Brinavess

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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. 
 
Each 10 ml vial contains 200 mg of vernakalant hydrochloride equivalent to 181 mg of vernakalant. 
Each 25 ml vial contains 500 mg of vernakalant hydrochloride equivalent to 452.5 mg of vernakalant. 
 
After dilution the concentration of the solution is 4 mg/ml vernakalant hydrochloride. 
 
Excipient with known effect 
 
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) sodium. 
 
Each ml 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 (5 % glucose solution for injection) or 3.2 mg sodium 
(Lactated Ringers solution for injection). 
 
For the 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  
 
Brinavess is indicated in adults for rapid conversion of recent onset atrial fibrillation to sinus rhythm  
-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 
 
Vernakalant should be administered in a monitored clinical setting appropriate for cardioversion. Only 
a well-qualified healthcare professional should administer it.  
 
Posology 
 
Vernakalant is dosed by patient body weight, with a maximum calculated dose based upon 113 kg. 
The recommended initial infusion is 3 mg/kg to be infused over a 10-minute period with a 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 (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. 



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The initial infusion 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. 
 
If conversion to sinus rhythm has not occurred, the patient’s vital signs and cardiac rhythm should be 
observed for an additional 15 minutes. 
 
If conversion to sinus rhythm did not occur with the initial infusion or within the 15-minute 
observation period, a 2 mg/kg second infusion should be administered over 10 minutes. 
 
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 may be administered as patients may convert to sinus rhythm (see 
sections 4.4 and 4.8). 
 
Patients with body weight > 113 kg 
For patients above 113 kg, vernakalant has a fixed dose. The initial dose is 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 226 mg (56.5 ml of 4 mg/ml solution) may be 
administered. Cumulative doses above 565 mg have not been evaluated. 
 
Post-cardiac surgery  
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 vernakalant in children and adolescents < 18 years of age for rapid 
conversion of recent onset atrial fibrillation to sinus rhythm and therefore it should not be used in this 
population. 
 
Method of administration 
 
For intravenous use. 
 
Vernakalant should not be administered as an intravenous push or bolus. 
 
The vials are for single use only and must be diluted prior to administration. 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications  
 
• Hypersensitivity to the active substance or to any of the excipients listed in 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 ms), or severe bradycardia, sinus 

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



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• 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, vernakalant administration. 

• Acute coronary syndrome (including myocardial infarction) within the last 30 days. 
 
4.4 Special warnings and precautions for use  
 
Patient monitoring  
 
Cases of serious hypotension have been reported during and immediately following vernakalant 
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 vernakalant 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 vernakalant, patients should not receive the second 
dose. 
 
The patient should be further monitored for 2 hrs after the start of infusion and until clinical and ECG 
parameters have stabilised. 
 
Precautions before infusion 
 
Prior to attempting pharmacological cardioversion, patients should be adequately hydrated and 
haemodynamically optimised and if necessary patients should be anticoagulated in accordance with 
treatment guidelines. In patients with uncorrected hypokalaemia (serum potassium of less than 
3.5 mmol/l), potassium levels should be corrected prior to use of vernakalant. 
 
A pre-infusion checklist is provided with the medicinal product. Prior to administration the prescriber 
is asked to determine eligibility of the patient through use of the supplied checklist. The checklist 
should be placed on the infusion container to be read by the healthcare professional who will 
administer it. 
 
Hypotension  
 
Hypotension can occur in a small number of patients (vernakalant 5.7 %, placebo 5.5 % in the first 
2 hours post-dose). 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  
 



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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 (13.4 % 
versus 4.7 %, respectively). Hypotension reported as a serious adverse experience or leading to 
medicinal product discontinuation occurred in CHF patients following exposure to vernakalant in 
1.8 % of these patients compared to 0.3 % in placebo. 
 
Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first two 
hours post dose (6.4% for vernakalant compared to 1.6% in placebo). These arrhythmias typically 
presented as asymptomatic, monomorphic, non-sustained (average 3-4 beats) ventricular tachycardias.  
 
Due to the higher incidence of the adverse reactions 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).  
 
Valvular heart disease 
 
In patients with valvular heart disease, there was a higher incidence of ventricular arrhythmia events in 
vernakalant patients until 24 hours after dosing. Within the first 2 hours, ventricular arrhythmia 
occurred in 6.4 % of patients treated with vernakalant versus none after placebo. These patients should 
be monitored closely. 
 
Atrial flutter  
 
Vernakalant was not found to be effective in converting typical primary atrial flutter to sinus rhythm. 
Patients receiving vernakalant 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). In post-marketing experience rare cases of atrial flutter with 1:1 atrioventricular 
conduction are observed. 
 
Other diseases and conditions not studied 
 
Vernakalant has been administered to patients with an uncorrected QT less than 440 ms without an 
increased risk of torsade de pointes.  
 
Furthermore, it has not been evaluated in patients with clinically meaningful valvular stenosis, 
hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis and 
its use cannot be recommended in such cases. There is limited experience with vernakalant in patients 
with pacemakers. 
 
As the clinical trial experience in patients with advanced hepatic impairment is limited, vernakalant is 
not recommended in these patients. 
 
There are no clinical data on repeat doses after the initial and second infusions. 
 
Electrical cardioversion 
 
Direct-current cardioversion may be considered for patients who do not respond to therapy. There is 
no clinical experience with direct-current cardioversion under 2 hours post-dose. 
 
Use of AADs (antiarrhythmic drugs) prior to or after vernakalant 
 
Vernakalant cannot be recommended in patients previously administered intravenous AADs (class I 
and III) 4-24 hours prior to vernakalant due to lack of data. It must not be administered in patients who 
received intravenous AADs (class I and III) within 4 hours prior to vernakalant (see section 4.3). 



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Vernakalant 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 vernakalant administration, therefore these agents must 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. 
 
Sodium content 
 
This medicinal product contains 32 mg sodium per 200 mg vial, equivalent to 1.6 % of the WHO 
recommended maximum daily intake of 2 g sodium for an adult.  
This medicinal product contains 80 mg sodium per 500 mg vial, equivalent to 4 % of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed.  
 
Vernakalant must not be administered in patients who received intravenous AADs (class I and III) 
within 4 hours prior to vernakalant (see section 4.3). 
 
Within the clinical development program, oral maintenance antiarrhythmic therapy was halted for a 
minimum of 2 hours after vernakalant 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. Studies in animal 
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  
 



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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 newborns/infants cannot be 
excluded.  
Caution should be exercised when used in breast-feeding women.  
 
Fertility 
 
Vernakalant was not shown to alter fertility in animal studies. 
 
4.7 Effects on ability to drive and use machines  
 
Vernakalant has minor to moderate influence on the ability to drive and use machines. Dizziness has 
been reported within the first 2 hours after receiving it (see section 4.8). 
 
4.8 Undesirable effects  
 
Summary of the safety profile 
 
The most commonly reported adverse reactions (> 5 %) seen in the first 24 hours after receiving 
vernakalant were dysgeusia (taste disturbance) (17.9 %), sneezing (12.5 %), and paraesthesia (6.9 %). 
These reactions occurred around the time of infusion, were transient and were rarely treatment limiting. 
 
Tabulated list of adverse reactions 
 
The adverse reaction profile presented below is based on the analysis of pooled clinical trials, a 
post-authorisation safety study and spontaneous reporting. 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). 
 
Table 1: Adverse reactions a 

Nervous system 
disorders  

Very common: Dysgeusia  
 
Common: Paraesthesia; dizziness 
 
Uncommon: Hypoaesthesia; burning sensation; parosmia; syncope; 
somnolence  

Eye disorders  Uncommon: Lacrimation increased; eye irritation; visual impairment 

Cardiac disorders  Common: Bradycardia b; atrial flutter b 
 
Uncommon: Sinus arrest; ventricular tachycardia; palpitations; bundle 
branch block left; ventricular extrasystoles; AV block first degree; AV 
block complete; bundle branch block right; sinus bradycardia; ECG 
QRS complex prolonged; cardiogenic shock, blood pressure diastolic 
increased 
 
Rare: Atrial flutter with 1:1 atrioventricular conduction b, c 

Vascular disorders  Common: Hypotension  
 
Uncommon: Flushing; hot flush; pallor  



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Respiratory, thoracic and 
mediastinal disorders  

Very common: Sneezing  
 
Common: Cough; nasal discomfort 
 
Uncommon: Dyspnoea; throat irritation; oropharyngeal pain; nasal 
congestion; suffocation feeling; choking sensation; rhinorrhoea 

Gastrointestinal disorders  Common: Nausea; paraesthesia oral; vomiting 
 
Uncommon: Dry mouth; diarrhoea; hypoaesthesia oral; defecation 
urgency  

Skin and subcutaneous 
tissue disorders  

Common: Pruritus; hyperhidrosis  
 
Uncommon: Pruritus generalised; cold sweat 

Musculoskeletal and 
connective tissue 
disorders  

Uncommon: Pain in extremity  
 

General disorders and 
administration site 
conditions  

Common: Infusion site pain; feeling hot; infusion site paraesthesia 
 
Uncommon: Fatigue; infusion site irritation; infusion site 
hypersensitivity; infusion site pruritus; malaise 

a The adverse reactions included in the table occurred within 24 hours of administration of vernakalant 
(see sections 4.2 and 5.2) with an incidence > 0.1 % of vernakalant patients and higher than placebo 
b See subheadings atrial flutter and bradycardia below 
c Identified in post-marketing experience 
 
Description of selected adverse reactions 
 
Clinically significant adverse reactions observed in clinical trials included hypotension and ventricular 
arrhythmia (see section 4.4). 
 
Bradycardia 
Bradycardia was observed predominantly at the time of conversion to sinus rhythm. With a 
significantly higher conversion rate in patients treated with vernakalant, the incidence of bradycardia 
events was higher within the first 2 hours in vernakalant treated patients than in placebo-treated 
patients (1.6 % versus 0 %, respectively). Of the patients who did not convert to sinus rhythm, the 
incidence of bradycardia events in the first 2 hours post-dose was similar in placebo and vernakalant 
treated groups (4.0% and 3.8%, respectively). In general, bradycardia responded well to 
discontinuation of treatment and/or administration of atropine. 
 
Atrial flutter 
Atrial fibrillation patients receiving vernakalant have a higher incidence of converting to atrial flutter 
within the first 2 hours post-dose (1.2 % versus 0 % in placebo). With continuation of the 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 vernakalant did not develop 1:1 atrioventricular 
conduction. However, in post-marketing experience rare cases of atrial flutter with 1:1 atrioventricular 
conduction are observed. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 



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professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
One patient who received 3 mg/kg of vernakalant 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 medicinal product 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 regulated by ion channels 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. 
 
Pharmacodynamic effects 
 
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 medicinal product 
toward rapidly activating and partially depolarised atrial tissue rather than toward the normally 
polarised 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 ms and 18.8 ms placebo-subtracted peaks after first and second infusions, respectively). By 
90 minutes after the start of infusion, this difference was reduced to 8.1 ms. 
 
Clinical efficacy and safety 
 
Clinical Trial Design: The clinical effect of vernakalant 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 vernakalant 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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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 vernakalant 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 vernakalant 
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 vernakalant 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 2 possible dose steps. In the performed clinical studies, the 
additive effect of the second dose, if any, cannot be independently established. 
 
Table 2: Conversion of atrial fibrillation to sinus rhythm in ACT I and ACT III 
Duration of 
Atrial 
Fibrillation 

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 
 
Vernakalant 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 medicinal products, use of antiarrhythmic medicinal products, use of warfarin, history of 
ischaemic heart disease, renal impairment or expression of the cytochrome P450 2D6 enzyme. 
 
Treatment with vernakalant 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 medicinal product 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 vernakalant 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 vernakalant effectively converted atrial 



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fibrillation to sinus rhythm (47.0 % vernakalant, 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).  
 
Efficacy from Post-Marketing Observational Study 
In the post-approval safety study SPECTRUM that included 1,778 patients with 2,009 BRINAVESS 
treatment episodes, effectiveness was assessed as the proportion of patients who converted to sinus 
rhythm for at least one (1) minute within 90 minutes from the start of the infusion, excluding patients 
who received electrical cardioversion or intravenous Class I/III antiarrhythmics for cardioversion 
within the 90-minute window. Overall, BRINAVESS was effective in 70.2% (1,359/1,936) of these 
patients. Median time to conversion to SR as reported among all patients who, as per the investigator 
judgement, converted to SR was 12 minutes and in most of the treatment episodes (60.4%) only one 
infusion was administered. The higher cardioversion rate in SPECTRUM as compared to clinical 
phase 3 studies (70.2% vs 47% to 51%) is correlated with a shorter duration of the duration of the 
index atrial fibrillation period (median duration of 11.1 hours in SPECTRUM vs 17.7 to 28.2 hours in 
clinical studies). 
 
If patients who received electrical cardioversion, intravenous antiarrhythmics or oral 
propafenone/flecainide within 90 minutes from the start of the infusion are regarded as treatment 
failures in addition to patients who did not convert for one minute within 90 minutes, the conversion 
rate among the 2,009 patients who received BRINAVESS was 67.3 % (1,352/2,009). There was no 
meaningful difference when stratifying the analysis by therapeutic indication (i.e. non-surgery and 
post-cardiac surgery patients). 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
vernakalant 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.  
 



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Elimination 
 
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. By 24 hours there appears to be insignificant levels of vernakalant. 
 
Special patient groups 
 
Acute vernakalant pharmacokinetics is not significantly influenced by gender, history of congestive 
heart failure, renal impairment, or concomitant administration of beta blockers and other medicinal 
products, including warfarin, metoprolol, furosemide and digoxin. In patients with hepatic impairment, 
exposures were elevated by 9 to 25 %. No dose adjustment 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 reveal 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, embryo-foetal 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 embryo-foetal 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 embryo-foetal lethality, increased number of foetuses 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 injections  
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 6.6. 
 
6.3 Shelf life  
 
5 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 medicinal 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. 
 



13 
 

6.4 Special precautions for storage  
 
This medicinal product does not require any special storage conditions.  
 
For storage conditions after dilution of the 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 10 ml or 25 ml of concentrate.  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Read all steps before administration. 
 
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. 
 
Preparation of BRINAVESS for infusion 
 
Step 1:  
BRINAVESS vials should be visually inspected for particulate matter and discolouration before 
administration. Any vials exhibiting particulate matter or discolouration should not be used.  
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. 
 
Recommended diluents are sodium chloride 9 mg/ml (0.9 %) solution for injection, Lactated Ringers 
solution for injection, or 5 % glucose solution for injection. 
 
Step 3: Inspection of the solution 
The diluted sterile solution should be clear, colourless to pale yellow. The solution should be visually 
re-inspected for particulate matter and discolouration before administering. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER  
 
Correvio  
15 rue du Bicentenaire 
92800 Puteaux 
France  
 
 



14 
 

8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/10/645/001 
EU/1/10/645/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
 
Date of first authorisation: 01 September 2010 
Date of latest renewal: 06 September 2015 
 
 
10. DATE OF REVISION OF THE TEXT  
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  

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


15 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



16 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Geodis Logistics Netherlands B.V. 
Columbusweg 16 
5928 LC Venlo 
The Netherlands  
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 
• Additional risk minimisation measures 
 
The Marketing Authorisation Holder shall provide a check list in each pack, the text of which is 
included in Annex IIIA. The company will start to include the pre-infusion check list in packs packed 
at the packaging site as soon as possible but at the latest on 15 November 2012. The check list will be 
provided with an adhesive in order to be placed on the infusion container. 
 
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 



17 
 

 
The Marketing Authorisation Holder must agree about the content and format of the educational 
material, together with a communication plan, with the national competent authority prior to 
distribution. 
 
Key elements to be included in the educational material: 
 
1. 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). 
 
2. Appropriate measures to manage and minimise 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: 

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• Patients with prolonged QT at baseline (uncorrected > 440 ms), 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 
• 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 reactions, which may occur after BRINAVESS administration, including 
hypotension, bradycardia, atrial flutter, or ventricular arrhythmia. 

- Alert HCP for use of antiarrhythmic drugs (AADs) prior to or after BRINAVESS. 
• BRINAVESS cannot 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 not be used 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.  



18 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



19 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



20 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
BRINAVESS 20 mg/ml concentrate for solution for infusion 
vernakalant hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each vial contains 200 mg vernakalant hydrochloride equivalent to 181 mg vernakalant. 
Each vial contains 500 mg vernakalant hydrochloride equivalent to 452.5 mg vernakalant. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains citric acid, sodium chloride, water for injections, sodium hydroxide (E524). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
1 vial  
200 mg/10 ml 
 
1 vial 
500 mg/25 ml 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Read the package leaflet before use.  
For intravenous use after dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNINGS, IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Diluted solution: use within 12 hours and store at or below 25 °C.  
 
 
 



21 
 

9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
Correvio  
15 rue du Bicentenaire 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
10 mL: 
EU/1/10/645/001 
 
25 mL: 
EU/1/10/645/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



22 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
BRINAVESS 20 mg/ml sterile concentrate 
vernakalant hydrochloride 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
Dilute before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 mL: 
200 mg/10 ml 
 
25 mL: 
500 mg/25 mL 
 
 
6. OTHER 
 
 



23 
 

 PARTICULARS TO APPEAR WITHIN THE OUTER PACKAGING (CARTON) 
 
PRE-INFUSION CHECK-LIST 
 
 

Important Instructions when using BRINAVESS 
 
Prior to administration the prescriber is asked to determine eligibility of the patient through use 
of the supplied checklist. The checklist should be placed on the infusion container to be read by 
the healthcare professional who will administer BRINAVESS. 
 
BRINAVESS should be administered in a monitored clinical setting appropriate for cardioversion by a 
well-qualified healthcare professional. Patients should be frequently monitored 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. 
 
Read carefully the Summary of Product Characteristics and the Health Care Professional 
Information Card prior to the administration of BRINAVESS 
 
BRINAVESS must NOT be given to any patients with a “YES” response below: 
Does the patient have heart failure class NYHA III or NYHA IV? YES  NO 
Has the patient presented with an acute coronary syndrome (including myocardial infarction) in the 
last 30 days? YES  NO 
Does the patient have severe aortic stenosis? YES  NO 
Does the patient have a systolic blood pressure < 100 mm Hg? YES  NO 
Does the patient have prolonged QT interval at baseline (uncorrected > 440 ms)? YES  NO 
Does the patient have severe bradycardia, sinus node dysfunction or second and third degree heart 
block, in the absence of a pacemaker? YES  NO 
Has the patient received an intravenous rhythm control antiarrhythmic drug (class I and/or class III) 
within 4 hours of the time when BRINAVESS will be infused? YES  NO 
Does the patient have hypersensitivity to the active substance or to any of the excipients? YES  NO 
 
Do NOT give other IV antiarrhythmic medicines (class I and/or class III) for at least 4 hours 
after infusion of BRINAVESS. 
When giving BRINAVESS, follow these instructions: 
• The patient should be adequately hydrated and haemodynamically optimised and adequately 

anticoagulated (if necessary) prior to administering BRINAVESS 
• Observe the patient frequently and carefully for the entire duration of the infusion and for at 

least 15 minutes after completion of the infusion for: 
o Any signs or symptoms of a sudden decrease in blood pressure or heart rate, with or 

without symptomatic hypotension or bradycardia 
o Bradycardia  
o Hypotension 
o Unexpected ECG changes (see SmPC) 
If such signs develop, discontinue BRINAVESS immediately and provide appropriate medical 
management. Do not re-start BRINAVESS. 
 

• Continue to monitor the patient for 2 hrs after the start of infusion and until clinical and ECG 
parameters have stabilised. 

 
  



24 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



25 
 

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 start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What BRINAVESS is and what it is used for 
2. What you need to know before you use BRINAVESS 
3. How to use BRINAVESS  
4. Possible side effects 
5. How to store BRINAVESS 
6. Contents of the pack and other 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, less than or equivalent to 7 days, for non-surgery patients and less than or equivalent 
to 3 days for post-cardiac surgery patients.  
 
 
2. What you need to know before you use BRINAVESS 
 
Do not use BRINAVESS 
• if you are allergic to vernakalant hydrochloride or any of the other ingredients of this medicine 

(listed in section 6) 
• if 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  
• if you have a very narrow heart valve, systolic blood pressure less than 100 mm Hg or advanced 

heart failure with symptoms at minimal exertion or at rest 
• if 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 

• if you take certain other intravenous medicines (antiarrhythmics Class I and III) used to 
normalise an abnormal heart rhythm, 4 hours before BRINAVESS is to be used 

 
You must not use BRINAVESS if any of the above apply to you. If you are not sure, talk to your 
doctor before you use this medicine. 
 
Warnings and precautions 
Talk to your doctor before using BRINAVESS if you have: 
• heart failure  
• certain heart diseases involving the heart muscle, lining that surrounds the heart and a severe 

narrowing of the heart valves 



26 
 

• a disease of the heart valves 
• liver problems 
• 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 will stop your treatment. 
Your doctor will consider if you need additional rhythm control medicine 4 hours after using 
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. Detailed information on 
warnings and precautions relating to side effects that could occur are presented in section 4.  
 
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.  
 
Children and adolescents 
Do not give this medicine to children and adolescents less than 18 years of age because there is no 
experience on its use in this population.  
 
Other medicines and BRINAVESS 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Do not use BRINAVESS if you take certain other intravenous medicines (antiarrhythmics Class I and 
III) used to normalise an abnormal heart rhythm, 4 hours before BRINAVESS is to be used. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. 
  
It is preferable to avoid the use of BRINAVESS during pregnancy. 
It is not known whether BRINAVESS passes into the breast milk. 
 
Driving and using machines 
It should be taken into account that some people may get dizzy after receiving BRINAVESS, usually 
within the first 2 hours (see section “Possible side effects”). If you get dizzy, you should avoid driving 
or operating machinery after receiving BRINAVESS. 
 
BRINAVESS contains sodium 
This medicine contains 32 mg sodium (main component of cooking/table salt) in each 200 mg vial. 
This is equivalent to 1.6 % of the recommended maximum daily dietary intake of sodium for an adult. 
This medicine contains 80 mg of sodium (main component of cooking/table salt) in each vial of 
500 mg. This is equivalent to 4 % of the recommended maximum daily dietary intake of sodium for an 
adult. 
 
 
3. How to use BRINAVESS  
 
The amount of BRINAVESS you may be given will depend on your weight. The recommended initial 
dose is 3 mg/kg, with a maximum calculated dose based upon 113 kg. If you weigh more than 113 kg, 
you will receive a fixed dose of 339 mg. While you are being given BRINAVESS, your breathing, 
heart beat, blood pressure and the electrical activity of your heart will be checked.  
 



27 
 

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, with a maximum calculated dose 
based upon 113 kg. If you weigh more than 113 kg, you will receive a fixed dose of 226 mg. Total 
doses of greater than 5 mg/kg should not be administered within 24 hours. 
 
BRINAVESS will be given to you by a health care professional. BRINAVESS will be diluted before 
being given to you. Information on how to prepare the solution is available at the end of this leaflet. 
 
It will be given to you into your vein over 10 minutes. 
 
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 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Your doctor may decide to stop the infusion if he observes any of the following abnormal changes of: 
• your heart beat (such as a very fast (uncommon) or very slow heart beat (common), a missed 

beat (uncommon), or a short pause in the normal activity of your heart (uncommon)) 
• your blood pressure (such as a very low blood pressure causing a serious heart condition) 

(uncommon) 
• the electrical activity of your heart (uncommon) 
 
Other side effects: 
  
Very common (may affect more than 1 in 10 people)  
• taste disturbances  
• sneezing 
 
Common (may affect up to 1 in 10 people) 
• fast heart beat 
• pain or numbness at the infusion site, numbness, decreased skin sensation, or tingling feelings  
• nausea and vomiting  
• feeling hot 
• low blood pressure, slow heart beat, feeling dizzy 
• coughing, sore nose 
• excessive sweating, itching 
• numbness or tingling that occurs in the mucosa or tissues of the oral cavity 
 
Uncommon (may affect up to 1 in 100 people) 
• certain kinds of heart beat problems, (such as an awareness of your heart beating (palpitations) 

or an extra heart beat) 
• decreased feeling or sensitivity  
• eye irritation, 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 
• urgency to have a bowel movement, diarrhoea 
• shortness of breath or a tightness in the chest 
• choking sensation 
• pain in your mouth or throat 



28 
 

• irritation, itching at the infusion site  
• high blood pressure 
• feeling light-headed or fainting, generally feeling unwell, feeling drowsy or sleepy 
• runny nose, sore throat 
• stuffy nose 
• dry mouth 
• pale skin 
• generalised itching 
• fatigue 
• decreased feeling or sensitivity of the mouth 
 
These effects, seen within 24 hours of being given BRINAVESS, should pass quickly, however, if 
they do not you should consult your doctor. 
 
Reporting of side effects  
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store BRINAVESS 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP. 
The expiry date refers to the last day of that month. 
 
This medicine 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 medicineshould 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 use this medicine if you notice particulate matter or discolouration. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other 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. 
Each vial of 200 mg vernakalant hydrochloride is equivalent to 181 mg vernakalant.  
Each vial of 500 mg of vernakalant hydrochloride is equivalent to 452.5 mg of vernakalant. 

• The other ingredients are citric acid, sodium chloride, sodium hydroxide (E524) and water for 
injections (see section 2 “ BRINAVESS contains sodium”). 

 
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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


29 
 

 
BRINAVESS is available in pack of 1 vial containing 200 mg or 500 mg of vernakalant 
hydrochloride.  
 
Marketing Authorisation Holder: 
Correvio  
15 rue du Bicentenaire 
92800 Puteaux 
France  

Manufacturer: 
Geodis Logistics Netherlands B.V. 
Columbusweg 16 
5928 LC Venlo 
The Netherlands 

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

België/Belgique/Belgien 
Correvio 
Tél/Tel: +32 28 08 86 20 
 

Lietuva 
Correvio 
Tel: +41 848 00 79 70 
 

България 
Correvio 
Тел.: +41 848 00 79 70 
 

Luxembourg/Luxemburg 
Correvio 
Tél/Tel: +41 848 00 79 70 
 

Česká republika 
Correvio 
Tel: +41 848 00 79 70 
 

Magyarország 
Correvio 
Tel.: +41 848 00 79 70 
 

Danmark 
Correvio 
Tlf: +45 8082 6022 
 

Malta 
Correvio 
Tel: +41 848 00 79 70 
 

Deutschland 
Correvio 
Tel: +49 69 33 29 62 76 

Nederland 
Correvio 
Tel: +31 20 808 32 06 
 

Eesti 
Correvio 
Tel: +41 848 00 79 70 
 

Norge 
Correvio 
Tlf: +41 848 00 79 70 

Ελλάδα 
Correvio 
Τηλ: +41 848 00 79 70 

Österreich 
Correvio 
Tel: +41 848 00 79 70 
 

España 
Correvio 
Tel: + 34 93 179 05 36 
 

Polska 
Correvio 
Tel: +41 848 00 79 70 
 

France 
Correvio 
Tél: +33 1 77 68 89 17 
 

Portugal 
Correvio 
Tel: +41 848 00 79 70 
 

Hrvatska 
Correvio 
Tel: +41 848 00 79 70 
 
Ireland 
Correvio 
Tel: +41 848 00 79 70 

România 
Correvio 
Tel: +41 848 00 79 70 
 
Slovenija 
Correvio 
Tel: +41 848 00 79 70 
 



30 
 

Ísland 
Correvio 
Sími: +41 848 00 79 70 
 

Slovenská republika 
Correvio 
Tel: +41 848 00 79 70 
 

Italia 
Correvio 
Tel: +39 02 600 63037 
 

Suomi/Finland 
Correvio 
Puh/Tel: +41 848 00 79 70 
 

Κύπρος 
Correvio 
Τηλ: +41 848 00 79 70 
 

Sverige 
Correvio 
Tel: +46 8 408 38440 
 

Latvija 
Correvio 
Tel: +41 848 00 79 70 
 

United Kingdom 
Correvio 
Tel: +44 203 002 8114 
 

   
This leaflet was last revised in  
 
Other sources of information  
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 healthcare professionals only: 
 
Please refer to the Summary of Product Characteristics and the educational material for additional 
information prior to the use of BRINAVESS 
 
CLINICAL PARTICULARS  
 
Therapeutic indications  
 
Brinavess is indicated in adults for rapid conversion of recent onset atrial fibrillation to sinus rhythm   
-For non-surgery patients: atrial fibrillation ≤ 7 days duration 
-For post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration 
 
Posology and method of administration 
 
Vernakalant should be administered in a monitored clinical setting appropriate for cardioversion. Only 
a well-qualified healthcare professional should administer it.  
 
Posology 
 
Vernakalant is dosed by patient body weight, with a maximum calculated dose based upon 113 kg.  
The recommended initial infusion is 3 mg/kg to be infused over a 10-minute period with a 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 (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.  
  
The initial infusion 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. 
 

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


31 
 

If conversion to sinus rhythm has not occurred, the patient’s vital signs and cardiac rhythm should be 
observed for an additional 15 minutes. 
 
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. 
 
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 may be administered as patients may convert to sinus rhythm (see 
“Special warnings and precautions for use” and “Undesirable effects”). 
 
Patients with body weight > 113 kg 
For patients above 113 kg, vernakalant has a fixed dose. The initial dose is 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 226 mg (56.5 ml of 4 mg/ml solution) may be 
administered. Cumulative doses above 565 mg have not been evaluated. 
 
Post-cardiac surgery 
No dose adjustment necessary. 
 
Renal impairment 
No dose adjustment necessary (see “Pharmacokinetic properties”).  
 
Hepatic impairment 
No dose adjustment necessary (see “Special warnings and precautions for use” and “Pharmacokinetic 
properties”).  
 
Elderly (≥ 65 years)  
No dose adjustment necessary.  
 
Paediatric population 
There is no relevant use of vernakalant in children and adolescents < 18 years of age for rapid 
conversion of recent onset atrial fibrillation to sinus rhythm and therefore it should not be used in this 
population. 
 
Method of administration 
 
For intravenous use. 
 
Vernakalant should not be administered as an intravenous push or bolus. 
 
The vials are for single use only and must be diluted prior to administration. 
 
For instructions on dilution of the medicinal product before administration, see section “Special 
precautions for disposal and other handling”. 
 
Contraindications  
 
• Hypersensitivity to the active substance or to any of the excipients listed in “List of 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. 
• Patients with prolonged QT at baseline (uncorrected > 440 ms), 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, vernakalant administration. 
• Acute coronary syndrome (including myocardial infarction) within the last 30 days. 
 



32 
 

Special warnings and precautions for use  
 
Patient monitoring 
 
Cases of serious hypotension have been reported during and immediately following vernakalant 
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 vernakalant 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 vernakalant, patients should not receive the second 
dose. 
 
The patient should be further monitored for 2 hrs after the start of infusion and until clinical and ECG 
parameters have stabilised. 
 
Precautions before infusion 
 
Prior to attempting pharmacological cardioversion, patients should be adequately hydrated and 
haemodynamically optimised and if necessary patients should be anticoagulated in accordance with 
treatment guidelines. In patients with uncorrected hypokalaemia (serum potassium of less than 
3.5 mmol/l), potassium levels should be corrected prior to use of vernakalant. 
A pre-infusion checklist is provided with the medicinal product. Prior to administration the prescriber 
is asked to determine eligibility of the patient through use of the supplied checklist. The checklist 
should be placed on the infusion container to be read by the healthcare professional who will 
administer it. 
 
Hypotension 
 
Hypotension can occur in a small number of patients (vernakalant 5.7 %, placebo 5.5 % in the first 
2 hours post-dose). 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 “Undesirable effects”.) 
 
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 
(13.4 % versus 4.7 %, respectively). Hypotension reported as a serious adverse experience or leading 
to medicinal product discontinuation occurred in CHF patients following exposure to vernakalant in 
1.8 % of these patients compared to 0.3 % in placebo. 
 



33 
 

Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first two 
hours post dose (6.4% for vernakalant compared to 1.6% in placebo). These arrhythmias typically 
presented as asymptomatic, monomorphic, non-sustained (average 3-4 beats) ventricular tachycardias.  
Due to the higher incidence of the adverse reactions 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 
“Contraindications”).  
 
Valvular heart disease 
 
In patients with valvular heart disease, there was a higher incidence of ventricular arrhythmia events in 
vernakalant patients until 24 hours after dosing. Within the first 2 hours, ventricular arrhythmia 
occurred in 6.4% of patients treated with vernakalant versus none after placebo. These patients should 
be monitored closely. 
 
Atrial flutter  
 
Vernakalant was not found to be effective in converting typical primary atrial flutter to sinus rhythm. 
Patients receiving vernakalant 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 
“Undesirable effects”). If atrial flutter is observed as secondary to treatment, continuation of infusion 
should be considered (see “Posology and method of administration”). In post-marketing experience 
rare cases of atrial flutter with 1:1 atrioventricular conduction are observed. 
 
Other diseases and conditions not studied 
 
Vernakalant has been administered to patients with an uncorrected QT less than 440 ms without an 
increased risk of torsade de pointes. 
 
Furthermore, it has not been evaluated in patients with clinically meaningful valvular stenosis, 
hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis and 
its use cannot be recommended in such cases. There is limited experience with vernakalant in patients 
with pacemakers. 
 
As the clinical trial experience in patients with advanced hepatic impairment is limited, vernakalant is 
not recommended in these patients. 
 
There are no clinical data on repeat doses after the initial and second infusions. 
 
Electrical cardioversion 
 
Direct-current cardioversion may be considered for patients who do not respond to therapy. There is 
no clinical experience with direct-current cardioversion under 2 hours post-dose. 
 
Use of AADs (antiarrhythmic drugs) prior to or after vernakalant 
 
Vernakalant cannot be recommended in patients previously administered intravenous AADs (class I 
and III) 4-24 hours prior to vernakalant, due to lack of data. It must not be administered in patients 
who received intravenous AADs (class I and III) within 4 hours prior to vernakalant (see 
“Contraindications”). 
 
Vernakalant 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). 
 



34 
 

There is limited experience with the use of intravenous rhythm control antiarrhythmics (class I and 
class III) in the first 4 hours after vernakalant administration, therefore these agents must not be used 
within this period (see “Contraindications”). 
 
Resumption or initiation of oral maintenance antiarrhythmic therapy can be considered starting 
2 hours after vernakalant administration. 
 
Sodium content  
 
This medicinal product contains 32 mg sodium per 200 mg vial, equivalent to 1.6 % of the WHO 
recommended maximum daily intake of 2 g sodium for an adult.  
This medicinal product contains 80 mg sodium per 500 mg vial, equivalent to 4 % of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed.  
 
Vernakalant must not be administered in patients who received intravenous AADs (class I and III) 
within 4 hours prior to vernakalant (see “Contraindications”).  
 
Within the clinical development program, oral maintenance antiarrhythmic therapy was halted for a 
minimum of 2 hours after vernakalant administration. Resumption or initiation of oral maintenance 
antiarrhythmic therapy after this time period can be considered (see “Contraindications” and “Special 
warnings and precautions for use”). 
 
Although vernakalant is a substrate of CYP2D6, population pharmacokinetic (PK) analyses 
demonstrated that no substantial differences in the acute exposure of vernakalant (Cmax and 
AUC0-90 min) 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 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. 
 
Special precautions for disposal and other handling 
 
Read all steps before administration. 
 
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. 
 
Preparation of BRINAVESS for infusion  
 
Step 1:  
BRINAVESS vials should be visually inspected for particulate matter and discolouration before 
administration. Any vials exhibiting particulate matter or discolouration should not be used. Note: 
BRINAVESS concentrate for solution for infusion ranges from colourless to pale yellow. Variations 
of colour within this range do not affect potency. 



35 
 

 
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. 
 
Recommended diluents are sodium chloride 9 mg/ml (0.9 %) solution for injection, Lactated Ringers 
solution for injection, or 5 % glucose solution for injection. 
 
Step 3: Inspection of the solution 
The diluted sterile solution should be clear, colourless to pale yellow. The solution should be visually 
re-inspected for particulate matter and discolouration before administering. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  


	SUMMARY OF PRODUCT CHARACTERISTICS
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	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
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