What is the active ingredient in BRINAVESS 20MG/ML Concentrate for solution for infusion?

Vernakalanti hydrochloridum (Vernakalant hydrochloride)

What pharmaceutical form is BRINAVESS 20MG/ML Concentrate for solution for infusion available in?

BRINAVESS 20MG/ML Concentrate for solution for infusion: Koncentrat do sporządzania roztworu do infuzji 20 mg/ml (dożylna)

Is BRINAVESS 20MG/ML Concentrate for solution for infusion OTC or prescription only?

BRINAVESS 20MG/ML Concentrate for solution for infusion requires a doctor's prescription.

What are the side effects of BRINAVESS 20MG/ML Concentrate for solution for infusion?

Summary of the safety profile The most commonly reported adverse reactions (> 5%) observed during the first 24 hours after vernakalant administration were dysgeusia (17.9%), sneezing (12.5%) and paraesthesia (6.9%). These effects occurred around the time of infusion, were transient, and rarely limited treatment. Tabulated list of adverse reactions The adverse reaction profile presented below is based on a pooled analysis of clinical studies, the post-marketing safety study, and spontaneous repor

Who should NOT take BRINAVESS 20MG/ML Concentrate for solution for infusion?

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 440 ms) or severe bradycardia, sinus node dysfunction, or second- and third-degree heart block without a pacemaker. Use of intravenous antiarrhythmics (class I and class III) within 4 hours

Does BRINAVESS 20MG/ML Concentrate for solution for infusion interact with other medications?

No interaction studies have been performed. Vernakalant must not be administered to patients who have received intravenous antiarrhythmics (class I and III) within 4 hours prior to vernakalant administration (see section 4.3). Within the clinical development programme, oral maintenance antiarrhythmic therapy was withheld for at least 2 hours after vernakalant administration. After this period, resumption or initiation of oral maintenance antiarrhythmic therapy may be considered (see sections 4.3

Can BRINAVESS 20MG/ML Concentrate for solution for infusion be used during pregnancy?

Pregnancy No data are available on the use of vernakalant hydrochloride in pregnant women. Animal studies have demonstrated malformations following repeated oral exposure (see section 5.3). As a precautionary measure, use of vernakalant during pregnancy should be avoided. Breast-feeding It is not known whether vernakalant/metabolites are excreted in human breast milk. No information is available on the excretion of vernakalant/metabolites in animal milk. A risk to the newborn/infant cannot be ex

BRINAVESS 20MG/ML Concentrate for solution for infusion

This information is for educational purposes only. It is not intended as medical advice. Always consult a qualified healthcare professional.

Pharmacotherapeutic group: cardiac therapy, other class I and III antiarrhythmics, ATC code: C01BG11. Mechanism of action Vernakalant is an antiarrhythmic agent that acts predominantly in the atria by prolonging atrial refractoriness and rate-dependently slowing impulse conduction. These antifibrillatory effects on refractoriness and conduction are believed to suppress re-entry, and are potentiated in the atria during atrial fibrillation. The relative selectivity of vernakalant for atrial over ventricular refractoriness is believed to result from blockade of currents regulated by ion channels that are expressed in the atria but not in the ventricles, as well as the unique electrophysiological state of fibrillating atria. However, blockade of cation currents, including hERG channels and cardiac voltage-gated sodium channels 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 arise specifically in the atria (e.g. the ultra-rapid delayed rectifier potassium current and the acetylcholine-dependent potassium current). During atrial fibrillation, frequency- and voltage-dependent sodium channel blockade further concentrates the effect of the medicinal product on rapidly activating and partially depolarised atrial tissue rather than on the normally polarised ventricle beating at a slower rate. In addition, the ability of vernakalant to block the late component of the sodium current limits the effects on ventricular repolarisation induced by ventricular potassium current blockade. The targeted effects on atrial tissue combined with late sodium current blockade suggest that vernakalant has a low pro-arrhythmic potential. Overall, the combination of vernakalant's effects on cardiac potassium and sodium currents results in substantial antiarrhythmic effects that are focused predominantly in the atria. In an electrophysiology study in patients, vernakalant significantly prolonged atrial effective refractory periods in a dose-dependent manner, which was not associated with significant prolongation of ventricular effective refractory periods. Across the phase 3 population, patients treated with vernakalant compared with placebo experienced prolongation of heart-rate-corrected QT (using Fridericia's correction, QTcF) (placebo-subtracted peaks of 22.1 ms after the first infusion and 18.8 ms after the second infusion). At 90 minutes after start of infusion, this difference was reduced to 8.1 ms. Clinical efficacy and safety Clinical study design: the clinical effect of vernakalant in the treatment of patients with atrial fibrillation was evaluated in three randomised, double-blind, placebo-controlled studies (ACT I, ACT II and ACT III) and in a study with an active comparator, intravenous amiodarone (AVRO). Studies ACT II and ACT III included some patients with typical atrial flutter; vernakalant was not found to be effective in the conversion of atrial flutter. In clinical evaluations, the need for anticoagulation prior to vernakalant administration was assessed according to the treating physician's clinical practice. For atrial fibrillation lasting less than 48 hours, immediate cardioversion was permitted. For atrial fibrillation lasting longer than 48 hours, anticoagulation was required in accordance with therapeutic guidelines. Studies ACT I and ACT III evaluated the effects of vernakalant in the treatment of patients with atrial fibrillation lasting > 3 hours but no more than 45 days. Study ACT II evaluated the effects of vernakalant in patients who developed atrial fibrillation lasting < 3 days following coronary artery bypass grafting (CABG) and/or valvular surgery (atrial fibrillation occurred more than 1 day but less than 7 days after surgery). The AVRO study evaluated the effects of vernakalant compared with intravenous amiodarone in patients with recent-onset atrial fibrillation (3 to 48 hours). In all studies, patients received a 10-minute infusion of 3.0 mg/kg of BRINAVESS (or matching placebo), followed by a 15-minute observation period. If the patient was still 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 of 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 with standard methods. Efficacy in patients with sustained atrial fibrillation (ACT I and ACT III) The primary efficacy endpoint was the proportion of subjects with short-duration atrial fibrillation (3 hours to 7 days) who experienced treatment-induced conversion of atrial fibrillation to sinus rhythm for a minimum of 1 minute within 90 minutes of first exposure to the study drug. Efficacy was evaluated 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 congestive heart failure (10.8%). In these studies, vernakalant treatment compared with placebo effectively converted atrial fibrillation to sinus rhythm (see Table 2). Conversion of atrial fibrillation to sinus rhythm occurred rapidly (median time to conversion in responders was 10 minutes from start of the first infusion) and sinus rhythm was maintained at 24 hours (97%). The recommended dosing regimen for vernakalant is a titration regimen with two possible dosing steps. In the clinical evaluations conducted, the additive effect of the second dose, if any, cannot be independently evaluated. Table 2: Conversion of atrial fibrillation to sinus rhythm in studies 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 from symptoms of atrial fibrillation by conversion to sinus rhythm. No differences in safety or efficacy were observed with regard to age, sex, use of heart rate control medications, use of antiarrhythmics, use of warfarin, history of ischaemic heart disease, renal impairment or cytochrome P450 2D6 enzyme expression. Vernakalant treatment did not affect the response rate to electrical cardioversion (including the median number of shocks or joules needed for successful cardioversion) when it occurred within 2 to 24 hours after administration of the study drug. Conversion of atrial fibrillation in patients with longer-duration atrial fibrillation (> 7 days and ≤ 45 days), evaluated as a secondary endpoint in a total of 185 patients, did not show statistically significant differences between vernakalant and placebo. Efficacy in patients who developed atrial fibrillation after cardiac surgery (ACT II) Efficacy was evaluated in patients with atrial fibrillation following cardiac surgery in study ACT II, a phase 3, double-blind, placebo-controlled, parallel-group study (ACT II) conducted in 150 patients with sustained atrial fibrillation (duration 3 to 72 hours) that occurred between 24 hours and 7 days after coronary artery bypass grafting and/or valvular surgery. Vernakalant treatment effectively converted atrial 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 start of infusion). Efficacy compared with amiodarone (AVRO): Vernakalant was evaluated in 116 patients with atrial fibrillation (3 to 48 hours), including patients with hypertension (74.1%), ischaemic heart disease (19%), valvular heart disease (3.4%) and congestive heart failure (17.2%). No patients with NYHA III/IV were enrolled in the study. In the AVRO study, the amiodarone infusion was administered 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 who achieved sinus rhythm 90 minutes after the start of treatment, which limits conclusions to effects observed within this time window. Vernakalant treatment resulted in conversion of 51.7% of patients to sinus rhythm compared with 5.2% for amiodarone, resulting in significantly faster conversion from atrial fibrillation to sinus rhythm during the first 90 minutes compared with amiodarone (log-rank p-value < 0.0001). Efficacy in a post-marketing observational study In the post-authorisation safety study SPECTRUM, which included 1,778 patients with 2,009 treatment episodes with BRINAVESS, efficacy 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 infusion, excluding patients who underwent electrical cardioversion or received intravenous class I/III antiarrhythmics for cardioversion during the 90-minute period. In these patients, BRINAVESS was effective overall in 70.2% (1,359/1,936). The reported median time to conversion to sinus rhythm in all patients who, per investigator assessment, converted to sinus rhythm was 12 minutes, and in the majority of treatment episodes (60.4%) only a single infusion was administered. The higher cardioversion rate in the SPECTRUM study compared with phase 3 clinical studies (70.2% vs. 47% to 51%) correlated with shorter duration of index atrial fibrillation (median duration 11.1 hours in the SPECTRUM group versus 17.7 to 28.2 hours in clinical studies). If patients who underwent electrical cardioversion or received intravenous antiarrhythmics or oral propafenone/flecainide within 90 minutes of the start of infusion are considered treatment failures, along with patients who did not convert for one minute within 90 minutes, the conversion rate in 2,009 patients who received BRINAVESS was 67.3% (1,352/2,009). When the analysis was stratified by therapeutic indication (i.e. non-cardiac surgery patients and post-cardiac surgery patients), no significant difference was observed. 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 with regard to atrial fibrillation (see section 4.2 for information on paediatric use).

⚠️ Warnings

Patient monitoring Cases of severe hypotension have been reported during and immediately after infusion of vernakalant. Patients must be carefully monitored throughout the duration of the infusion and for at least 15 minutes after its completion, with vital signs monitoring and continuous cardiac rhythm monitoring. If any of the following signs or symptoms appear, vernakalant administration must be discontinued and affected patients must be appropriately managed: sudden drop in blood pressure or heart rate, with or without symptomatic hypotension or bradycardia hypotension bradycardia ECG changes (such as clinically significant sinus pause, complete heart block, new bundle branch block, significant QRS or QT interval prolongation, changes consistent with ischaemia or myocardial infarction, and ventricular arrhythmia). If these events occur during the first infusion of vernakalant, patients must not receive the second dose. The patient must continue to be monitored for two hours after the start of infusion until the clinical picture and ECG parameters are stabilised. Pre-infusion measures Before attempting pharmacological cardioversion, patients must be adequately hydrated and haemodynamically optimised, and anticoagulants should be administered as necessary in accordance with therapeutic guidelines. In patients with uncorrected hypokalaemia (serum potassium below 3.5 mmol/l), potassium levels must be corrected before vernakalant administration. A pre-infusion checklist is provided with the medicinal product. Before administration, the prescribing physician is asked to use the supplied checklist to determine whether the patient is eligible for treatment. This checklist must be placed on the infusion container so that the healthcare professional administering the product can review it. Hypotension Hypotension may occur in a small number of patients (vernakalant 5.7%, placebo 5.5% in the first two hours after dosing). Hypotension usually occurs early, either during the infusion or shortly after its completion, and can usually be corrected with standard supportive measures. Cases of severe hypotension were observed with a frequency classified as uncommon. Patients with congestive heart failure were identified as a population at higher risk of hypotension (see section 4.8). The patient must be monitored for signs and symptoms of a sudden drop in blood pressure or heart rate throughout the infusion and for at least 15 minutes after its completion. Congestive heart failure Patients with congestive heart failure showed a higher overall incidence of hypotensive events during the first 2 hours after dosing in vernakalant-treated patients compared with placebo-treated patients (13.4% versus 4.7%, respectively). Hypotension reported as a serious adverse event or leading to discontinuation of the medicinal product occurred in 1.8% of patients with congestive heart failure following exposure to vernakalant, compared with 0.3% of placebo-treated patients. Patients with a history of congestive heart failure exhibited a higher incidence of ventricular arrhythmias during the first two hours after dosing (6.4% for vernakalant compared with 1.6% for placebo). These arrhythmias were generally asymptomatic, monomorphic, non-sustained (average of 3 to 4 beats) ventricular tachycardias. Due to the higher incidence of hypotension and ventricular arrhythmia adverse events in patients with congestive heart failure, vernakalant must be used with caution in haemodynamically stable patients with congestive heart failure NYHA functional class I to II. Experience with the use of vernakalant in patients with documented left ventricular ejection fraction (LVEF) ≤ 35% is limited. Its use in these patients is not recommended. Use in patients with congestive heart failure NYHA III or NYHA IV is contraindicated (see section 4.3). Valvular heart disease Patients with valvular heart disease treated with vernakalant had a higher incidence of ventricular arrhythmia events within 24 hours of administration. In the first 2 hours, ventricular arrhythmia occurred in 6.4% of vernakalant-treated patients compared with none after placebo. These patients must be carefully monitored. Atrial flutter Vernakalant was not found to be effective in the conversion of typical primary atrial flutter to sinus rhythm. Patients treated with vernakalant have a higher incidence of conversion to atrial flutter during the first 2 hours after dosing. This risk is higher in patients taking class I antiarrhythmics (see section 4.8). If atrial flutter is detected secondary to treatment, continuation of the infusion should be considered (see section 4.2). In post-marketing surveillance, cases of atrial flutter with 1:1 atrioventricular conduction ratio have been rarely observed. Other conditions and diseases that have not been evaluated Vernakalant was administered to patients with an uncorrected QT of less than 440 ms without an increased risk of torsade de pointes. Furthermore, vernakalant has not been evaluated in patients with clinically significant valvular stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy and constrictive pericarditis, and its use cannot be recommended in such cases. There is only limited experience with the use of vernakalant in patients with a pacemaker. As experience from clinical evaluations in patients with advanced hepatic impairment is limited, vernakalant is not recommended in these patients. No clinical data are available on repeat dosing beyond the first and second infusions. Electrical cardioversion In patients who do not respond to treatment, direct current electrical cardioversion may be considered. There is no clinical experience with direct current electrical cardioversion performed within 2 hours after dosing. Use of antiarrhythmics before or after vernakalant administration Vernakalant cannot be recommended in patients who received intravenous antiarrhythmics (class I and III) 4 to 24 hours before vernakalant administration due to the lack of data. It must not be administered to patients who received intravenous antiarrhythmics (class I and III) within 4 hours before vernakalant administration (see section 4.3). Vernakalant must be used with caution in patients receiving oral antiarrhythmics (class I and III) due to insufficient experience. Patients receiving class I antiarrhythmics have an increased risk of atrial flutter (see above). There is only limited experience with the use of intravenous antiarrhythmics (class I and class III) during the first 4 hours after vernakalant administration; therefore, these agents must not be used during this period (see section 4.3). Resumption or initiation of oral maintenance antiarrhythmic therapy may be considered after 2 hours following 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 dietary sodium intake of 2 g for an adult. This medicinal product contains 80 mg sodium per 500 mg vial, equivalent to 4% of the WHO recommended maximum daily dietary sodium intake of 2 g for an adult.

BRINAVESS 20MG/ML Concentrate for solution for infusion

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