BRINAVESS 20 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for theuser

BRINAVESS 20mg/ml concentrate for solution forinfusion

vernakalant hydrochloride

Read the entire package leaflet carefully before starting to use this medication,asitcontains important information foryou.

• Keep this package leaflet, as you may need to read it again.
• If you have any questions, consult your doctor.
• If you experience side effects, consult your doctor, even if they are not listed in this package leaflet. See section 4.

Contents of thepackage leaflet

1. What is BRINAVESS and what is it used for
2. What you need to know before using BRINAVESS
3. How to use BRINAVESS
4. Possible side effects
5. Storage of BRINAVESS
6. Package contents and additional information

1. What is BRINAVESS and what is it used for

BRINAVESS contains the active ingredient vernakalant hydrochloride. BRINAVESS works by changing your irregular or rapid heartbeat to a normal heartbeat.

In adults, it is used if you have a rapid or irregular heartbeat called atrial fibrillation that has started recently, within 7 days or less for non-surgical patients and within 3 days or less for patients after cardiac surgery.

2. What you need to know before using BRINAVESS

Do not use BRINAVESS:

• if you are allergic to vernakalant hydrochloride or any of the other components of this medication (listed in section 6)
• if you have new or worsening chest pain (angina) diagnosed by your doctor as acute coronary syndrome in the last 30 days or have had a heart attack in the last 30 days
• if you have a very narrow heart valve, a systolic blood pressure of less than 100 mm Hg, or advanced heart failure with symptoms after minimal exertion or at rest
• if you have an abnormally slow heartbeat or skip beats and do not have a pacemaker or have a conduction disorder called QT prolongation, which can be seen on an electrocardiogram performed by your doctor
• if you are taking certain intravenous medications (class I and III antiarrhythmics) used to normalize an abnormal heartbeat within 4 hours before using BRINAVESS

Do not use BRINAVESS if any of the above applies to you. If you are unsure, consult your doctor before using this medication.

Warnings andprecautions

Consult your doctor before starting to use BRINAVESS if you have:

• heart failure
• certain heart diseases, including heart muscle, the layer surrounding the heart, and severe narrowing of the heart valves
• a heart valve disease
• liver problems
• are taking other medications to control your heart rhythm

If you have very low blood pressure, a slow heartbeat, or certain changes in your electrocardiogram while using this medication, your doctor will interrupt your treatment.

Your doctor will consider whether you need additional medication to control your heart rhythm 4 hours after BRINAVESS.

BRINAVESS may not work to treat some other types of abnormal heart rhythms; however, your doctor may be familiar with them.

Tell your doctor if you have a pacemaker.

If any of the above circumstances apply to you (or you are unsure), consult your doctor. Section 4 provides detailed information on warnings and precautions related to side effects that may occur.

Bloodtests

Before administering this medication, your doctor will decide whether to perform blood tests to check how your blood clots and your potassium level.

Children andadolescents

Do not give this medication to children and adolescents under 18 years of age because there is no experience with its use in this population.

Othermedicines and BRINAVESS

Tell your doctor if you are using, have recently used, or may need to use any other medication.

Do not use BRINAVESS if you are taking other intravenous medications (class I and III antiarrhythmics) used to normalize an abnormal heartbeat 4 hours before using BRINAVESS.

Pregnancy andbreastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medication.

It is recommended to avoid using BRINAVESS during pregnancy.

It is unknown whether BRINAVESS passes into breast milk.

Driving and usingmachines

Note that some people may feel dizzy after receiving BRINAVESS, usually within the first two hours (see section "Possible side effects"). If you feel dizzy, you should avoid driving or using machines after receiving BRINAVESS.

BRINAVESS containssodium

This medication contains 32 mg of sodium (a major component of table salt/cooking salt) per 200 mg vial. This is equivalent to 1.6% of the maximum recommended daily sodium intake for an adult.

This medication contains 80 mg of sodium (a major component of table salt/cooking salt) per 500 mg vial. This is equivalent to 4% of the maximum recommended daily sodium intake for an adult.

3. How to use BRINAVESS

The amount of BRINAVESS that you may be given will depend on your weight. The recommended initial dose is 3 mg/kg, with a maximum calculated dose based on 113 kg. If you weigh more than 113 kg, you will receive a fixed dose of 339 mg. While you are receiving BRINAVESS, your breathing, heartbeat, blood pressure, and heart electrical activity will be monitored.

If your heartbeat 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, 2 mg/kg, with a maximum calculated dose based on 113 kg. If you weigh more than 113 kg, you will receive a fixed dose of 226 mg. Total doses of more than 5 mg/kg should not be administered within 24 hours.

A healthcare professional will administer BRINAVESS. BRINAVESS must be diluted before administration. Information on how to prepare the solution is available at the end of this package leaflet.

You will be given it in a vein over 10 minutes.

If you receive more BRINAVESS than youshould

If you think you may have been given too much BRINAVESS, inform your doctor immediately.

If you have any further questions on the use of this medication, ask your doctor.

4. Possible side effects

Like all medications, this medication can cause side effects, although not everybody gets them.

Your doctor may decide to stop the infusion if they observe any of the following abnormal changes in

• your heartbeat (such as very rapid or very slow heartbeat, skipped beats, or a short pause in heart activity)
• your blood pressure (such as very low blood pressure that causes a severe heart condition)
• the electrical activity of your heart

Other sideeffects:

Very common(may affect more than 1 in 10 patients)

• taste disturbances
• sneezing

Common(may affect up to 1 in 10 patients)

• rapid heartbeat
• pain or numbness at the infusion site, numbness, decreased skin sensation, or tingling sensation
• nausea and vomiting
• feeling of warmth
• low blood pressure, slow heartbeat, feeling of dizziness
• cough, nose pain
• excessive sweating, itching
• numbness or tingling sensation in the mucosa or tissues of the oral cavity

Uncommon(may affect up to 1 in 100 patients)

• certain types of heartbeat problems (such as awareness of your own heartbeat or irregular heartbeats)
• decreased sense of touch
• irritation, tearing in the eyes, or changes in vision
• change in sense of smell
• pain in the fingers of the hands and feet, burning sensation
• cold sweats, hot flashes
• urgent need to defecate, diarrhea
• shortness of breath or feeling of tension in the chest
• feeling of suffocation
• mouth or throat pain
• irritation, itching at the infusion site
• high blood pressure
• feeling dizzy or fainting, generally feeling unwell, feeling sleepy
• runny nasal secretions, sore throat
• nasal congestion
• dry mouth
• pale skin
• generalized itching
• fatigue
• decreased sensitivity in the mouth

These effects, observed within 24 hours after administration of BRINAVESS, should disappear quickly. However, if they do not, you should consult your doctor.

Reporting of sideeffects:

If you experience any side effects, consult your doctor or pharmacist, even if they are not listed in this package leaflet. You can also report them directly through the national reporting system included in Annex V. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of BRINAVESS

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date stated on the carton and vial label after EXP. The expiration date is the last day of the month indicated.

This medication does not require special storage precautions.

BRINAVESS must be diluted before use. The diluted sterile concentrate is chemically and physically stable for 12 hours at 25 °C or below.

From a microbiological point of view, the medication should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user and are normally not more than 24 hours at 2 to 8 °C, unless the dilution has taken place in controlled and validated aseptic conditions.

Do not use this medication if you notice particles or a color change.

Medications should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medications that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Composition ofBRINAVESS

• The active ingredient is vernakalant hydrochloride. Each ml of concentrate contains 20 mg of vernakalant hydrochloride, equivalent to 18.1 mg of vernakalant.

Each vial of 200 mg of vernakalant hydrochloride is equivalent to 181 mg of vernakalant.

Each vial of 500 mg of vernakalant hydrochloride is equivalent to 452.5 mg of vernakalant.

• The other components are citric acid, sodium chloride, sodium hydroxide (E524), and water for injectable preparations (see section 2 "BRINAVESS contains sodium").

Appearance and Package Contents of theproduct

BRINAVESS is a concentrate for solution for infusion (sterile concentrate) that is transparent, colorless to pale yellow.

BRINAVESS is available in a package size of 1 vial containing either 200 mg or 500 mg of vernakalant hydrochloride.

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of Last Revision of thisprospect:

Other Sources ofinformation

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

This information is intended for healthcare professionals only:

Please consult the Summary of Product Characteristics and educational material for additional information before using BRINAVESS.

CLINICAL DATA

Therapeutic Indications

Brinavess is indicated in adults for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm

• In non-surgical patients: atrial fibrillation ≤ 7 days duration
• In patients after cardiac surgery: atrial fibrillation ≤ 3 days duration

Dosage and Administration

Vernakalant should be administered by intravenous infusion in a clinically monitored setting suitable for cardioversion. It should only be administered by a qualified healthcare professional.

Dosage

Vernakalant is dosed according to the patient's body weight, with a maximum calculated dose based on 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 the 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 the 4 mg/ml solution). Accumulated doses of more than 5 mg/kg should not be administered within 24 hours.

The initial infusion is administered at a dose of 3 mg/kg over 10 minutes. During this period, the patient should be carefully monitored for signs or symptoms of a sudden decrease in blood pressure or heart rate. If these signs occur, the infusion should be discontinued 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 has not occurred with the initial infusion or within the 15-minute observation period, a second infusion of 2 mg/kg may be administered over 10 minutes.

If conversion to sinus rhythm occurs during the initial or second infusion, the infusion should be continued to completion. If atrial flutter is observed after the initial infusion, the second infusion may be administered because patients may convert to sinus rhythm (see "Special Warnings and Precautions for Use" and "Adverse Reactions").

Patients weighing ≥ 113 kg

For patients weighing more than 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. Doses above 565 mg have not been evaluated.

Post-cardiac surgery

No dose adjustment is necessary.

Renal Impairment

No dose adjustment is necessary (see "Pharmacokinetic Properties").

Hepatic Impairment

No dose adjustment is necessary (see "Special Warnings and Precautions for Use" and "Pharmacokinetic Properties").

Elderly patients (≥ 65 years)

No dose adjustment is necessary.

Pediatric population

There is no specific recommendation for the use of vernakalant in children and adolescents under 18 years for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm, and therefore vernakalant should not be used in this population.

Method of Administration

By intravenous route.

Vernakalant should not be administered as a bolus or rapid injection.

The vials are for single use and should be diluted before 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".
• Patient with severe aortic stenosis, patients with systolic blood pressure < 100 mmHg, and patients with heart failure of NYHA class III and IV.
• Patient with prolonged QT interval at baseline (> 440 ms uncorrected) or severe bradycardia, sick sinus syndrome, or second- and third-degree atrioventricular block in the absence of a pacemaker.
• Use of intravenous antiarrhythmic agents for rhythm control (classes I and III) within 4 hours before administration, as well as within the first 4 hours after administration of vernakalant.
• Acute coronary syndrome (including myocardial infarction) within the last 30 days.

Special Warnings and Precautions for Use

Patient Monitoring

During and immediately after the infusion of vernakalant, cases of severe hypotension have been reported. Patients should be closely monitored during the entire duration of the infusion and for at least 15 minutes after the end of the infusion, with evaluation of vital signs and continuous monitoring of cardiac rhythm.

If any of the following signs or symptoms occur, the infusion of vernakalant should be discontinued, and these patients should receive appropriate medical treatment:

• A sudden decrease in blood pressure or heart rate, with or without symptomatic hypotension or bradycardia
• Hypotension
• Bradycardia
• Changes in the ECG (such as clinically significant sinus pause, complete atrioventricular block, new bundle branch block, significant prolongation of the QRS or QT interval, changes compatible with ischemia or infarction, and ventricular arrhythmia)

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

In addition, the patient should be monitored for 2 hours after starting the infusion and until clinical parameters and ECG have stabilized.

Precautions before Infusion

Before attempting pharmacological cardioversion, patients should be adequately hydrated and hemodynamically optimized, and if necessary, anticoagulated according to treatment guidelines. In patients with uncorrected hypokalemia (serum potassium < 3.5 mmol/l), potassium levels should be corrected before the use of vernakalant.

A checklist before infusion is provided with the medicinal product. Before administration, using the provided checklist, the prescriber should determine the patient's suitability. The checklist should be placed on the infusion container to be read by the healthcare professional who will administer it.

Hypotension

Hypotension may occur in a small number of patients (vernakalant, 5.7%, placebo, 5.5% in the first 2 hours after dosing). Hypotension typically occurs early, either during the infusion or shortly after the end of the infusion, and can usually be corrected with standard supportive measures. Rarely, cases of severe hypotension have been observed. Patients with congestive heart failure (CHF) have been identified as a population at higher risk of hypotension (see "Adverse Reactions").

Patient monitoring is required for signs and symptoms of a sudden decrease in blood pressure or heart rate during the infusion and for at least 15 minutes after the end of the infusion.

Congestive Heart Failure

Patient with CHF showed a higher incidence of hypotension events during the first 2 hours after administration in patients treated with vernakalant compared to those who received placebo (13.4% vs 4.7%, respectively). Hypotension reported as a serious adverse event or leading to discontinuation of the medicinal product occurred in 1.8% of these patients after exposure to vernakalant compared to 0.3% with placebo.

Patient with a history of CHF showed a higher incidence of ventricular arrhythmia in the first 2 hours after dosing (6.4% with vernakalant compared to 1.6% with placebo). These arrhythmias typically presented as asymptomatic, monomorphic, non-sustained ventricular tachycardias (average of 3-4 beats).

Due to the higher incidence of adverse events of hypotension and ventricular arrhythmia in patients with CHF, vernakalant should be used with caution in hemodynamically stable patients with CHF of NYHA functional classes I to II. There is limited experience with the use of vernakalant in patients with previously documented left ventricular ejection fraction ≤ 35%. Its use is not recommended in these patients. It is contraindicated in patients with CHF corresponding to NYHA III or IV (see "Contraindications").

Valvulopathy

In patients with valvulopathy, there is a higher incidence of ventricular arrhythmia events in patients treated with vernakalant up to 24 hours after dosing. In the first 2 hours, 6.4% of patients treated with vernakalant showed ventricular arrhythmia compared to none of those treated with placebo. These patients should be closely monitored.

Atrial Flutter

Vernakalant was not effective in converting typical atrial flutter to sinus rhythm. Patients receiving vernakalant have a higher incidence of converting to atrial flutter during the first 2 hours after dosing. This risk is higher in patients using class I antiarrhythmic agents (see "Adverse Reactions"). If atrial flutter is observed after treatment, the continuation of treatment should be assessed (see "Dosage and Administration"). In post-marketing experience, rare cases of atrial flutter with 1:1 atrioventricular conduction have been observed.

Other Diseases and Unstudied Problems

Vernakalant has been administered to patients with an uncorrected QT interval < 440 ms without increased risk of torsades de pointes.

Additionally, vernakalant has not been studied in patients with clinically significant valvular stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis, and its use cannot be recommended in these cases. There is limited experience with BRINAVESS in patients with pacemakers.

As experience in clinical trials in patients with advanced hepatic impairment is limited, vernakalant is not recommended in these patients.

There are no clinical data on repeated administration after initial and second infusions.

Electrical Cardioversion

Electrical cardioversion with direct current may be considered in patients who do not respond to treatment. There is no clinical experience with electrical cardioversion with direct current within 2 hours after administration.

Use of Antiarrhythmic Agents before or after Administration of Vernakalant

Due to the lack of data, vernakalant is not recommended in patients who have been administered intravenous antiarrhythmic agents (classes I and III) 4-24 hours before administration of vernakalant. Vernakalant should not be administered to patients who have received intravenous antiarrhythmic agents (classes I and III) within 4 hours before vernakalant (see "Contraindications").

Due to limited experience, vernakalant should be used with caution in patients on oral antiarrhythmic therapy (classes I and III). The risk of atrial flutter may be increased in patients receiving class I antiarrhythmic agents (see above).

There is limited experience with the use of intravenous antiarrhythmic agents for rhythm control (classes I and III) in the first 4 hours after administration of vernakalant; therefore, these medicinal products should not be used during this period (see "Contraindications").

Resumption or initiation of oral antiarrhythmic maintenance therapy may be considered 2 hours after administration of vernakalant.

Sodium Content

This medicinal product contains 32 mg of sodium in each 200 mg vial, equivalent to 1.6% of the maximum daily intake of 2 g of sodium recommended by the WHO for an adult. This medicinal product contains 80 mg of sodium in each 500 mg vial, equivalent to 4% of the maximum daily intake of 2 g of sodium recommended by the WHO for an adult.

a dose of 2 g of sodium recommended by the WHO for an adult.

Interaction with other medications and other forms ofinteraction

No interaction studies have been conducted.

Vernakalant should not be administered to patients who have received intravenous antiarrhythmics (Class I and III) in the 4 hours prior to vernakalant administration (see "Contraindications").

Within the clinical development program, oral maintenance antiarrhythmic treatment was discontinued for a minimum of 2 hours after vernakalant administration. Re-initiation or initiation of oral maintenance antiarrhythmic treatment may be considered after this time period (see "Contraindications" and "Special precautions for disposal and other manipulations").

Although vernakalant is a substrate of CYP2D6, population pharmacokinetic (PK) analyses showed that no substantial differences in acute exposure to vernakalant (Cmax and AUC0-90 min) were observed when weak or potent CYP2D6 inhibitors were administered within 1 day before vernakalant infusion compared to patients not receiving concomitant CYP2D6 inhibitor treatment. Additionally, acute exposure to vernakalant in patients with poor CYP2D6 metabolism is only minimally different compared to that of extensive metabolizers. No dose adjustment of vernakalant is required based on CYP2D6 metabolism status or when vernakalant is administered concomitantly with CYP2D6 inhibitors.

Vernakalant is a moderate, competitive inhibitor of CYP2D6. However, due to the short half-life of vernakalant and the consequent transient nature of 2D6 inhibition, it is not expected that acute intravenous administration of vernakalant will have a notable impact on the PK of chronically administered 2D6 substrates. Due to rapid distribution and ephemeral exposure, low protein binding, lack of inhibition of other studied CYP450 enzymes (CYP3A4, 1A2, 2C9, 2C19, or 2E1), and no inhibition of P-glycoprotein in a digoxin transport assay, it is not expected that vernakalant, when administered by infusion, will have significant interactions with medications.

Special precautions for disposal and othermanipulations

Read all the steps before administration.

The preferred administration device is the infusion pump. However, a continuous infusion pump with syringe is acceptable as long as the calculated volume can be administered adequately within the specified infusion time.

Preparation of BRINAVESS for infusion

Step1:

Prior to administration, visually inspect the BRINAVESS vials for particles or color change. Do not use any vial that exhibits particles or color change. Note: BRINAVESS concentrated solution for infusion ranges from colorless to pale yellow. Color variations within this range do not affect potency.

Step2: dilution of theconcentrate

To ensure adequate administration, prepare a sufficient amount of BRINAVESS 20 mg/ml at the start of treatment to administer both the initial infusion and the second infusion if necessary.

Prepare a solution with a concentration of 4 mg/ml by following the dilution guidelines:

Patients ≤ 100 kg: add 25 ml of BRINAVESS 20 mg/ml to 100 ml of diluent.

Patients > 100 kg: add 30 ml of BRINAVESS 20 mg/ml to 120 ml of diluent.

Recommended diluents are sodium chloride 0.9% for injectables, lactated Ringer's solution for injectables, or glucose 5% for injectables.

Step3: inspect thesolution

The diluted sterile solution should be clear, colorless to pale yellow. Prior to administration, visually re-inspect the solution for particles or color change.

Disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.