BRINAVESS 20mg / ml perfusive solution concentrate medication leaflet

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 ofvernakalant.

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.

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.

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

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

Vernakalant should be administered in a monitored clinical setting appropriate for cardioversion. Onlya well-qualified healthcare professional should administer it.

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 maximuminitial dose of 339 mg (84.7 ml of 4 mg/ml solution). If conversion to sinus rhythm does not occurwithin 15 minutes after the end of the initial infusion, a second 10-minute infusion of 2 mg/kg may beadministered (maximum second infusion of 226 mg (56.5 ml of 4 mg/ml solution)). Cumulative dosesof 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 patientshould be carefully monitored for any signs or symptoms of a sudden decrease in blood pressure orheart rate. If such signs develop, with or without symptomatic hypotension or bradycardia, theinfusion should be stopped immediately.

If conversion to sinus rhythm has not occurred, the patient’s vital signs and cardiac rhythm should beobserved for an additional 15 minutes.

If conversion to sinus rhythm did not occur with the initial infusion or within the 15-minuteobservation 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 shouldbe continued to completion. If haemodynamically stable atrial flutter is observed after the initialinfusion, the second infusion may be administered as patients may convert to sinus rhythm (seesections 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 of4 mg/ml solution). If conversion to sinus rhythm does not occur within 15 minutes after the end of theinitial infusion, a second 10-minute infusion of 226 mg (56.5 ml of 4 mg/ml solution) may beadministered. Cumulative doses above 565 mg have not been evaluated.

Post-cardiac surgery

No dose adjustment necessary.

No dose adjustment necessary (see section 5.2).

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

No dose adjustment necessary.

There is no relevant use of vernakalant in children and adolescents < 18 years of age for rapidconversion of recent onset atrial fibrillation to sinus rhythm and therefore it should not be used in thispopulation.

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.

* 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, andpatients with heart failure class NYHA III and NYHA IV.

* Patients with prolonged QT at baseline (uncorrected > 440 ms), or severe bradycardia, sinusnode 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.

Patient monitoring

Cases of serious hypotension have been reported during and immediately following vernakalantinfusion. Patients should be carefully observed for the entire duration of the infusion and for at least15 minutes after completion of the infusion with assessment of vital signs and continuous cardiacrhythm monitoring.

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

* A sudden drop in blood pressure or heart rate, with or without symptomatic hypotension orbradycardia

* Hypotension

* Bradycardia

* ECG changes (such as a clinically meaningful sinus pause, complete heart block, new bundlebranch block, significant prolongation of the QRS or QT interval, changes consistent withischaemia or infarction and ventricular arrhythmia)

If these events occur during the first infusion of vernakalant, patients should not receive the seconddose.

The patient should be further monitored for 2 hrs after the start of infusion and until clinical and ECGparameters have stabilised.

Precautions before infusion

Prior to attempting pharmacological cardioversion, patients should be adequately hydrated andhaemodynamically optimised and if necessary patients should be anticoagulated in accordance withtreatment guidelines. In patients with uncorrected hypokalaemia (serum potassium of less than3.5 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 prescriberis asked to determine eligibility of the patient through use of the supplied checklist. The checklistshould be placed on the infusion container to be read by the healthcare professional who willadminister it.

Hypotension can occur in a small number of patients (vernakalant 5.7 %, placebo 5.5 % in the first2 hours post-dose). Hypotension typically occurs early, either during the infusion or early after the endof the infusion, and can usually be corrected by standard supportive measures. Uncommonly, cases ofsevere hypotension have been observed. Patients with congestive heart failure (CHF) have beenidentified 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 pressureor heart rate for the duration of the infusion and for at least 15 minutes after the completion of theinfusion.

Patients with CHF showed a higher overall incidence of hypotensive events, during the first 2 hoursafter 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 tomedicinal product discontinuation occurred in CHF patients following exposure to vernakalant in1.8 % 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 twohours post dose (6.4% for vernakalant compared to 1.6% in placebo). These arrhythmias typicallypresented 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 inpatients 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 inpatients with previously documented LVEF ≤ 35 %. Its use in these patients is not recommended. Theuse 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 invernakalant patients until 24 hours after dosing. Within the first 2 hours, ventricular arrhythmiaoccurred in 6.4 % of patients treated with vernakalant versus none after placebo. These patients shouldbe 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 first2 hours post-dose. This risk is higher in patients who use Class I antiarrhythmics (see section 4.8). Ifatrial flutter is observed as secondary to treatment, continuation of infusion should be considered (seesection 4.2). In post-marketing experience rare cases of atrial flutter with 1:1 atrioventricularconduction are observed.

Other diseases and conditions not studied

Vernakalant has been administered to patients with an uncorrected QT less than 440 ms without anincreased 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 andits use cannot be recommended in such cases. There is limited experience with vernakalant in patientswith pacemakers.

As the clinical trial experience in patients with advanced hepatic impairment is limited, vernakalant isnot 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 isno 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 Iand III) 4-24 hours prior to vernakalant due to lack of data. It must not be administered in patients whoreceived intravenous AADs (class I and III) within 4 hours prior to vernakalant (see section 4.3).

Vernakalant should be used with caution in patients on oral AADs (class I and III), due to limitedexperience. 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 andclass III) in the first 4 hours after vernakalant administration, therefore these agents must not be usedwithin this period (see section 4.3).

Resumption or initiation of oral maintenance antiarrhythmic therapy can be considered starting2 hours after vernakalant administration.

This medicinal product contains 32 mg sodium per 200 mg vial, equivalent to 1.6 % of the WHOrecommended 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 WHOrecommended maximum daily intake of 2 g sodium for an adult.

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 aminimum of 2 hours after vernakalant administration. Resumption or initiation of oral maintenanceantiarrhythmic 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) analysesdemonstrated 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 tovernakalant infusion compared to patients that were not on concomitant therapy with

CYP2D6 inhibitors. In addition, acute exposure of vernakalant in poor metabolisers of CYP2D6 isonly minimally different when compared to that of extensive metabolisers. No dose adjustment ofvernakalant is required on the basis of CYP2D6 metaboliser status, or when vernakalant isadministered concurrently with 2D6 inhibitors.

Vernakalant is a moderate, competitive inhibitor of CYP2D6. However, acute intravenousadministration of vernakalant is not expected to markedly impact the PK of chronically administered2D6 substrates, as a consequence of vernakalant's short half-life and the ensuing transient nature of2D6 inhibition. Vernakalant given by infusion is not expected to perpetrate meaningful druginteractions due to the rapid distribution and transient exposure, low protein binding, lack of inhibitionof other CYP P450 enzymes tested (CYP3A4, 1A2, 2C9, 2C19 or 2E1) and lack of P-glycoproteininhibition in a digoxin transport assay.

There are no data from the use of vernakalant hydrochloride in pregnant women. Studies in animalhave 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.

It is unknown whether vernakalant/metabolites are excreted in human milk. There is no information onthe excretion of vernakalant/metabolites in animal milk. A risk to the newborns/infants cannot beexcluded.

Caution should be exercised when used in breast-feeding women.

Vernakalant was not shown to alter fertility in animal studies.

Vernakalant has minor to moderate influence on the ability to drive and use machines. Dizziness hasbeen reported within the first 2 hours after receiving it (see section 4.8).

The most commonly reported adverse reactions (> 5 %) seen in the first 24 hours after receivingvernakalant 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.

The adverse reaction profile presented below is based on the analysis of pooled clinical trials, apost-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 Very common: Dysgeusiadisorders

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; bundlebranch block left; ventricular extrasystoles; AV block first degree; AVblock complete; bundle branch block right; sinus bradycardia; ECG

QRS complex prolonged; cardiogenic shock, blood pressure diastolicincreased

Rare: Atrial flutter with 1:1 atrioventricular conduction b, c

Vascular disorders Common: Hypotension

Uncommon: Flushing; hot flush; pallor

Respiratory, thoracic and Very common: Sneezingmediastinal disorders

Common: Cough; nasal discomfort

Uncommon: Dyspnoea; throat irritation; oropharyngeal pain; nasalcongestion; suffocation feeling; choking sensation; rhinorrhoea

Gastrointestinal disorders Common: Nausea; paraesthesia oral; vomiting

Uncommon: Dry mouth; diarrhoea; hypoaesthesia oral; defecationurgency

Skin and subcutaneous Common: Pruritus; hyperhidrosistissue disorders

Uncommon: Pruritus generalised; cold sweat

Musculoskeletal and Uncommon: Pain in extremityconnective tissuedisorders

General disorders and Common: Infusion site pain; feeling hot; infusion site paraesthesiaadministration siteconditions Uncommon: Fatigue; infusion site irritation; infusion sitehypersensitivity; infusion site pruritus; malaisea 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 placebob See subheadings atrial flutter and bradycardia belowc Identified in post-marketing experience

Clinically significant adverse reactions observed in clinical trials included hypotension and ventriculararrhythmia (see section 4.4).

Bradycardia

Bradycardia was observed predominantly at the time of conversion to sinus rhythm. With asignificantly higher conversion rate in patients treated with vernakalant, the incidence of bradycardiaevents was higher within the first 2 hours in vernakalant treated patients than in placebo-treatedpatients (1.6 % versus 0 %, respectively). Of the patients who did not convert to sinus rhythm, theincidence of bradycardia events in the first 2 hours post-dose was similar in placebo and vernakalanttreated groups (4.0% and 3.8%, respectively). In general, bradycardia responded well todiscontinuation of treatment and/or administration of atropine.

Atrial flutter

Atrial fibrillation patients receiving vernakalant have a higher incidence of converting to atrial flutterwithin the first 2 hours post-dose (1.2 % versus 0 % in placebo). With continuation of the infusion asrecommended above, the majority of these patients continue to convert to sinus rhythm. In theremaining patients, electrical cardioversion can be recommended. In clinical studies to date, patientswho developed atrial flutter following treatment with vernakalant did not develop 1:1 atrioventricularconduction. However, in post-marketing experience rare cases of atrial flutter with 1:1 atrioventricularconduction are observed.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

One patient who received 3 mg/kg of vernakalant over 5 minutes (instead of the recommended10 minutes) developed haemodynamically stable wide complex tachycardia which resolved withoutsequelae.

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

C01BG11.

Vernakalant is an antiarrhythmic medicinal product that acts preferentially in the atria to prolong atrialrefractoriness and to rate-dependently slow impulse conduction. These anti-fibrillatory actions onrefractoriness and conduction are thought to suppress re-entry, and are potentiated in the atria duringatrial fibrillation. The relative selectivity of vernakalant on atrial versus ventricular refractoriness ispostulated 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-dependentsodium channels, which are present in the ventricles has been documented.

In preclinical studies, vernakalant blocks currents in all phases of the atrial action potential, includingpotassium currents that are expressed specifically in the atria (e.g., the ultra-rapid delayed rectifier andthe acetylcholine dependent potassium currents). During atrial fibrillation, the frequency- andvoltage-dependent block of sodium channels further focuses the action of the medicinal producttoward rapidly activating and partially depolarised atrial tissue rather than toward the normallypolarised ventricle beating at lower heart rates. Additionally, the ability of vernakalant to block thelate component of the sodium current limits effects on ventricular repolarisation induced by blockadeof potassium currents in the ventricle. Targeted effects on atrial tissue coupled with block of latesodium current suggests that vernakalant has a low proarrhythmic potential. Overall, the combinationof effects of vernakalant on cardiac potassium and sodium currents results in substantialantiarrhythmic effects that are mainly concentrated in the atria.

In an electrophysiological study in patients, vernakalant significantly prolonged atrial effectiverefractory period in a dose-dependent manner, which was not associated with a significant increase inventricular effective refractory period. Across the Phase 3 population, vernakalant treated patients hadan 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). By90 minutes after the start of infusion, this difference was reduced to 8.1 ms.

Clinical Trial Design: The clinical effect of vernakalant in the treatment of patients with atrialfibrillation 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). Somepatients with typical atrial flutter were included in ACT II and ACT III and vernakalant was not foundto be effective in converting atrial flutter. In clinical studies, the need for anticoagulation prior toadministration of vernakalant was assessed as per clinical practice of the treating physician. For atrialfibrillation lasting less than 48 hours, immediate cardioversion was allowed. For atrial fibrillationlasting 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 atrialfibrillation > 3 hours but not more than 45 days in duration. ACT II examined the effect of vernakalanton patients who developed atrial fibrillation of < 3 days duration after recently undergoing coronaryartery bypass graft, (CABG) and/or valvular surgery (atrial fibrillation occurred more than 1 day butless than 7 days after surgery). AVRO studied the effect of vernakalant versus intravenous amiodaronein 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-minuteobservation period. If the patient was in atrial fibrillation or atrial flutter at the end of the 15-minuteobservation 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 tosinus rhythm within 90 minutes. Patients who did not respond to treatment were managed by thephysician 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 hoursto 7 days) who had a treatment-induced conversion of atrial fibrillation to sinus rhythm for a minimumduration of one minute within 90 minutes of first exposure to study drug. Efficacy was studied in atotal of 390 haemodynamically stable adult patients with short duration atrial fibrillation includingpatients 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 fibrillationto sinus rhythm as compared with placebo (see Table 2). Conversion of atrial fibrillation to sinusrhythm occurred rapidly (in responders the median time to conversion was 10 minutes from start offirst infusion) and sinus rhythm was maintained through 24 hours (97 %). The vernakalant doserecommendation is a titrated therapy with 2 possible dose steps. In the performed clinical studies, theadditive 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 ACT I ACT III

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

Fibrillation> 3 hours to 74/145 3/75 44/86 3/84< 0.0001 < 0.0001 7 days (51.0 %) (4.0 %) (51.2 %) (3.6 %)†Cochran-Mantel-Haenszel test

Vernakalant was shown to provide relief of atrial fibrillation symptoms consistent with conversion tosinus rhythm.

No significant differences in safety or effectiveness were observed based on age, gender, use of ratecontrol medicinal products, use of antiarrhythmic medicinal products, use of warfarin, history ofischaemic 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 themedian number of shocks or joules required for successful cardioversion) in cases when attemptedwithin 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 showstatistically 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 atrialfibrillation (3 hours to 72 hours duration) that occurred between 24 hours and 7 days post coronaryartery bypass graft and/or valvular surgery. Treatment with vernakalant effectively converted atrialfibrillation to sinus rhythm (47.0 % vernakalant, 14.0 % placebo; P value = 0.0001). Conversion ofatrial fibrillation to sinus rhythm occurred rapidly (median time to conversion 12 minutes from thestart of infusion).

Efficacy versus amiodarone (AVRO)

Vernakalant was studied in 116 pts with atrial fibrillation (3 hrs to 48 hrs) including patients withhypertension (74.1 %), IHD (19 %), valvular heart disease (3.4 %) and CHF (17.2 %). No patientswith NYHA III/IV were included in the study. In AVRO, the amiodarone infusion was given over2 hours (i.e., 1 hour loading dose of 5 mg/kg, followed by 1 hour maintenance infusion of 50 mg). Theprimary endpoint was the proportion of patients that achieved sinus rhythm (SR) at 90 minutes afterinitiating therapy, limiting the conclusions to the effects seen in this time window. Treatment withvernakalant, converted 51.7 % of patients to SR at 90 minutes versus 5.2 % with amiodarone resultingin a significantly faster conversion rate from AF to SR within the first 90 minutes compared toamiodarone (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 BRINAVESStreatment episodes, effectiveness was assessed as the proportion of patients who converted to sinusrhythm for at least one (1) minute within 90 minutes from the start of the infusion, excluding patientswho received electrical cardioversion or intravenous Class I/III antiarrhythmics for cardioversionwithin the 90-minute window. Overall, BRINAVESS was effective in 70.2% (1,359/1,936) of thesepatients. Median time to conversion to SR as reported among all patients who, as per the investigatorjudgement, converted to SR was 12 minutes and in most of the treatment episodes (60.4%) only oneinfusion was administered. The higher cardioversion rate in SPECTRUM as compared to clinicalphase 3 studies (70.2% vs 47% to 51%) is correlated with a shorter duration of the duration of theindex atrial fibrillation period (median duration of 11.1 hours in SPECTRUM vs 17.7 to 28.2 hours inclinical studies).

If patients who received electrical cardioversion, intravenous antiarrhythmics or oralpropafenone/flecainide within 90 minutes from the start of the infusion are regarded as treatmentfailures in addition to patients who did not convert for one minute within 90 minutes, the conversionrate among the 2,009 patients who received BRINAVESS was 67.3 % (1,352/2,009). There was nomeaningful difference when stratifying the analysis by therapeutic indication (i.e. non-surgery andpost-cardiac surgery patients).

The European Medicines Agency has waived the obligation to submit the results of studies withvernakalant in all subsets of the paediatric population in atrial fibrillation (see section 4.2 forinformation on paediatric use).

In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single10-minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusionof 2 mg/kg with a 15-minute interval between doses.

Vernakalant is extensively and rapidly distributed in the body, with a volume of distribution ofapproximately 2 l/kg. The Cmax and AUC were dose proportional between 0.5 mg/kg and 5 mg/kg. Inpatients, the typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg. The freefraction of vernakalant in human serum is 53-63 % at concentration range of 1-5 μg/ml.

Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensivemetabolisers. Glucuronidation and renal excretion are the main mechanisms of elimination in

CYP2D6 poor metabolisers. The mean elimination half-life of vernakalant in patients wasapproximately 3 hours in CYP2D6 extensive metabolisers and approximately 5.5 hours in poormetabolisers. 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 congestiveheart failure, renal impairment, or concomitant administration of beta blockers and other medicinalproducts, 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 thebasis of age, serum creatinine or CYP2D6 metaboliser status.

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

With respect to reproduction no effects on pregnancy, embryo-foetal development, parturition orpostnatal development were observed after intravenous administration of vernakalant at exposurelevels (AUC) similar or below the human exposure levels (AUC) achieved after a single intravenousdose of vernakalant. In embryo-foetal development studies with oral administration of vernakalant twotimes a day resulting in exposure levels (AUC) generally higher than those achieved in humans after asingle intravenous dose of vernakalant malformations (misshapen/absent/fused skull bones includingcleft palates, bent radius, bent/misshapen scapula, constricted trachea, absent thyroid, undescendenttestes) occurred in rats and increased embryo-foetal lethality, increased number of foetuses with fusedand/or additional sternebrae were seen in rabbits at the highest doses tested.

Citric acid (E330)

Sodium chloride

Water for injections

Sodium hydroxide (E524) (for pH-adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

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 usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place incontrolled and validated aseptic conditions.

This medicinal product does not require any special storage conditions.

For storage conditions after dilution of the 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 10 ml or 25 ml of concentrate.

Not all pack sizes may be marketed.

Read all steps before administration.

An infusion pump is the preferred delivery device. However, a syringe pump is acceptable providedthat 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 beforeadministration. 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 atthe 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 Ringerssolution 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 visuallyre-inspected for particulate matter and discolouration before administering.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Correvio15 rue du Bicentenaire92800 Puteaux

France

EU/1/10/645/001

EU/1/10/645/002

Date of first authorisation: 01 September 2010

Date of latest renewal: 06 September 2015

December 2021

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

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