVESS, if patients develop clinically meaningful bradycardia and/or

hypotension or develop ECG changes (such as a clinically meaningful sinus pause, complete heart

block, new bundle branch block, significant prolongation of the QRS or QT interval, changes

consistent with ischaemia or infarction and ventricular arrhythmia), the administration of

BRINAVESS should be discontinued and these patients should receive appropriate medical

management. If these events occur during the first infusion of BRINAVESS, patients should not

receive the second dose of BRINAVESS.

Hypotension

Hypotension can occur in a small number of patients (vernakalant 7.6%, 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. (See section 4.8.)

Congestive Heart Failure

Patients with CHF showed a higher overall incidence of hypotensive events, during the first 2 hours

after dose in patients treated with vernakalant compared to patients receiving placebo

(16.1% versus 4.7%, respectively). In patients without CHF the incidence of hypotension was not

significantly different during the first 2 hours after dose in patients treated with vernakalant compared

to patients receiving placebo (5.7% versus. 5.2%, respectively). Hypotension reported as a serious

adverse experience or leading to medicine discontinuation occurred in CHF patients following

exposure to BRINAVESS in 2.9% of these patients compared to 0% in placebo.

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Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first two

hours post dose (7.3% for BRINAVESS compared to 1.6% in placebo). These arrhythmias typically

presented as asymptomatic, monomorphic, non-sustained (average 3-4 beats) ventricular tachycardias.

By contrast, ventricular arrhythmias were reported with similar frequencies in patients without a

history of CHF who were treated with either BRINAVESS or placebo (3.2% for BRINAVESS versus

3.6% for placebo).

Due to the higher incidence of the adverse events of hypotension and ventricular arrhythmia in

patients with CHF, vernakalant should be used cautiously in haemodynamically stable patients with

CHF functional classes NYHA I to II. There is limited experience with the use of vernakalant in

patients with previously documented LVEF ≤ 35%. its use in these patients is not recommended. The

use in CHF patients corresponding to NYHA III or NYHA IV is contraindicated (see section 4.3).

Atrial Flutter

BRINAVESS was not found to be effective in converting typical primary atrial flutter to sinus rhythm.

Patients receiving BRINAVESS have a higher incidence of converting to atrial flutter within the

first 2 hours post-dose. This risk is higher in patients who use Class I antiarrhythmics (see section 4.8).

If atrial flutter is observed as secondary to treatment, continuation of infusion should be considered

(see section 4.2)

Use of AADs (anti-arrhythmic drugs) prior to or after BRINAVESS

BRINAVESS can not be recommended in patients previously administered intravenous AADs (class I

and III) 4-24 hours prior to vernakalant due to lack of data. BRINAVESS should not be administered

in patients who received intravenous AADs (class I and III) within 4 hours prior to vernakalant (see

section 4.3).

BRINAVESS should be used with caution in patients on oral AADs (class I and III), due to limited

experience. Risk of atrial flutter may be increased in patients receiving class I AADs (see above).

There is limited experience with the use of intravenous rhythm control anti-arrhythmics (class I and

class III) in the first 4 hours after BRINAVESS administration, therefore these agents should be used

cautiously within this period. Resumption or initiation of oral maintenance antiarrhythmic therapy can

be considered starting 2 hours after vernakalant administration.

Valvular Heart Disease

In patients with valvular heart disease, there was a higher incidence of ventricular arrhythmia events in

vernakalant patients. These patients should be monitored closely.

Other Diseases and Conditions not Studied

BRINAVESS has been administered to patients with an uncorrected QT less than 440 msec without an

increased risk of torsade de pointes.

Furthermore, BRINAVESS has not been evaluated in patients with clinically meaningful valvular

stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive

pericarditis and its use can not be recommended in such cases. There is limited experience with

BRINAVESS in patients with pacemakers.

As the clinical trial experience in patients with advanced hepatic impairment is limited, vernakalant is

not recommended in these patients.

This medicinal product contains approximately 1.4 mmol (32 mg) sodium in each 200 mg vial. Each

vial of 500 mg contains approximately 3.5 mmol (80 mg) of sodium.

This should be taken into consideration by patients on a controlled sodium diet.

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4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been undertaken with vernakalant injection. Within the clinical

development program, oral maintenance antiarrhythmic therapy was halted for a minimum of 2 hours

after BRINAVESS administration. Resumption or initiation of oral maintenance antiarrhythmic

therapy after this time period can be considered (see sections 4.3 and 4.4) .

Although vernakalant is a substrate of CYP2D6, population pharmacokinetic (PK) analyses

demonstrated that no substantial differences in the acute exposure of vernakalant (Cmax and AUC0-

90min) were observed when weak or potent CYP2D6 inhibitors were administered within 1 day prior

to vernakalant infusion compared to patients that were not on concomitant therapy with CYP2D6

inhibitors. In addition, acute exposure of vernakalant in poor metabolisers of CYP2D6 is only

minimally different when compared to that of extensive metabolisers. No dose adjustment of

vernakalant is required on the basis of CYP2D6 metaboliser status, or when vernakalant is

administered concurrently with 2D6 inhibitors.

Vernakalant is a moderate, competitive inhibitor of CYP2D6. However, acute intravenous

administration of vernakalant is not expected to markedly impact the PK of chronically administered

2D6 substrates, as a consequence of vernakalant's short half life and the ensuing transient nature of

2D6 inhibition. Vernakalant given by infusion is not expected to perpetrate meaningful drug

interactions due to the rapid distribution and transient exposure, low protein binding, lack of inhibition

of other CYP P450 enzymes tested (CYP3A4, 1A2, 2C9, 2C19 or 2E1) and lack of P-glycoprotein

inhibition in a digoxin transport assay.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of vernakalant hydrochloride in pregnant women. Animal studies have

shown malformations after repeated oral exposure (see section 5.3).As a precautionary measure, it is

preferable to avoid the use of vernakalant during pregnancy.

Breast-feeding

It is unknown whether vernakalant/metabolites are excreted in human milk.

There is no information on the excretion of vernakalant/metabolites in animal milk.

A risk to the suckling child cannot be excluded.

Caution should be exercised when used in breastfeeding women.

Fertility

Vernakalant was not shown to alter fertility in animal studies.

4.7 Effects on ability to drive and use machines

No studies on the effects of BRINAVESS on the ability to drive and use machines have been

performed. However, when driving vehicles or operating machines, it should be taken into account

that, dizziness has been reported within the first two hours after taking BRINAVESS.

(see section 4.8).

4.8 Undesirable effects

The safety of BRINAVESS has been evaluated in clinical studies involving 883 subjects (patients and

healthy volunteers) who received treatment with BRINAVESS. Based on data from 773 patients in six

phase 2 and phase 3 trials, the most commonly reported adverse reactions (> 5%) seen in the first

24 hours after receiving BRINAVESS were dysgeusia (taste disturbance) (20.1%), sneezing (14.6%)

and paraesthesia (9.7%). These events occurred around the time of infusion, were transient and were

rarely treatment limiting.

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Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon

(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000), not known (cannot

be estimated from the available data)

Table1:

Adverse reactions with BRINAVESS *

Nervous system disorders Very common: Dysgeusia

Common: Paraesthesia, dizziness, headache, hypoaesthesia

Uncommon: Burning sensation, parosmia, somnolence, vasovagal

syncope

Eye disorders

Uncommon: Eye irritation, lacrimation increased, visual disturbance

Cardiac disorders

Common: Bradycardia**, atrial flutter**

Uncommon : Sinus arrest, complete AV block, first degree AV block, left

bundle branch block, ventricular extrasystoles, palpitations, sinus

bradycardia, ventricular tachycardia, ECG QRS complex prolonged, ECG

QT prolonged

Vascular disorders

Common: Hypotension

Uncommon: Flushing, hot flush, pallor

Respiratory, thoracic and

mediastinal disorders

Very common: Sneezing

Common: Cough, nasal discomfort

Uncommon: Dyspnoea, suffocation feeling, rhinorrhoea, throat irritation

Gastrointestinal disorders Common: Nausea, vomiting, dry mouth

Uncommon: Diarrhoea, defecation urgency

Skin and subcutaneous

tissue disorders

Common: Pruritus, hyperhidrosis

Uncommon: Generalised pruritis, cold sweat

Musculoskeletal and

connective tissue

disorders

Uncommon: Pain in extremity

Common: Infusion site pain, infusion site paraesthesia, feeling hot,

fatigue

Uncommon: Infusion site irritation, infusion site hypersensitivity,

malaise, chest discomfort

* The adverse reactions included in the table occurred within 24 hours of administration of

BRINAVESS (see sections 4.2 and 5.2)

**see section below

Description of selected adverse reactions :

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

arrhythmia. (See sections 4.4 Hypotension, Congestive Heart Failure).

Bradycardia was observed predominantly at the time of conversion to sinus rhythm. With a

significantly higher conversion rate in patients treated with BRINAVESS, the incidence of

bradycardia events was higher within the first 2 hours in vernakalant treated patients than in placebo-

treated patients (5.4% versus 3.8%, respectively). Of the patients who did not convert to sinus rhythm,

the incidence of bradycardia events in the first 2 hours postdose was similar in placebo and

vernakalant treated groups (4.0% and 3.8%, respectively). In general, bradycardia responded well to

discontinuation of BRINAVESS and/or administration of atropine.

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General disorders and

administrative site

conditions

Atrial Flutter

Atrial fibrillation patients receiving BRINAVESS have a higher incidence of converting to atrial

flutter within the first 2 hours postdose (10% versus 2.5% in placebo). With continuation of the

medicine infusion as recommended above, the majority of these patients continue to convert to sinus

rhythm. In the remaining patients, electrical cardioversion can be recommended. In clinical studies to

date, patients who developed atrial flutter following treatment with BRINAVESS did not develop

1:1 atrioventricular conduction.

AVRO Study

In a clinical trial involving 116 patients with recent onset atrial fibrillation who received

BRINAVESS, the observed adverse experience profile appeared to be consistent with that reported in

the prior trials.

4.9 Overdose

No case of overdose with BRINAVESS has been reported in clinical trials. One patient who received

3 mg/kg of BRINAVESS over 5 minutes (instead of the recommended 10 minutes) developed

haemodynamically stable wide complex tachycardia which resolved without sequelae.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : Cardiac therapy, other antiarrhythmics class I and III, ATC code:

C01BG11.

Mechanism of Action: Vernakalant is an antiarrhythmic medicine that acts preferentially in the atria to

prolong atrial refractoriness and to rate-dependently slow impulse conduction. These anti-fibrillatory

actions on refractoriness and conduction are thought to suppress re-entry, and are potentiated in the

atria during atrial fibrillation. The relative selectivity of vernakalant on atrial versus ventricular

refractoriness is postulated to result from the block of currents that are expressed in the atria, but not in

the ventricles, as well as the unique electrophysiologic condition of the fibrillating atria. However,

blockade of cationic currents, including hERG channels and cardiac voltage-dependent sodium

channels, which are present in the ventricles has been documented.

Pharmacodynamics: In preclinical studies, vernakalant blocks currents in all phases of the atrial action

potential, including potassium currents that are expressed specifically in the atria (e.g., the ultra-rapid

delayed rectifier and the acetylcholine dependent potassium currents). During atrial fibrillation, the

frequency- and voltage-dependent block of sodium channels further focuses the action of the medicine

toward rapidly activating and partially depolarized atrial tissue rather than toward the normally

polarized ventricle beating at lower heart rates. Additionally, the ability of vernakalant to block the

late component of the sodium current limits effects on ventricular repolarisation induced by blockade

of potassium currents in the ventricle. Targeted effects on atrial tissue coupled with block of late

sodium current suggests that vernakalant has a low proarrhythmic potential. Overall, the combination

of effects of vernakalant on cardiac potassium and sodium currents results in substantial

antiarrhythmic effects that are mainly concentrated in the atria.

In an electrophysiological study in patients, vernakalant significantly prolonged atrial effective

refractory period in a dose-dependent manner, which was not associated with a significant increase in

ventricular effective refractory period. Across the Phase 3 population, vernakalant treated patients had

an increase in heart rate-corrected QT (using Fridericia's correction, QTcF) compared to placebo

(22.1 msec and 18.8 msec placebo-subtracted peaks after first and second infusions, respectively). By

90 minutes after the start of infusion, this difference was reduced to 8.1 msec.

Clinical efficacy

8

Clinical Trial Design: The clinical effect of BRINAVESS in the treatment of patients with atrial

fibrillation has been evaluated in three, randomised, double-blind, placebo-controlled studies, (ACT I,

ACT II and ACT III) and in an active comparator trial versus intravenous amiodarone (AVRO). Some

patients with typical atrial flutter were included in ACT II and ACT III and BRINAVESS was not

found to be effective in converting atrial flutter. In clinical studies, the need for anticoagulation prior

to administration of vernakalant was assessed as per clinical practice of the treating physician. For

atrial fibrillation lasting less than 48 hours, immediate cardioversion was allowed. For atrial

fibrillation lasting longer than 48 hours, anticoagulation was required as per treatment guidelines.

ACT I and ACT III studied the effect of BRINAVESS in the treatment of patients with sustained atrial

fibrillation > 3 hours but not more than 45 days in duration. ACT II examined the effect of

BRINAVESS on patients who developed atrial fibrillation of < 3 days duration after recently

undergoing coronary artery bypass graft, (CABG) and/or valvular surgery (atrial fibrillation occurred

more than 1 day but less than 7 days after surgery). AVRO studied the effect of vernakalant versus

intravenous amiodarone in patients with recent onset atrial fibrillation (3 hrs to 48 hrs). In all studies,

patients received a 10-minute infusion of 3.0 mg/kg BRINAVESS (or matching placebo) followed by

a 15-minute observation period. If the patient was in atrial fibrillation or atrial flutter at the end of the

15-minute observation period, a second 10-minute infusion of 2.0 mg/kg BRINAVESS (or matching

placebo) was administered. Treatment success (responder) was defined as conversion of atrial

fibrillation to sinus rhythm within 90 minutes. Patients who did not respond to treatment were

managed by the physician using standard care.

Efficacy in patients with sustained atrial fibrillation, (ACT I and ACT III)

Primary efficacy endpoint was the proportion of subjects with short duration atrial fibrillation (3 hours

to 7 days) who had a treatment-induced conversion of atrial fibrillation to sinus rhythm for a minimum

duration of one minute within 90 minutes of first exposure to study drug. Efficacy was studied in a

total of 390 haemodynamically stable adult patients with short duration atrial fibrillation including

patients with hypertension (40.5%), ischaemic heart disease (12.8%), valvular heart disease (9.2%)

and CHF (10.8%). In these studies treatment with BRINAVESS effectively converted atrial

fibrillation to sinus rhythm as compared with placebo (see Table 2). Conversion of atrial fibrillation to

sinus rhythm occurred rapidly (in responders the median time to conversion was 10 minutes from start

of first infusion) and sinus rhythm was maintained through 24 hours (97%). The vernakalant dose

recommendation is a titrated therapy with two possible dose steps. In the performed clinical studies,

the additive effect of the second dose, if any, can not be independently established.

Table 2: Conversion of Atrial Fibrillation to Sinus Rhythm in ACT I and ACT III

ACT I

ACT III

BRINAVESS Placebo P-Value† BRINAVESS Placebo P-Value†

> 3 hours to

≤ 7 days

74/145

(51.0%)

3/75

(4.0%)

< 0.0001

44/86

(51.2%)

3/84

(3.6%)

< 0.0001

†Cochran-Mantel-Haenszel test

BRINAVESS was shown to provide relief of atrial fibrillation symptoms consistent with conversion to

sinus rhythm.

No significant differences in safety or effectiveness were observed based on age, gender, use of rate

control medications, use of antiarrhythmic medications, use of warfarin, history of ischaemic heart

disease, renal impairment or expression of the cytochrome P450 2D6 enzyme.

Treatment with BRINAVESS did not affect the response rate to electrical cardioversion (including the

median number of shocks or joules required for successful cardioversion) in cases when attempted

within 2 to 24 hours of study medicine administration.

Conversion of atrial fibrillation in patients with longer-duration atrial fibrillation (> 7 days and ≤ 45

days) assessed as a secondary efficacy endpoint in a total of 185 patients did not show statistically

significant differences between BRINAVESS and placebo.

9

Duration of

Atrial

Fibrillation

Efficacy in patients who developed atrial fibrillation post cardiac surgery (ACT II)

Efficacy was studied in patients with atrial fibrillation after cardiac surgery in ACT II, a phase 3,

double-blind, placebo-controlled, parallel group study (ACT II) in 150 patients with sustained atrial

fibrillation (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 atrial

fibrillation to sinus rhythm (47.0% BRINAVESS, 14.0% placebo; P value = 0.0001). Conversion of

atrial fibrillation to sinus rhythm occurred rapidly (median time to conversion 12 minutes from the

start of infusion).

Efficacy versus amiodarone (AVRO):

Vernakalant was studied in 116 pts with atrial fibrillation (3 hrs to 48 hrs) including patients with

hypertension (74.1%), IHD (19%), valvular heart disease (3.4%) and CHF (17.2%). No patients with

NYHA III/IV were included in the study . In AVRO, the amiodarone infusion was given over 2 hours

(i.e., 1 hour loading dose of 5 mg/kg, followed by 1 hour maintenance infusion of 50 mg). The

primary endpoint was the proportion of patients that achieved sinus rhythm (SR) at 90 minutes after

initiating therapy, limiting the conclusions to the effects seen in this time window. Treatment with

vernakalant, converted 51.7% of patients to SR at 90 minutes versus 5.2% with amiodarone resulting

in a significantly faster conversion rate from AF to SR within the first 90 minutes compared to

amiodarone (log-rank P-value < 0.0001).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

BRINAVESS in all subsets of the paediatric population in atrial fibrillation (see section 4.2 for

information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single

10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion

of 2 mg/kg with a 15 minute interval between doses.

Distribution

Vernakalant is extensively and rapidly distributed in the body, with a volume of distribution of

approximately 2 l/kg. The Cmax and AUC were dose proportional between 0.5 mg/kg and 5 mg/kg. In

patients, the typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg. The free

fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml.

Elimination/excretion

Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive

metabolisers. Glucuronidation and renal excretion are the main mechanisms of elimination in

CYP2D6 poor metabolisers. The mean elimination half life of vernakalant in patients was

approximately 3 hours in CYP2D6 extensive metabolisers and approximately 5.5 hours in poor

metabolisers.

Special patient groups

Acute exposure is not significantly influenced by gender, history of congestive heart failure, renal

impairment, or concomitant administration of beta blockers and other medications, including warfarin,

metoprolol, furosemide and digoxin. In patients with hepatic impairment, exposures were elevated by

9 to 25%. No dose adjustment of BRINAVESS is required for these conditions, nor on the basis of

age, serum creatinine or CYP2D6 metaboliser status.

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety

pharmacology, single- and repeated-dose toxicity, and genotoxicity.

10

With respect to reproduction no effects on pregnancy, embryofetal development, parturition or

postnatal development were observed after intravenous administration of vernakalant at exposure

levels (AUC) similar or below the human exposure levels (AUC) achieved after a single intravenous

dose of vernakalant. In embryofetal development studies with oral administration of vernakalant two

times a day resulting in exposure levels (AUC) generally higher than those achieved in humans after a

single intravenous dose of vernakalant malformations (misshapen/absent/fused skull bones including

cleft palates, bent radius, bent/misshapen scapula, constricted trachea, absent thyroid,

undescendent testes) occurred in rats and increased embryofetal lethality, increased number of fetuses

with fused and/or additional sternebrae were seen in rabbits at the highest doses tested.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid E330

Sodium chloride

Water for injection

Sodium hydroxide E524 (for pH-adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 4.2.

6.3 Shelf life

3 years

The diluted sterile concentrate is chemically and physically stable for 12 hours at or below 25°C.

From a microbiological point of view, the product should be used immediately. If not used

immediately, in-use storage times and conditions prior to use are the responsibility of the user and

would normally not be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place in

controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Single-use glass (Type 1) vials with a chlorobutyl rubber stopper and an aluminium overseal. Pack

size of 1 vial includes either a 10 ml solution of 200 mg or a 25 ml solution of 500 mg.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

See section 4.2 for Preparation of BRINAVESS for infusion.

Any unused product or waste material should be disposed of in accordance with local requirements.

BRINAVESS does not contain a preservative.

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7.

MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

{MM/YYYY}

<Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/>

12

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

13

A. Manufacturing authorisation holder responsible for batch release

Name and address of the manufacturer(s) responsible for batch release

Merck Sharp & Dohme B.V.

Waarderweg 39

NL-2031 BN Haarlem

The Netherlands

B. Conditions of the marketing authorisation

• Conditions or restrictions regarding supply and use imposed on the marketing authorisation

holder

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product

Characteristics, section 4.2).

• Conditions or restrictions with regard to the safe and effective use of the medicinal product

The Marketing Authorisation Holder shall ensure that all Healthcare Professionals (HCP) involved in

the administration of BRINAVESS are provided with a healthcare professional information pack

containing the following:

Educational material for Healthcare Professionals

Summary of Product Characteristics, Package Leaflet and Labelling

Key elements to be included in the educational material:

1. BRINAVESS should be administered by intravenous infusion, by qualified medical personnel in a

monitored clinical setting appropriate for cardioversion.

2. Appropriate measures to manage and minimize the risks, including the need for close monitoring

during and after administration of BRINAVESS

3. Patient selection criteria, including contraindications, special warnings and precautions for use and

information about patient populations with limited information from clinical trials

- Alert HCP on BRINAVESS contraindications:

•

Patients with prolonged QT at baseline (uncorrected > 440 msec), or severe bradycardia,

sinus node dysfunction or second degree and third degree heart block in the absence of a

pacemaker.

•

Use of intravenous rhythm control anti-arrhythmics (class I and class III) within 4 hours

prior to BRINAVESS administration.

•

Acute coronary syndrome (including myocardial infarction) within the last 30 days

•

Patients with severe aortic stenosis, patients with systolic blood pressure <100 mm Hg,

and patients with heart failure class NYHA III and NYHA IV.

- Alert HCP about BRINAVESS special warnings and precautions in patients with, clinically

meaningful valvular stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or

constrictive pericarditis, previously documented LVEF ≤ 35%, advanced hepatic impairment.

- Alert HCP about the need of precautions when using BRINAVESS in haemodynamically stable

patients with congestive heart failure NYHA I and NYHA II and the need to monitor patients with

valvular heart disease closely.,

- Alert HCP for adverse events, which may occur after BRINAVESS administration, including

hypotension, bradycardia, atrial flutter, or ventricular arrhythmia.

14

- Alert HCP for use of AADs (anti-arrhythmic drugs) prior to or after BRINAVESS.

- BRINAVESS can not be recommended in patients previously administered intravenous

AADs (class I and III) 4-24 hours prior to vernakalant, due to lack of data.

- BRINAVESS should be used with caution in patients on oral AADs (class I and III), due to

limited experience. Risk of atrial flutter may be increased in patients receiving class I AADs.,

- Resumption or initiation of oral-maintenance antiarrhythmic therapy can be considered 2

hours after BRINAVESS administration.

- Intravenous rhythm control AADs should be used cautiously in the first 4 hours after

BRINAVESS administration.

4. Instructions on dose calculation, preparation of the solution for infusion, and method of

administration.

5. BRINAVESS may be available in different vial sizes [available vial sizes to be inserted locally].

The number of vials of BRINAVESS concentrate required to prepare the appropriate quantity of

solution for the treatment of an individual patient will depend on the patient’s weight, and the vial

size.

• Other conditions

Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance, as described in version 6 (22nd June

2009) presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and

functioning before and whilst the product is on the market.

Risk Management Plan

The MAH commits to performing the studies and additional pharmacovigilance activities detailed in

the Pharmacovigilance Plan, as agreed in version 1.3 (23 June 2010) of the Risk Management Plan

(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent

updates of the RMP agreed by the CHMP.

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the

updated RMP should be submitted at the same time as the next Periodic Safety Update Report

(PSUR).

In addition, an updated RMP should be submitted:

When new information is received that may impact on the current Safety Specification,

Pharmacovigilance Plan or risk minimisation activities

Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached

At the request of the EMEA .

15

ANNEX III

LABELLING AND PACKAGE LEAFLET

16

A. LABELLING

17

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON FOR THE 10 ML VIAL

1.

NAME OF THE MEDICINAL PRODUCT

BRINAVESS 20 mg/ml concentrate for solution for infusion

vernakalant hydrochloride

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

Each 10 ml vial contains 200 mg vernakalant hydrochloride equivalent to 181 mg vernakalant free

base.

3.

LIST OF EXCIPIENTS

Contains citric acid, sodium chloride, water for injections, sodium hydroxide.

Read the package leaflet before use.

4.

PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion

200 mg/10 ml

1 vial

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use.

Before use, dilute to 4 mg/ml.

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

EXP

Diluted solution: use within 12 hours and store at or below 25°C. Please refer to the leaflet.

9.

SPECIAL STORAGE CONDITIONS

18

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

UK

12. MARKETING AUTHORISATION NUMBER(S)

EU/0/00/000/000

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

19

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON FOR THE 25 ML VIAL

1.

NAME OF THE MEDICINAL PRODUCT

BRINAVESS 20 mg/ml concentrate for solution for infusion

vernakalant hydrochloride

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

Each 25 ml vial contains 500 mg vernakalant hydrochloride equivalent to 452.5 mg vernakalant free

base.

3.

LIST OF EXCIPIENTS

Contains citric acid, sodium chloride, water for injections, sodium hydroxide.

Read the package leaflet before use.

4.

PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion

500 mg/25 ml

1 vial

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use.

Before use, dilute to 4 mg/ml.

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

EXP

Diluted solution: use within 12 hours and store at or below 25°C. Please refer to the leaflet.

9.

SPECIAL STORAGE CONDITIONS

20

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

UK

12. MARKETINGAUTHORISATIONNUMBER(S)

EU/0/00/000/000

13. BATCHNUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATIONINBRAILLE

Justification for not including Braille accepted

21

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Label for the 10 ml Vial

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

BRINAVESS 20 mg/ml sterile concentrate

vernakalant hydrochloride

IV use

2. METHOD OF ADMINISTRATION

Dilute before use.

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

200 mg/10 ml

6. OTHER

22

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Label for the 25 ml vial

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

BRINAVESS 20 mg/ml sterile concentrate

vernakalant hydrochloride

IV use

2. METHOD OF ADMINISTRATION

Dilute before use.

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

500 mg/25 ml

6. OTHER

23

B. PACKAGE LEAFLET

24

PACKAGE LEAFLET: INFORMATION FOR THE USER

BRINAVESS 20 mg/ml concentrate for solution for infusion

vernakalant hydrochloride

Read all of this leaflet carefully before you are given this medicine.

-

If you have any further questions, ask your doctor.

-

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor.

The full name of your medicine is BRINAVESS 20 mg/ml concentrate for solution for infusion. In

this leaflet the shorter name BRINAVESS is used.

In this leaflet :

1.

What BRINAVESS is and what it is used for

3.

How BRINAVESS is given

4.

Possible side effects

5.

How to store BRINAVESS

6.

Further information

1.

WHAT BRINAVESS IS AND WHAT IT IS USED FOR

BRINAVESS contains the active substance vernakalant hydrochloride. BRINAVESS works by

changing your irregular or fast heart beat to a normal heart beat.

In adults it is used if you have a fast, irregular heart beat called atrial fibrillation which has started

recently (≤ 7 days) for non-surgery patients and ≤ 3 days for post-cardiac surgery patients . Your doctor

will decide whether you should be treated with BRINAVESS.

2.

BEFORE YOU ARE GIVEN BRINAVESS

You should not be given BRINAVESS if:

•

you are allergic (hypersensitive) to vernakalant hydrochloride or any of the other ingredients of

BRINAVESS (see section 6)

•

you have had new or worsening chest pain (angina) diagnosed by your doctor as an acute

coronary syndrome in the last 30 days or you have had a heart attack in the last 30 days

•

you have a very narrow heart valve, systolic blood pressure <100 mm Hg or advanced heart

failure with symptoms at minimal exertion or at rest

•

you have an abnormally slow heart rate or skipped heart beats and do not have a pacemaker, or

you have conduction disturbance called QT prolongation - which can be seen on an ECG by

your doctor

•

you have been given certain otherintravenous medicines (anti-arrhythmics Class I and III) used

to normalize an abnormal heart rhythm, 4 hours before BRINAVESS is to be given

You should not be given BRINAVESS if any of the above apply to you. If you are not sure, talk to

your doctor before you are given this medicine.

Take special care with BRINAVESS

Check with your doctor before you are given BRINAVESS if:

•

you have any of the following problems:

-

heart failure

25

-

Keep this leaflet. You may need to read it again.

2.

Before you are given BRINAVESS

-

certain heart diseases involving the heart muscle, lining that surrounds the heart and a

severe narrowing of the heart valves

-

a disease of the heart valves

-

you are taking other rhythm control medicines

If you have very low blood pressure or slow heart rate or certain changes in your ECG while using this

medicine, your doctor may stop your treatment.

Your doctor will consider if you need additional rhythm control medicine 4 hours after BRINAVESS.

BRINAVESS may not work in treating some other kinds of abnormal heart rhythms, however your

doctor will be familiar with these

Tell your doctor if you have a pacemaker.

If any of the above apply to you (or you are not sure), talk to your doctor.

Blood tests

Before giving you this medicine, your doctor will decide whether to test your blood to see how well it

clots and also to see your potassium level.

Use in Children

There is no experience on the use of BRINAVESS in children and adolescents less than 18 years of

age; therefore its use is not recommended.

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including

medicines obtained without a prescription or herbal medicines and natural products.

Pregnancy and breast-feeding

•

Talk to your doctor before having this medicine if you are pregnant or might become pregnant.

This is because it is preferable to avoid the use of BRINAVESS during pregnancy.

•

If you are breast-feeding or planning to breast-feed you should talk to your doctor before you

are given BRINAVESS. This is because it should be used with care as it is not known whether

BRINAVESS passes into the breast milk.

Ask your doctor for advice before taking any medicine, if you are pregnant or breast-feeding.

Driving and using machines

It should be taken into account that some people may get dizzy after receiving BRINAVESS, usually

within the first two hours. (See POSSIBLE SIDE EFFECTS.) If you get dizzy, you should avoid

driving or operating machinery after receiving BRINAVESS.

Important information about some of the ingredients of BRINAVESS

This medicinal product contains approximately 1.4 mmol (32 mg) sodium in each 200 mg vial.

Each vial of 500 mg contains approximately 3.5 mmol (80 mg) of sodium.

Take into consideration if you are on a controlled sodium diet.

3.

HOW BRINAVESS IS GIVEN

•

BRINAVESS will be given to you by a health care professional.

•

It will be given to you into your vein over 10 minutes.

•

The amount of BRINAVESS you may be given will depend on your weight. The recommended

initial dose is 3 mg/kg. While you are being given BRINAVESS, your breathing, heart beat,

blood pressure and the electrical activity of your heart will be checked.

•

If your heart beat has not returned to normal 15 minutes after the end of your first dose, you

may be given a second dose. This will be a slightly lower dose of 2 mg/kg. Total doses of

greater than 5 mg/kg should not be administered within 24 hours.

26

-

liver problems

If you are given more BRINAVESS than you should

If you think that you may have been given too much BRINAVESS, tell your doctor straight away.

If you have any further questions on the use of this medicine, ask your doctor.

4.

POSSIBLE SIDE EFFECTS

The following terms are used to describe how often side effects have been reported.

very common: affects more than 1 user in 10

common: affects 1 to 10 users in 100

uncommon: affects 1 to 10 users in 1,000

Like all medicines, BRINAVESS can cause side effects, although not everybody gets them.

Your doctor may decide to stop the infusion if your doctor observes any abnormal changes of:

• your heart beat

• your blood pressure

• the electrical activity of your heart

Very common side effects seen within 24 hours of being given BRINAVESS include:

• taste disturbances

• sneezing

These effects should pass quickly.

Other side effects include:

Common:

•

numbness or pain at the infusion site, numbness or decreased skin sensation, tingling feelings or

numbness

•

nausea and vomiting

•

feeling hot and tired

•

low blood pressure, slow, fast or irregular heart beat,feeling dizzy

•

headache

•

coughing,dry mouth,sore nose

•

sweating,itching

Uncommon:

•

certain kinds of heart beat problems, (such as a short pause in the normal activity of your heart

or a missed beat;awareness of your heart beating (palpitations))

•

eye irritation or watery eyes or changes in your vision;a change in your sense of smell;pain in

your fingers and toes; a burning feeling; cold sweats; hot flush; itching

•

urgency to have a bowel movement; diarrhoea

•

shortness of breath or a tight chest

•

irritation at the infusion site

•

feeling light-headed or fainting;generally feeling unwell;feeling drowsy or sleepy

•

runny nose; sore throat

•

pale skin

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor.

5.

HOW TO STORE BRINAVESS

Keep out of the reach and sight of children.

27

Do not use BRINAVESS after the expiry date which is stated on the carton and vial after EXP. The

expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

BRINAVESS must be diluted before it is used. The diluted sterile concentrate is chemically and

physically stable for 12 hours at or below 25° C

From a microbiological point of view, the product should be used immediately. If not used

immediately, in-use storage times and conditions prior to use are the responsibility of the user and

would normally not be longer than 24 hours at 2° C to 8 C, unless dilution has taken place in

controlled and validated aseptic conditions.

Do not administer BRINAVESS if you notice particulate matter or discolouration.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

6.

FURTHER INFORMATION

What BRINAVESS contains

•

The active substance is vernakalant hydrochloride. Each ml of concentrate contains 20 mg

vernakalant hydrochloride equivalent to 18.1 mg vernakalant free base.

Each vial of 200 mg vernakalant hydrochloride is equivalent to 181 mg vernakalant free base.

Each vial of 500 mg of vernakalant hydrochloride is equivalent to 452.5 mg of vernakalant free

base.

•

The other ingredients are citric acid, sodium chloride, sodium hydroxide and water for injection.

What BRINAVESS looks like and contents of the pack

BRINAVESS is a concentrate for solution for infusion (sterile concentrate) which is clear and

colourless to pale yellow.

Pack size of 1 vial

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder :

Manufacturer :

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

Merck Sharp & Dohme B. V.

Waarderweg 39, Postbus 581

NL-2003 PC Haarlem

The Netherlands

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder.

BE/LU

Merck Sharp & Dohme B.V. Succursale

belge/Belgisch bijhuis

Tél/Tel: +32 (0) 800 38693

MSDBelgium_info@merck.com

LT

Lietuva UAB “Merck Sharp & Dohme”

Tel.: +370 5 278 02 47

msd_lietuva@merck.com

28

BG

Мерк Шарп и Доум България ЕООД

Тел.: +359 2 819 3740

info-msdbg@merck.com

HU

MSD Magyarország Kft.

Tel.: +361 888 53 00

hungary_msd@merck.com

CS

Merck Sharp & Dohme IDEA, Inc., org. sl.

Tel.: +420 233 010 111

msd_cr@merck.com

MT

Merck Sharp & Dohme Cyprus Limited

Tel: +357 22866700

malta_info@merck.com

DK

Merck Sharp & Dohme

Tlf: +45 43 28 77 66

dkmail@merck.com

NL

Merck Sharp & Dohme BV

Tel: +31 (0) 23 5153153 ms

dbvnl@merck.com

DE

MSD SHARP & DOHME GMBH

Tel: +49 (0) 89 4561 2612

Infocenter@msd.de

NO

MSD (Norge) AS

Tlf: +47 32 20 73 00

msdnorge@msd.no

EE

Merck Sharp & Dohme OÜ

Tel.: +372 613 9750

msdeesti@merck.com

AT

Merck Sharp & Dohme Ges.m.b.H.

Tel: +43 (0) 1 26 044

msd-medizin@merck.com

EL

Ελλάδα MSD ΑΦΒΕΕ

Τηλ: +30 210 98 97 300

cora.greece.gragcm@merck.com

PL

MSD Polska Sp.z o.o.

Tel.: +48 22 549 51 00

msdpolska@merck.com

ES

España Merck Sharp & Dohme de España, S.A.

Tel: +34 91 321 06 00

BRINAVESS@msd.es

PT

Merck Sharp & Dohme, Lda

Tel: +351 21 4465700

informacao_doente@merck.com

FR

France Laboratoires Merck Sharp & Dohme –

Chibret

Tél: +33 (0) 1 47 54 87 00

contact@msd-france.com

RO

Merck Sharp & Dohme Romania S.R.L.

Tel: + 4021 529 29 00

msdromania@merck.com

IE

Merck Sharp and Dohme Ireland (Human Health)

Limited

Tel: +353 (0)1 2998700

medinfo_ireland@merck.com

SI

Merck Sharp & Dohme, inovativna zdravila d.o.o.

Tel: + 386 1 5204201

msd_slovenia@merck.com

ÍS

Icepharma hf. Sími

+354 540 8000

ISmail@merck.com

SK

Merck Sharp & Dohme IDEA, Inc.

Tel.: +421 2 58282010

msd_sk@merck.com

29

IT

Merck Sharp & Dohme (Italia) S.p.A.

Tel: +39 06 361911

doccen@merck.com

FI

MSD Finland Oy

Puh/Tel: +358 (0) 9 804650

info@msd.fi

CY

Κύπρος Merck Sharp & Dohme Cyprus Limited

Τηλ: +357 22866700

cyprus _ info @ merck . com

SE

Merck Sharp & Dohme (Sweden) AB

Tel: +46 (0) 8 626 1400

medicinskinfo@merck.com

LV

Latvija SIA “Merck Sharp & Dohme Latvija”

Tel: +371 67364 224

msd_lv@merck.com

UK

Merck Sharp and Dohme Limited

Tel: +44 (0) 1992 467272

medinfo_uk@merck.com

This leaflet was last approved in {MM/YYYY} .

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu/.

The following information is intended for medical or healthcare professionals only:

Please refer to the Summary of Product Characteristics and the educational material for additional

information prior to the use of BRINAVESS

4. CLINICAL PARTICULARS

4.1 Therapeuticindications

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

4.2 Posology and method of administration

BRINAVESS should be administered by intravenous infusion, by qualified medical personnel in a

monitored clinical setting appropriate for cardioversion.

Posology

BRINAVESS is dosed by patient body weight, with a maximum calculated dose based upon 113 kgs.

The recommended initial infusion is 3 mg/kg to be infused over a 10 minute period. For patients

weighing ≥ 113 kg, do not exceed the maximum initial dose of 339 mg (84.7 ml of 4 mg/ml solution).

If conversion to sinus rhythm does not occur within 15 minutes after the end of the initial infusion, a

second 10 minute infusion of 2 mg/kg may be administered. For patients weighing ≥ 113 kg, do not

exceed the maximum second infusion of 226 mg (56.5 ml of 4 mg/ml solution) .Cumulative doses of

greater than 5 mg/kg should not be administered within 24 hours. There are no clinical data on repeat

doses after the initial and second infusions. By 24 hours there appears to be insignificant levels of

vernakalant.

If conversion to sinus rhythm occurs during either the initial or second infusion, that infusion should

be continued to completion. If haemodynamically stable atrial flutter is observed after the initial

infusion, the second infusion of BRINAVESS may be administered as patients may convert to sinus

rhythm. (See sections 4.4 and 4.8.)

30

An infusion pump is the preferred delivery device. However, a syringe pump is acceptable provided

that the calculated volume can be accurately given within the specified infusion time.

Do not administer as an intravenous push or bolus.

Recommended diluents are 0.9% Sodium Chloride for Injection, Lactated Ringers for Injection, or 5%

Glucose for Injection.

Read all steps before administration.

Preparation of BRINAVESS for infusion

Step 1: Visually inspect BRINAVESS vials for particulate matter and discolouration before

administration. Do not use any vials exhibiting particulate matter or discolouration. Note:

BRINAVESS concentrate for solution for infusion ranges from colourless to pale yellow. Variations

of colour within this range do not affect potency.

Step 2: Dilution of concentrate

To ensure proper administration, a sufficient amount of BRINAVESS 20 mg/ml should be prepared at

the outset of therapy to deliver the initial and second infusion should it be warranted.

Create a solution with a concentration of 4 mg/ml following the dilution guidelines below:

Patients ≤ 100 kg: 25 ml of BRINAVESS 20 mg/ml is added to 100 ml of diluent.

Patients > 100 kg: 30 ml of BRINAVESS 20 mg/ml is added to 120 ml of diluent.

Step 3: Inspect solution

The diluted sterile solution should be clear, colourless to pale yellow. Visually re-inspect the solution

for particulate matter and discolouration before administering.

Method of administration

BRINAVESS vials are for single use only and must be diluted prior to administration.

Step 4: Administration of the initial infusion

The initial infusion of BRINAVESS is administered as a 3 mg/kg dose over 10 minutes.

Step 5: Patient observation

If conversion to sinus rhythm has not occurred, observe the patient’s vital signs and cardiac rhythm for

an additional 15 minutes.

Step 6: Administration of second infusion

If conversion to sinus rhythm did not occur with the initial infusion or within the 15 minute

observation period, administer a 2 mg/kg second infusion over 10 minutes.

Cumulative doses above 565 mg have not been evaluated.

Post-cardiac surgery patients :

No dose adjustment necessary.

Renal impairment:

No dose adjustment necessary (see section 5.2).

Hepatic impairment:

No dose adjustment necessary (see sections 4.4 and 5.2).

Elderly (≥ 65 years) :

No dose adjustment necessary.

Paediatric population :

There is no relevant use of BRINAVESS in children and adolescents < 18 years of age in the current

indication and therefore should not be used in this population.

31

4.3 Contraindications

•

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

•

Patients with severe aortic stenosis, patients with systolic blood pressure < 100 mm Hg, and