Label: information for theuser

BRINAVESS 20mg/ml concentrate for solution forinjection

hydrochloride ofvernakalant

Read this label carefully before starting to use this medication,becauseit contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult yourdoctor.
• If you experience any adverse effects, consult your doctor, even if they are not listed in this label. See section4.

Label contents

1. What BRINAVESS is and for what it is used

2. What you need to know before starting to use BRINAVESS

3. How to use BRINAVESS

4. Possible adverse effects

5. Storage of BRINAVESS

6. Contents of the package and additional information

BRINAVESS contains the active ingredient hydrochloride of vernakalant. BRINAVESS actscambingits irregular or rapid heart rhythm to a normal heart rhythm.

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

Do not use BRINAVESS:

•if you are allergic to hydrochloride vernakalant or any of the other components of thismedication (listed in section6)

•if you have new or worsening chest pain (angina) diagnosed by your doctor as acute coronary syndrome in the last 30days or have had a heart attack inlast 30days

•if you have a severely narrowed heart valve, a systolic blood pressure of less than100mmHg or advanced heart failure with symptoms after minimal exertion or at rest

•if you have an abnormally slow heart rate or skip some beats and do not have a pacemaker or have a condition called QT prolongation, which can be seen in an electrocardiogram performed by yourmédico

•if you are taking certain intravenous medications (class I and III antiarrhythmics) used to normalize an abnormal heart rhythm in the 4 hours prior to the use ofBRINAVESS

Do not use BRINAVESS if any of the above apply. If you are unsure, talk to your doctor before using thismedicamento.

Warnings andprecauciones

Consult your doctor before starting to useBRINAVESS if you have:

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

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

Your doctor will consider if you need additional medication to control your heart rhythm 4hours afterBRINAVESS.

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

Inform your doctor if you have apacemasos.

If any of the above circumstances apply (or you are unsure), talk to your doctor.Insection 4, detailed information is presented on the warnings and precautions relatedconthe potential side effects.

Blood tests:

Before administering this medication, your doctor will decide if you need blood tests to see how you coagulate and also to see your level ofpotasio.

Children andadolescentes

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

Othermedicamentos and BRINAVESS

Inform your doctor if you are using, have used recently or may need to usecualquierothermedicamento.

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

Pregnancy andlactancia

If you are pregnant or breastfeeding, think you may be pregnant or intend to become pregnant, consult your doctor before using thismedicamento.

It is preferable to avoid the use of BRINAVESS duringembarazo.

The passage of BRINAVESS into breast milk is unknown.

Driving and use ofmáquinas

You should be aware that some people may feel dizzy after receivingBRINAVESS,usually in the first two hours (see the section “Possible side effects”). If you feel dizzy, you should avoid driving or using machines after receivingBRINAVESS.

BRINAVESS containssodio

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

This medicationcontains 80mg of sodium (main component of table salt/for cooking) in each vial of 500mg. This is equivalent to 4% of the maximum daily sodium intake recommended for an adult.

The amount of BRINAVESS that can be administered to you will depend on your weight. The recommended initial dose is 3mg/kg,with a maximum dose calculated based on 113 kg. If you weigh more than 113kg, you will receive a fixed dose of 339 mg. While receiving BRINAVESS, your breathing,heart rate, blood pressure, and cardiacarrythmywill be monitored.

If your heart rate has not returned to normal 15minutes after the end of your first dose, you may be given a second dose. This will be a slightly lower dose, of 2mg/kg, with a maximum dose calculated based on 113 kg. If you weigh more than 113 kg, you will receive a fixed dose of 226 mg. No more than a total dose of 5mg/kg should be administered within 24hours.

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

You will be administered BRINAVESS through a vein over 10minutes.

If you receive more BRINAVESS thanyou

If you think you have been given too much BRINAVESS, inform yourmedicainimmediately.

If you have any other questions about the use of this medication, ask yourmedicain.

Like all medicines, this medicine can cause side effects, althoughnotall people experience them.

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

• your heart rate (such as a very fast (rare) or very slow (frequent) heartbeat, omission of aheartbeat(rare), or a short pause in heart activity (rare)
• your blood pressure (such as very low blood pressure that causes a serious heart condition)(rare)
• the electrical activity of your heart (rare)

Other side effects:adverseeffects:

Frequent(may affect more than 1 in 10 patients)

• alterations in taste
• stuffy nose

Common(may affect up to 1 in 10 patients)

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

Rare(may affect up to 1 in 100 patients)

• certain types of heart rhythm problems (such as awareness of one's own heartbeat (palpitations) 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, sensation of burning
• chills, hot flashes
• urgent need to defecate, diarrhea
• shortness of breath or sensation of tension in the chest
• sensation of choking
• mouth or throat pain
• irritation, itching at the infusion site
• high blood pressure
• feeling dizzy or faint, generally feeling unwell, feeling drowsy
• excessively runny nose, throat pain
• 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 side effects:adverseeffects:

If you experience any type of side effect, consult your doctor or pharmacist, even ifitstratesofpossibleadverse effects that do not appear in this prospectus. You can alsocommunicatedirectly through the national reporting system included in theAnexo V.By reporting side effects, you can contribute to providing more information aboutthesafetyofthismedicicament.

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

Do not use this medication after the expiration date that appears on the box and on the label after CAD. The expiration date is the last day of the month that is indicated.

This medication does not require special conservation precautions.

BRINAVESS must be diluted before use. The sterile concentrate diluted 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 storage times in use and the conditions before use, are the responsibility of the user and are normally not greater 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 observe particles or a change in color.

Medicines should not be disposed of through the drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. In this way, you will help protect the environment.

Composition ofBRINAVESS

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

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

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

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

Aspect of the product and contents of thepackaging

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

BRINAVESS is presented in a pack size of 1 vial containing either 200 mg or 500 mg of hydrochloride vernakant.

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

Last review date of thisprospectus:

Other sources ofinformation

The detailed information about this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu.

This information is intended solely for healthcare professionals:

Please, before using BRINAVESS, consult the Summary of Product Characteristics and educational materials for further information.

CLINICAL DATA

Indications for therapeutic use

Brinavess is indicated in adults with 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 route

Vernakalant should be administered by intravenous infusion in a clinically monitored setting for cardioversion. Only a qualified healthcare professional should administer it.

Dosage

Vernakalant is dosed according to the patient's body weight, with a maximum dose based on 113 kg body weight. The initial infusion recommended is 3 mg/kg to infuse over a 10-minute period with an initial maximum dose of 339 mg (84.7 ml of the 4 mg/ml solution). If conversion to sinus rhythm has not occurred within 15 minutes from the end of the initial infusion, a second infusion of 10 minutes of 2 mg/kg (second maximum infusion of 226 mg (56.5 ml of the 4 mg/ml solution) may be administered. No more than two cumulative doses of 5 mg/kg should be administered within 24 hours.

The initial infusion is administered at a dose of 3 mg/kg over a 10-minute period.

During this period, the patient should be closely monitored for signs or symptoms of sudden decrease in blood pressure or heart rate. If these signs or symptoms appear, the infusion should be discontinued.

If conversion to sinus rhythm has not occurred, the patient's vital signs and heart 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 over a 10-minute period may be administered.

If conversion to sinus rhythm occurs during the initial infusion or second infusion, the infusion should be continued until its completion. If atrial flutter is observed after the initial infusion, a second infusion may be administered because patients may convert to sinus rhythm (see “Precautions and warnings” and “Adverse reactions”).

Patients weighing ≥ 113 kg

For patients over 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 has not occurred within 15 minutes from the end of the initial infusion, a second infusion of 10 minutes of 226 mg (56.5 ml of 4 mg/ml solution) may be administered. No cumulative doses above 565 mg have been evaluated.

After cardiac surgery

No dose adjustment is required.

Renal insufficiency

No dose adjustment is required (see “Pharmacokinetics”).

Liver insufficiency

No dose adjustment is required (see “Precautions and warnings” and “Pharmacokinetics”).

Older patients (≥ 65 years)

No dose adjustment is required.

Paediatric population

No specific recommendation for use in children and adolescents under 18 years for rapid conversion of recent-onset atrial fibrillation to sinus rhythm has been established, and vernakalant should not be used in this population.

Administration route

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.

To see the instructions for diluting the medicine before administration, see “Precautions for disposal and other manipulations”.

Contraindications

• Hypersensitivity to the active ingredient or to any of the excipients included in “List of excipients”.
• Patients with severe aortic stenosis, patients with systolic blood pressure < 100 mm Hg, and patients with heart failure of NYHA class III and IV.
• Patients with prolonged QT interval in the initial situation (> 440 ms uncorrected) or severe bradycardia, sinus node dysfunction, or second- and third-degree atrioventricular block, in the absence of pacemakers.
• Use of intravenous antiarrhythmic drugs for rhythm control (classes I and III) within 4 hours before administration, as well as in the first 4 hours after administration, of vernakalant.
• Acute coronary syndrome (including myocardial infarction) within the last 30 days.

Precautions and warnings

Monitoring the patient

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

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

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

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

Additionally, the patient should be monitored for 2 hours after starting the infusion and until clinical parameters and ECG have been 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 (potassium serum < 3.5 mmol/l), potassium levels should be corrected before using vernakalant.

A checklist is provided with the medicine. Before administration, the prescriber should determine the patient's suitability using the checklist provided. The checklist should be placed on the infusion pack so that it can be read by the healthcare professional administering it.

Hypotension

Hypotension may occur in a small number of patients (vernakalant, 5.7%, placebo, 5.5% in the first 2 hours after the dose). Hypotension typically occurs early, either during infusion or shortly after the end of 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”).

Patients should be closely monitored for signs and symptoms of sudden decrease in blood pressure or heart rate during infusion and at least for 15 minutes after the infusion is completed.

Heart failure

Patients with CHF showed a higher incidence of adverse events of hypotension in the first 2 hours after the dose (13.4% with vernakalant vs 4.7% with placebo, respectively). Severe hypotension was reported as a serious adverse event or leading to discontinuation of the medicine in 1.8% of these patients compared with 0.3% with placebo.

Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first 2 hours after the dose (6.4% with vernakalant vs 1.6% with placebo). These arrhythmias typically presented as ventricular tachycardias in situ, monomorphic, non-sustained (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 patients with stable CHF of NYHA classes I and II. There is limited experience with the use of vernakalant in patients with a previously documented left ventricular ejection fraction ≤ 35%. Vernakalant 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 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 with none of those treated with placebo. These patients should be closely monitored.

Atrial flutter

Vernakalant was not effective in converting typical primary atrial flutter to sinus rhythm. Patients receiving vernakalant have a higher incidence of converting to atrial flutter during the first 2 hours after the dose. This risk is higher in patients using class I antiarrhythmic drugs (see “Adverse reactions”). If secondary atrial flutter is observed after treatment, the continuation of treatment should be evaluated (see “Dosage and administration route”). In post-marketing experience, rare cases of atrial flutter with 1:1 atrioventricular conduction have been observed.

Other diseases and other problems notstudied

Vernakalant has been administered to patients with a QT interval not corrected < 440 ms without increased risk of torsades de pointes.

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

Due to limited experience, vernakalant should be used with caution in patients with advanced liver disease. Vernakalant has not been studied in patients with severe liver disease, and its use is not recommended in these cases.

No clinical data are available on repeated administration after initial and second infusions.

Electrical cardioversion

Cardioversion with direct current may be considered in patients who do not respond to treatment. There is no clinical experience with direct current cardioversion in the 2 hours following administration.

Use of antiarrhythmic drugs before or after administration of vernakalant

Due to lack of data, vernakalant should not be used in patients who, 4-24 hours before vernakalant administration, have received previously intravenous antiarrhythmic drugs (classes I and III). Vernakalant should not be administered to patients who, 4 hours before vernakalant, received intravenous antiarrhythmic drugs (classes I and III) (see “Contraindications”).

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

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

It may be considered to restart or initiate oral antiarrhythmic maintenance treatment 2 hours after vernakalant administration.

Sodium content

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

Interactions with other medicines and other forms ofinteractions

No interactions have been studied.

Vernakalant should not be administered to patients who have received intravenous antiarrhythmic drugs (classes I and III) within 4 hours before vernakalant administration (see “Contraindications”).

During the clinical development program, antiarrhythmic oral maintenance treatment was discontinued for at least 2 hours after vernakalant administration. It may be considered to restart or initiate oral antiarrhythmic maintenance treatment after this period of time (see “Contraindications” and “Precautions for disposal and other manipulations”).

Although vernakalant is a CYP2D6 substrate, pharmacokinetic (PK) analyses of populations demonstrated that no substantial differences in acute exposure to vernakalant (Cmax and AUC0-90 min) were observed when weak or potent CYP2D6 inhibitors were administered 1 day before vernakalant infusion compared with patients who did not receive concomitant treatment with CYP2D6 inhibitors. Additionally, acute exposure to vernakalant in patients with poor CYP2D6 metabolism is only minimally different compared with 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, as a result of the short half-life of vernakalant and the consequent transient nature of the 2D6 inhibition, it is not expected that the acute intravenous administration of vernakalant will have a notable impact on the PK of chronically administered substrates of 2D6. Due to rapid distribution and low protein binding, lack of inhibition of other CYP P450 enzymes (CYP3A4, 1A2, 2C9, 2C19, or 2E1), and lack of inhibition of the P-glycoprotein in a digoxin transport study, it is not expected that vernakalant, administered by infusion, will have significant interactions with medicines.

Precautions for disposal and other manipulations

Read all 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 time for infusion.

Preparation of BRINAVESS for infusion

Step 1:

Before administration, visually inspect the BRINAVESS vials for particles or color change. Do not use any vial that shows particles or color change. Note: BRINAVESS sterile concentrate for solution for infusion is colorless to pale yellow. Variations in color within this range do not affect potency.

Step 2: Dilution of theconcentrate

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

To prepare a solution with a concentration of 4 mg/ml, follow the dilution guidelines below:

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 injection, Ringer lactate solution for injection, or 5% glucose solution for injection.

Step 3: Inspect thesolution

The diluted sterile solution should be transparent, colorless to pale yellow. Before administration, visually inspect the solution for particles or color change.

The disposal of unused medicine and all materials that have come into contact with it should be carried out in accordance with local regulations.