MSD Ireland (Human Health) Limited

BRINAVESS 20 mg/ml, concentrate for solution for infusion

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.

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

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

BRINAVESS should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion. Only a well-qualified healthcare professional should administer BRINAVESS and should frequently monitor the patient for the duration of the infusion and for at least 15 minutes after the completion of the infusion for signs and symptoms of a sudden decrease in blood pressure or heart rate (see section 4.4).

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.)

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. During this period, the patient should be carefully monitored for any signs or symptoms of a sudden decrease in blood pressure or heart rate. If such signs develop, with or without symptomatic hypotension or bradycardia, the infusion should be stopped immediately.

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.

• 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 antiarrhythmics (class I and class III) within 4 hours prior to, as well as in the first 4 hours after, BRINAVESS administration.

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

Cases of serious hypotension have been reported during and immediately following BRINAVESS infusion. Patients should be carefully observed for the entire duration of the infusion and for at least 15 minutes after completion of the infusion with assessment of vital signs and continuous cardiac rhythm monitoring.

If any of the following signs or symptoms occurs, the administration of BRINAVESS should be discontinued and these patients should receive appropriate medical management:

• A sudden drop in blood pressure or heart rate, with or without symptomatic hypotension or bradycardia

• Hypotension

• Bradycardia

• 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)

If these events occur during the first infusion of BRINAVESS, patients should not receive the second dose of BRINAVESS.

The patient should be further monitored for 2 hrs after the start of infusion and 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.

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. Uncommonly, cases of severe hypotension have been observed. Patients with congestive heart failure (CHF) have been identified as a population at higher risk for hypotension. (See section 4.8.)

The patient is required to be monitored for signs and symptoms of a sudden decrease in blood pressure or heart rate for the duration of the infusion and for at least 15 minutes after the completion of the infusion.

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.

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 (antiarrhythmic 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 antiarrhythmics (class I and class III) in the first 4 hours after BRINAVESS administration, therefore these agents should not be used within this period (see section 4.3).

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.

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.

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.

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).

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.

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:

* The adverse reactions included in the table occurred within 24 hours of administration of BRINAVESS (see sections 4.2 and 5.2)

**Estimated frequency including event observed in an ongoing clinical trial

***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.

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.

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.

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

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.

†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.

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).

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.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, single- and repeated-dose toxicity, and genotoxicity.

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.

Citric acid E330

Sodium chloride

Water for injection

Sodium hydroxide E524 (for pH-adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned in section 4.2.

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.

This medicinal product does not require any special storage conditions.

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

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.

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.

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

EU/1/10/645/001

EU/1/10/645/002

Date of first authorisation: 1 September 2010

26 March 2012

<Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/>