BRIVANESS Concentrate for solution for infusion Ref.[8656] Active ingredients: Vernakalant

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

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).

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.

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 (C_max and AUC_0-90min) were observed when weak or potent CYP2D6 inhibitors were administered within 1 day prior to vernakalant infusion compared to patients that were not on concomitant therapy with CYP2D6 inhibitors. In addition, acute exposure of vernakalant in poor metabolisers of CYP2D6 is only minimally different when compared to that of extensive metabolisers. No dose adjustment of vernakalant is required on the basis of CYP2D6 metaboliser status, or when vernakalant is administered concurrently with 2D6 inhibitors.

Vernakalant is a moderate, competitive inhibitor of CYP2D6. However, acute intravenous administration of vernakalant is not expected to markedly impact the PK of chronically administered 2D6 substrates, as a consequence of vernakalant’s short half-life and the ensuing transient nature of 2D6 inhibition. Vernakalant given by infusion is not expected to perpetrate meaningful drug interactions due to the rapid distribution and transient exposure, low protein binding, lack of inhibition of other CYP P450 enzymes tested (CYP3A4, 1A2, 2C9, 2C19 or 2E1) and lack of P-glycoprotein inhibition in a digoxin transport assay.

Pregnancy

There are no data from the use of vernakalant hydrochloride in pregnant women. 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 BRINAVESS during pregnancy.

Breast-feeding

It is unknown whether vernakalant/metabolites are excreted in human milk. There is no information on the excretion of vernakalant/metabolites in animal milk. A risk to the 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.

Vernakalant has a 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).

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:

^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 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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