Brinavess 20 mg/ml, concentrate for solution for infusion
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Table of Contents
Package leaflet: Information for the user
Introduction
Package leaflet: information for the user
BRINAVESS 20mg/ml concentrate for solution for infusion
vernakalant hydrochloride
Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.
- Keep this leaflet, as you may need to read it again.
- If you have any questions, consult your doctor.
- If you experience any adverse reactions, consult your doctor, even if they are adverse reactions not listed in this leaflet. See section 4.
Contents of the leaflet
- What BRINAVESS is and what it is used for
- What you need to know before using BRINAVESS
- How to use BRINAVESS
- Possible adverse effects
- How to store BRINAVESS
- Contents of the pack and other information
1. What BRINAVESS is and what it is used for
BRINAVESS contains the active substance vernakalant hydrochloride. BRINAVESS works by converting your irregular or fast heartbeat into a normal heartbeat.
In adults, it is used when you have a fast or irregular heartbeat called atrial fibrillation that has recently started—within 7 days or less for non-surgical patients and within 3 days or less for patients following cardiac surgery.
2. What you need to know before using BRINAVESS
Do not use BRINAVESS:
- if you are allergic to vernakalant hydrochloride or to any of the other ingredients of this medicine (listed in section 6)
- if you have new or worsening chest pain (angina) diagnosed by your doctor as acute coronary syndrome within the last 30 days, or if you have had a heart attack within the last 30 days
- if you have severe heart valve narrowing, systolic blood pressure less than 100 mm Hg, or advanced heart failure with symptoms even with minimal exertion or at rest
- if you have an abnormally slow heart rate or skipped beats and do not have a pacemaker, or if you have a conduction disorder known as QT prolongation, which can be seen on an electrocardiogram performed by your doctor
- if you are taking certain intravenous antiarrhythmic medications (class I and III) used to normalize an abnormal heart rhythm within the 4 hours prior to using BRINAVESS
You must not use BRINAVESS if any of the above apply to you. If you are unsure, speak with your doctor before using this medicine.
Warnings and precautions
Talk to your doctor before using BRINAVESS if you have:
- heart failure
- certain heart conditions including heart muscle disease, the lining surrounding the heart, or severe narrowing of heart valves
- heart valve disease
- liver problems
- are taking other medications to control your heart rhythm
If you develop very low blood pressure, a slow heart rate, or certain changes in your electrocardiogram while receiving this medicine, your doctor will stop your treatment.
Your doctor will consider whether you need additional rhythm-controlling medication 4 hours after BRINAVESS administration.
BRINAVESS may not be effective in treating certain other types of abnormal heart rhythms; however, your doctor may be familiar with managing these.
Inform your doctor if you have a pacemaker.
If any of the above conditions apply to you (or if you are unsure), speak with your doctor. Section 4 provides detailed information on warnings and precautions related to potential adverse effects.
Blood tests
Before administering this medicine, your doctor will decide whether to perform blood tests to assess your blood clotting function and to check your potassium levels.
Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age, as there is no experience with use in this population.
Other medicines and BRINAVESS
Inform your doctor if you are using, have recently used, or might need to use any other medicines.
Do not use BRINAVESS if you are taking other intravenous antiarrhythmic medications (class I and III) used to normalize an abnormal heart rhythm within 4 hours before using BRINAVESS.
Pregnancy and breastfeeding
If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medicine.
Use of BRINAVESS during pregnancy is not recommended.
It is unknown whether BRINAVESS passes into breast milk.
Driving and using machines
You should be aware that some people may experience dizziness after receiving BRINAVESS, usually within the first two hours (see section "Possible side effects"). If you feel dizzy, you should avoid driving or operating machinery after receiving BRINAVESS.
BRINAVESS contains sodium
This medicine contains 32 mg of sodium (a main component of table/cooking salt) in each 200 mg vial. This corresponds to 1.6% of the maximum daily recommended sodium intake for an adult.
This medicine contains 80 mg of sodium (a main component of table/cooking salt) in each 500 mg vial. This corresponds to 4% of the maximum daily recommended sodium intake for an adult.
3. How to use BRINAVESS
The amount of BRINAVESS you will be given depends on your body weight. The recommended initial dose is 3 mg/kg, with a maximum dose calculated 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, heart rate, blood pressure, and electrical activity of your heart will be monitored.
If your heart rhythm has not returned to normal within 15 minutes after the end of your first dose, a second dose may be given. This will be a slightly lower dose of 2 mg/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. Total doses exceeding 5 mg/kg within 24 hours must not be administered.
A healthcare professional will administer BRINAVESS to you. BRINAVESS must be diluted before administration. Information on how to prepare the solution is provided at the end of this leaflet.
It will be given to you into a vein over 10 minutes.
If you receive more BRINAVESS than you should
If you think that you may have been given too much BRINAVESS, inform your doctor immediately.
If you have any further questions about the use of this medicine, ask your doctor.
4. Possible adverse effects
Like all medicines, this medicine can cause adverse effects, although not everyone 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 fast heartbeat (uncommon), very slow heartbeat (common), missed beats (uncommon), or a brief pause in heart activity (uncommon))
- your blood pressure (such as very low blood pressure causing a serious heart condition) (uncommon)
- the electrical activity of your heart (uncommon)
Other adverse effects:
Very common (may affect more than 1 in 10 people)
- taste disturbances
- sneezing
Common (may affect up to 1 in 10 people)
- fast heart rate
- pain or numbness at the infusion site, numbness, reduced skin sensation, or tingling sensation
- nausea and vomiting
- feeling of warmth
- low blood pressure, slow heartbeat, feeling dizzy
- cough, nasal pain
- excessive sweating, itching
- numbness or tingling sensation occurring in the mucosa or tissues of the oral cavity
Uncommon (may affect up to 1 in 100 people)
- certain types of heart rhythm problems (such as awareness of your own heartbeat (palpitations) or irregular heartbeats)
- reduced sense of touch
- eye irritation, tearing, or changes in vision
- change in sense of smell
- pain in fingers and toes, burning sensation
- cold sweats, hot flushes
- urgent need to defecate, diarrhoea
- shortness of breath or feeling of tightness in the chest
- feeling of suffocation
- mouth or throat pain
- irritation, itching at the infusion site
- high blood pressure
- feeling drowsy or faint, general feeling of being unwell, feeling sleepy
- very runny nose, sore throat
- nasal congestion
- dry mouth
- paleness of the skin
- generalized itching
- fatigue
- decreased sensitivity in the mouth
These effects, observed within 24 hours after administration of BRINAVESS, should resolve quickly. However, if they do not, you should consult your doctor.
Reporting of adverse effects
If you experience any type of adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system listed in Annex V. By reporting adverse effects, you can help provide more information on the safety of this medicine.
5. Storage of BRINAVESS
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the label of the vial after EXP. The expiry date refers to the last day of the month indicated.
This medicine does not require any special storage conditions.
BRINAVESS must be diluted before use. The sterile concentrate, once diluted, is chemically and physically stable for 12 hours at 25 °C or below.
From a microbiological standpoint, the medicine should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2 to 8 °C, unless the dilution was carried out under controlled and validated aseptic conditions.
Do not use this medicine if you observe particles or any change in colour.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.
6. Contents of the pack and other information
Composition of BRINAVESS
- The active substance is vernakalant hydrochloride. Each ml of concentrate contains 20 mg of vernakalant hydrochloride, equivalent to 18.1 mg of vernakalant.
Each vial containing 200 mg of vernakalant hydrochloride is equivalent to 181 mg of vernakalant.
Each vial containing 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 injections (see section 2 “BRINAVESS contains sodium”).
Appearance of the product and contents of the pack
BRINAVESS is a sterile concentrate for infusion solution that is transparent and colourless to pale yellow.
BRINAVESS is available in pack sizes of 1 vial containing either 200 mg or 500 mg of vernakalant hydrochloride.
Marketing Authorization Holder: Advanz Pharma Limited Unit 17, Northwood House Northwood Crescent Dublin 9, D09 V504 Ireland | Responsible for Manufacturing: Geodis CL Netherlands B.V. Columbusweg 16 5928 LC Venlo Netherlands |
You can request further information about this medicinal product by contacting the local representative of the marketing authorization holder:
Belgium/Belgium/Belgium Correvio Tel/Tel: +32 (0)800 78 941 | Lithuania Correvio Tel: +44 (0) 208 588 9131 |
Greece Correvio Tel: +44 (0) 208 588 9131 | Luxembourg/Luxembourg Correvio Tél/Tel: +44 (0) 208 588 9131 |
Czech Republic Correvio Tel: +44 (0) 208 588 9131 | Hungary Correvio Tel: +44 (0) 208 588 9131 |
Denmark Correvio Tlf: +44 (0) 208 588 9131 | Malta Correvio Tel: +44 (0) 208 588 9131 |
Germany Correvio Tel: +49 (0)800 180 20 91 | Netherlands Correvio Tel: +31 (0)800 022 93 82 |
Estonia Correvio Tel: +44 (0) 208 588 9131 | Norway Correvio Tlf: +44 (0) 208 588 9131 |
Greece Correvio Tel: +44 (0) 208 588 9131 | Austria Correvio Tel: +43 (0)800 298 022 |
Spain Advanz Pharma Spain S.L.U. Tel: +34 900 834 889 | Poland Correvio Tel: +44 (0) 208 588 9131 |
France Correvio Tél: +33 1 77 68 89 17 | Portugal Correvio Tel: +44 (0) 208 588 9131 |
Croatia Correvio Tel: +44 (0) 208 588 9131 | Romania Correvio Tel: +44 (0) 208 588 9131 |
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Italy Correvio Tel: +39 800 909 792 | Finland/Sweden Correvio Puh/Tel: +44 (0) 208 588 9131 |
Cyprus Correvio Tel: +44 (0) 208 588 9131 | Sweden Correvio Tel: +46 (0)20 088 02 36 |
Latvia Correvio Tel: +44 (0) 208 588 9131 | United Kingdom Correvio Tel: +44 (0) 208 588 9131 |
Date of last revision of this package leaflet:
Other sources of information
Detailed information on this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu.
This information is intended for healthcare professionals only:
Please, before using BRINAVESS, consult the Summary of Product Characteristics and the educational material for additional information.
CLINICAL DATA
Therapeutic indications
Brinavess is indicated in adults for rapid conversion of recent-onset atrial fibrillation to sinus rhythm
- In non-surgical patients: atrial fibrillation ≤ 7 days in duration
- In patients after cardiac surgery: atrial fibrillation ≤ 3 days in duration
Posology and method of administration
Vernakalant must be administered by intravenous infusion in a clinically monitored setting appropriate 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 calculated based on 113 kg. The recommended initial infusion is 3 mg/kg administered over a period of 10 minutes, with a maximum initial dose of 339 mg (84.7 ml of the 4 mg/ml solution). If conversion to sinus rhythm has not occurred 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)). Cumulative doses exceeding 5 mg/kg within 24 hours must not be administered.
The initial infusion is given at a dose of 3 mg/kg over 10 minutes. During this period, the patient must be carefully monitored for signs or symptoms of sudden drop in blood pressure or heart rate. If such signs occur, with or without symptomatic hypotension or bradycardia, the infusion must be immediately discontinued.
If conversion to sinus rhythm has not occurred, the patient's vital signs and cardiac rhythm must be observed for an additional 15 minutes.
If conversion to sinus rhythm has not occurred after the initial infusion or within the 15-minute observation period, administer a second 10-minute infusion of 2 mg/kg.
If conversion to sinus rhythm occurs during the initial or second infusion, the infusion should continue until completion. If stable atrial flutter is observed after the initial infusion, the second infusion may be administered, as patients may convert to sinus rhythm (see “Warnings and special precautions for use” and “Adverse effects”).
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 the 4 mg/ml solution). If conversion to sinus rhythm has not occurred within 15 minutes after the end of the initial infusion, a second 10-minute infusion of 226 mg (56.5 ml of the 4 mg/ml solution) may be administered. Cumulative doses above 565 mg have not been evaluated.
After cardiac surgery
Dose adjustment is not required.
Renal impairment
Dose adjustment is not required (see “Pharmacokinetic properties”).
Hepatic impairment
Dose adjustment is not required (see “Warnings and special precautions for use” and “Pharmacokinetic properties”).
Elderly patients (≥65 years)
Dose adjustment is not required.
Paediatric population
There is no specific recommendation for the use of vernakalant in children and adolescents under 18 years of age for rapid conversion of recent-onset atrial fibrillation to sinus rhythm, and therefore vernakalant should not be used in this population.
Method of administration
Intravenous use.
Vernakalant must not be administered as a bolus or rapid injection.
Vials are for single use only and must be diluted before administration.
For instructions on dilution of the medicinal product prior to administration, see section “Special precautions for disposal and other handling”.
Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in the “List of excipients”.
- Patients with severe aortic stenosis, patients with systolic blood pressure < 100 mm Hg, and patients with NYHA class III and IV heart failure.
- Patients with prolonged QT interval at baseline (> 440 ms uncorrected) or severe bradycardia, sinus node dysfunction, or second- or third-degree atrioventricular block in the absence of a pacemaker.
- Use of intravenous antiarrhythmic drugs for rate or rhythm control (classes I and III) within 4 hours prior to administration, as well as within the first 4 hours after administration, of vernakalant.
- Acute coronary syndrome (including myocardial infarction) within the last 30 days.
Warnings and special precautions for use
Patient monitoring
Severe hypotension has been reported during and immediately after vernakalant infusion. Patients must be carefully observed throughout the entire 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 occur, the vernakalant infusion must be discontinued and appropriate medical treatment initiated:
- 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 atrioventricular block, new bundle branch block, significant QRS or QT interval prolongation, changes consistent with ischemia or infarction, or ventricular arrhythmia)
If such events occur during the first vernakalant infusion, the patient must not receive the second dose.
Additionally, the patient must be monitored for 2 hours after the start of the infusion until clinical parameters and ECG have stabilized.
Precautions prior to infusion
Before attempting pharmacological cardioversion, patients should be adequately hydrated and hemodynamically optimized. If necessary, patients should be anticoagulated in accordance with treatment guidelines. In patients with uncorrected hypokalemia (serum potassium < 3.5 mmol/l), potassium levels must be corrected before using vernakalant.
A pre-infusion checklist is provided with the medicinal product. Prior to administration, prescribers are required to use the provided checklist to determine patient suitability. The checklist must be attached to the infusion container so that it can be reviewed by the healthcare professional administering the drug.
Hypotension
Hypotension may occur in a small number of patients (vernakalant, 5.7%; placebo, 5.5% within the first 2 hours after dosing). Hypotension typically occurs early, either during or shortly after the infusion, and is usually manageable with standard supportive measures. Severe hypotension has been reported infrequently. Patients with congestive heart failure (CHF) have been identified as being at higher risk for hypotension (see “Adverse effects”).
Patients must be monitored for signs and symptoms of sudden drop in blood pressure or heart rate during the infusion and for at least 15 minutes after completion.
Congestive heart failure (CHF)
Patients with CHF showed a higher overall incidence of hypotension events within the first 2 hours after administration in those treated with vernakalant compared to placebo (13.4% vs. 4.7%, respectively). Hypotension reported as a serious adverse event or leading to drug discontinuation occurred in 1.8% of CHF patients after exposure to vernakalant compared to 0.3% with placebo.
Patients with a history of CHF showed a higher incidence of ventricular arrhythmia within the first 2 hours after dosing (6.4% with vernakalant vs. 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 hypotension and ventricular arrhythmia adverse events in CHF patients, vernakalant should be used with caution in hemodynamically stable patients with NYHA functional classes I–II heart failure. Experience with vernakalant in patients with previously documented left ventricular ejection fraction ≤ 35% is limited. Its use is not recommended in these patients. Use is contraindicated in patients with CHF corresponding to NYHA class III or IV (see “Contraindications”).
Valvular heart disease
In patients with valvular heart disease, there is a higher incidence of ventricular arrhythmia events in those treated with vernakalant up to 24 hours after dosing. Within the first 2 hours, 6.4% of patients treated with vernakalant experienced ventricular arrhythmia compared to none in the placebo group. 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 within the first 2 hours after dosing. This risk is higher in patients taking class I antiarrhythmic drugs (see “Adverse effects”). If atrial flutter occurs secondary to treatment, continuation of therapy should be evaluated (see “Posology and method of administration”). In post-marketing experience, rare cases of atrial flutter with 1:1 atrioventricular conduction have been observed.
Other diseases and unstudied conditions
Vernakalant has been administered to patients with uncorrected QT interval < 440 ms without increased risk of torsade de pointes.
Furthermore, vernakalant has not been studied in patients with clinically significant valvular stenosis, obstructive hypertrophic cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis, and its use cannot be recommended in these cases. Experience with BRINAVESS in patients with pacemakers is limited.
As clinical experience in patients with advanced hepatic impairment is limited, vernakalant is not recommended in these patients.
There are no clinical data on repeated administration after the initial and second infusions.
Electrical cardioversion
Electrical cardioversion may be considered in patients who do not respond to treatment. There is no clinical experience with direct current cardioversion within 2 hours following administration.
Use of antiarrhythmic drugs before or after vernakalant administration
Due to lack of data, vernakalant is not recommended in patients who have received intravenous antiarrhythmic drugs (classes I and III) 4–24 hours prior to vernakalant administration. Vernakalant must not be administered to patients who received intravenous antiarrhythmic drugs (classes I and III) within 4 hours prior to vernakalant (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).
Experience with intravenous rhythm-controlling antiarrhythmic drugs (classes I and III) within the first 4 hours after vernakalant administration is limited; therefore, these medications should not be used during this period (see “Contraindications”).
Resumption or initiation of maintenance oral antiarrhythmic therapy may be considered 2 hours after vernakalant administration.
Sodium content
This medicinal product contains 32 mg of sodium per 200 mg vial, equivalent to 1.6% of the maximum daily intake of 2 g sodium recommended by the WHO for adults. This medicinal product contains 80 mg of sodium per 500 mg vial, equivalent to 4% of the maximum daily intake of 2 g sodium recommended by the WHO for adults.
Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Vernakalant must not be administered to patients who have received intravenous antiarrhythmics (classes I and III) within 4 hours prior to vernakalant administration (see “Contraindications”).
Within the clinical development program, maintenance oral antiarrhythmic therapy was withheld for at least 2 hours after vernakalant administration. Resumption or initiation of maintenance oral antiarrhythmic therapy may be considered after this period (see “Contraindications” and “Special precautions for disposal and other handling”).
Although vernakalant is a substrate of CYP2D6, population pharmacokinetic (PK) analyses showed no substantial differences in acute vernakalant exposure (Cmax and AUC0–90 min) when weak or potent CYP2D6 inhibitors were administered within 1 day prior to vernakalant infusion, compared to patients not receiving concomitant CYP2D6 inhibitors. Additionally, acute vernakalant exposure in poor CYP2D6 metabolizers is only minimally different compared to extensive metabolizers. No dose adjustment of vernakalant is required based on CYP2D6 metabolizer 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 resulting transient nature of 2D6 inhibition, intravenous administration of vernakalant is not expected to have a significant impact on the PK of chronically administered CYP2D6 substrates. Due to rapid distribution, transient exposure, low protein binding, lack of inhibition of other studied CYP P450 enzymes (CYP3A4, 1A2, 2C9, 2C19, or 2E1), and no inhibition of P-glycoprotein in a digoxin transport assay, vernakalant administered by infusion is not expected to have significant interactions with other medications.
Special precautions for disposal and other handling
Read all steps before administration.
The preferred administration device is an infusion pump. However, a syringe pump may be used provided the calculated volume can be adequately administered within the specified infusion time.
Preparation of BRINAVESS for infusion
Step 1:
Before administration, visually inspect BRINAVESS vials for particles or discoloration. Do not use any vial showing particles or discoloration. Note: BRINAVESS concentrate for infusion solution ranges from colourless to pale yellow. Colour variations within this range do not affect potency.
Step 2: Dilution of concentrate
To ensure adequate preparation, sufficient BRINAVESS 20 mg/ml should be prepared at the beginning of treatment to administer both the initial and second infusion if needed.
Prepare a solution with a concentration of 4 mg/ml following these 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 0.9% sodium chloride for injection, Ringer's lactate solution for injection, or 5% glucose solution for injection.
Step 3: Inspect the solution
The diluted sterile solution should be clear, colourless to pale yellow. Before administration, visually re-inspect the solution for particles or discoloration.
Any unused medicinal product and materials that have come into contact with it must be disposed of in accordance with local regulations.