Package leaflet: Information for the user
BRINAVESS 20 mg/ml concentrate for solution for infusion
vernakalant hydrochloride
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor.
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What BRINAVESS is and what it is used for
2. What you need to know before you use BRINAVESS
3. How to use BRINAVESS
4. Possible side effects
5. How to store BRINAVESS
6. 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 changing your irregular or fast heart beat to a normal heart beat.
In adults it is used if you have a fast, irregular heart beat called atrial fibrillation which has started recently (less than or equivalent to 7 days) for non-surgery patients and less than or equivalent to 3 days for post-cardiac surgery patients.
2. What you need to know before you use BRINAVESS
Do not use BRINAVESS if:
• you are allergic to vernakalant hydrochloride or any of the other ingredients of this medicine (listed in section 6)
• you have had new or worsening chest pain (angina) diagnosed by your doctor as an acute coronary syndrome in the last 30 days or you have had a heart attack in the last 30 days
• you have a very narrow heart valve, systolic blood pressure less than 100 mm Hg or advanced heart failure with symptoms at minimal exertion or at rest
• you have an abnormally slow heart rate or skipped heart beats and do not have a pacemaker, or you have conduction disturbance called QT prolongation - which can be seen on an ECG by your doctor
• you take certain other intravenous medicines (antiarrhythmics Class I and III) used to normalize an abnormal heart rhythm, 4 hours before BRINAVESS is to be used
You must not use BRINAVESS if any of the above apply to you. If you are not sure, talk to your doctor before you use this medicine.
Warnings and precautions
Talk to your doctor before using BRINAVESS:
• if you have any of the following problems:
- heart failure
- certain heart diseases involving the heart muscle, lining that surrounds the heart and a severe narrowing of the heart valves
- a disease of the heart valves
- liver problems
- you are taking other rhythm control medicines
If you have very low blood pressure or slow heart rate or certain changes in your ECG while using this medicine, your doctor will stop your treatment.
Your doctor will consider if you need additional rhythm control medicine 4 hours after using BRINAVESS.
BRINAVESS may not work in treating some other kinds of abnormal heart rhythms, however your doctor will be familiar with these.
Tell your doctor if you have a pacemaker.
If any of the above apply to you (or you are not sure), talk to your doctor. Detailed information on warnings and precautions relating to side effects that could occur are presented in section 4.
Blood tests
Before giving you this medicine, your doctor will decide whether to test your blood to see how well it clots and also to see your potassium level.
Children and adolescents
There is no experience on the use of BRINAVESS in children and adolescents less than 18 years of age; therefore its use is not recommended.
Other medicines and BRINAVESS
Tell your doctor if you are taking, have recently taken or might take any other medicines.
Do not use BRINAVESS if you take certain other intravenous medicines (antiarrhythmics Class I and III) used to normalize an abnormal heart rhythm, 4 hours before BRINAVESS is to be used.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking any medicine.
It is preferable to avoid the use of BRINAVESS during pregnancy.
It is not known whether BRINAVESS passes into the breast milk.
Driving and using machines
It should be taken into account that some people may get dizzy after receiving BRINAVESS, usually within the first two hours (see section “Possible side effects”) . If you get dizzy, you should avoid driving or operating machinery after receiving BRINAVESS.
BRINAVESS contains sodium
This medicinal product contains approximately 1.4 mmol (32 mg) sodium in each 200 mg vial.
Each vial of 500 mg contains approximately 3.5 mmol (80 mg) of sodium.
Please take these amounts into consideration if you are on a controlled sodium diet.
3. How to use BRINAVESS
• BRINAVESS will be given to you by a health care professional. BRINAVESS will be diluted before being given to you. Information on how to prepare the solution is available at the end of this leaflet.
• It will be given to you into your vein over 10 minutes.
• The amount of BRINAVESS you may be given will depend on your weight. The recommended initial dose is 3 mg/kg. While you are being given BRINAVESS, your breathing, heart beat, blood pressure and the electrical activity of your heart will be checked.
• If your heart beat 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 of 2 mg/kg. Total doses of greater than 5 mg/kg should not be administered within 24 hours.
If you are given more BRINAVESS than you should
If you think that you may have been given too much BRINAVESS, tell your doctor straight away.
If you have any further questions on the use of this medicine, ask your doctor.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Your doctor may decide to stop the infusion if he observes any of the following abnormal changes of:
• your heart beat (such as an irregular or very fast heart beat (common), a missed beat (uncommon), or a short pause in the normal activity of your heart(uncommon))
• your blood pressure (such as a very low blood pressure causing a serious heart condition) (uncommon)
• the electrical activity of your heart (uncommon)
Other side effects:
Very common: may affect more than 1 in 10 people
• taste disturbances
• sneezing
These effects, seen within 24 hours of being given BRINAVESS, should pass quickly, however, if they do not you should consult your doctor .
Common: may affect up to 1 in 10 people
• pain at the infusion site, numbness or decreased skin sensation, tingling feelings or numbness
• nausea and vomiting
• feeling hot
• low blood pressure, slow heart beat, feeling dizzy
• headache
• coughing, sore nose
• sweating, itching
• numbness or tingling that occurs in the mucosa or tissues of the oral cavity
Uncommon: may affect up to 1 in 100 people
• certain kinds of heart beat problems, (such as an awareness of your heart beating (palpitations))
• eye irritation or watery eyes or changes in your vision
• a change in your sense of smell
• pain in your fingers and toes, a burning feeling
• cold sweats, hot flush
• urgency to have a bowel movement, diarrhoea
• shortness of breath or a tightness in the chest
• choking sensation
• numbness at the infusion site
• irritation at the infusion site
• feeling light-headed or fainting, generally feeling unwell, feeling drowsy or sleepy
• runny nose, sore throat
• stuffy nose
• dry mouth
• pale skin
• fatigue
• decreased feeling or sensitivity of the mouth
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store BRINAVESS
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and vial after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
BRINAVESS must be diluted before it is used. The diluted sterile concentrate is chemically and physically stable for 12 hours at or below 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Do not administer BRINAVESS if you notice particulate matter or discolouration.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What BRINAVESS contains
• The active substance is vernakalant hydrochloride. Each ml of concentrate contains 20 mg vernakalant hydrochloride equivalent to 18.1 mg vernakalant.
Each vial of 200 mg vernakalant hydrochloride is equivalent to 181 mg vernakalant.
Each vial of 500 mg of vernakalant hydrochloride is equivalent to 452.5 mg of vernakalant.
• The other ingredients are citric acid, sodium chloride, sodium hydroxide (E524) and water for injections.
What BRINAVESS looks like and contents of the pack
BRINAVESS is a concentrate for solution for infusion (sterile concentrate) which is clear and colourless to pale yellow.
Pack size of 1 vial available in two presentations containing either 200 mg or 500 mg of vernakalant hydrochloride.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Manufacturer:
Cardiome UK Limited Geodis Logistics Netherlands B.V.
Lakeside House Columbusweg 16
1 Furzeground Way 5928 LC Venlo
Stockley Park The Netherlands
Uxbridge
Middlesex
UB11 1BD
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.
België/Belgique/Belgien Lietuva
Cardiome UK Limited Cardiome UK Limited
Tél/Tel: +32 28 08 86 20 Tel: +41 848 00 79 70
България Luxembourg/Luxemburg
Cardiome UK Limited Cardiome UK Limited
Тел.: +41 848 00 79 70 Tél/Tel: +41 848 00 79 70
Česká republika Magyarország
Cardiome UK Limited Cardiome UK Limited
Tel: +41 848 00 79 70 Tel: +41 848 00 79 70
Danmark Malta
Cardiome UK Limited Cardiome UK Limited
Tlf: +45 8082 6022 Tel: +41 848 00 79 70
Deutschland Nederland
Cardiome UK Limited Cardiome UK Limited
Tel: +49 69 33 29 62 76 Tel: +31 20 808 32 06
Eesti Norge
Cardiome UK Limited Cardiome UK Limited
Tel: +41 848 00 79 70 Tlf: +41 848 00 79 70
Ελλάδα Österreich
Cardiome UK Limited Cardiome UK Limited
Τηλ: +41 848 00 79 70 Tel: +41 848 00 79 70
España Polska
Cardiome UK Limited Cardiome UK Limited
Tel: + 34 93 179 05 36 Tel: +41 848 00 79 70
France Portugal
CORREVIO Cardiome UK Limited
Tél: +33 1 77 68 89 17 Tel: +41 848 00 79 70
Hrvatska România
Cardiome UK Limited Cardiome UK Limited
Tél/Tel: +41 848 00 79 70 Tel: +41 848 00 79 70
Ireland Slovenija
Cardiome UK Limited Cardiome UK Limited
Tel: +41 848 00 79 70 Tel: +41 848 00 79 70
Ísland Slovenská republika
Cardiome UK Limited Cardiome UK Limited
Sími: +41 848 00 79 70 Tel: +41 848 00 79 70
Italia Suomi/Finland
Cardiome UK Limited Cardiome UK Limited
Tel: +39 02 600 63037 Puh/Tel: +41 848 00 79 70
Κύπρος Sverige
Cardiome UK Limited Cardiome UK Limited
Τηλ: +41 848 00 79 70 Tel: +46 8 408 38440
Latvija United Kingdom
Cardiome UK Limited Cardiome UK Limited
Tel: +41 848 00 79 70 Tel: +44 203 002 8114
This leaflet was last revised in 09/2016.
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
The following information is intended for healthcare professionals only:
Please refer to the Summary of Product Characteristics and the educational material for additional information prior to the use of BRINAVESS
4. CLINICAL PARTICULARS 4.1 Therapeutic indications
Rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults -For non-surgery patients: atrial fibrillation ≤ 7 days duration
-For post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration 4.2 Posology and method of administration
BRINAVESS should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion. Only a well-qualified healthcare professional should administer BRINAVESS and should frequently monitor the patient for the duration of the infusion and for at least 15 minutes after the completion of the infusion for signs and symptoms of a sudden decrease in blood pressure or heart rate (see section 4.4). 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 BRINAVESS.
Posology
BRINAVESS is dosed by patient body weight, with a maximum calculated dose based upon 113 kg. The recommended initial infusion is 3 mg/kg to be infused over a 10 minute period. For patients weighing ≥ 113 kg, the maximum initial dose of 339 mg (84.7 ml of 4 mg/ml solution) should not exceeded. 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. For patients weighing
≥ 113 kg, the maximum second infusion of 226 mg (56.5 ml of 4 mg/ml solution) should not exceeded
.Cumulative doses of greater than 5 mg/kg should not be administered within 24 hours. Cumulative doses above 565 mg have not been evaluated.
There are no clinical data on repeat doses after the initial and second infusions. By 24 hours there appears to be insignificant levels of vernakalant.
The initial infusion of BRINAVESS is administered as a 3 mg/kg dose over 10 minutes. During this period, the patient should be carefully monitored for any signs or symptoms of a sudden decrease in blood pressure or heart rate. If such signs develop, with or without symptomatic hypotension or bradycardia, the infusion should be stopped 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 did not occur with the initial infusion or within the 15 minute observation period, administer a 2 mg/kg second infusion over 10 minutes.
If conversion to sinus rhythm occurs during either the initial or second infusion, that infusion should be continued to completion. If haemodynamically stable atrial flutter is observed after the initial infusion, the second infusion of BRINAVESS may be administered as patients may convert to sinus rhythm (see sections 4.4 and 4.8).
Post-cardiac surgery patients:
No dose adjustment necessary.
Patients with renal impairment:
No dose adjustment necessary (see section 5.2).
Patients with hepatic impairment:
No dose adjustment necessary (see sections 4.4 and 5.2).
Elderly (≥ 65 years):
No dose adjustment necessary.
Paediatric population:
There is no relevant use of BRINAVESS in children and adolescents < 18 years of age in the current indication and therefore BRINAVESS should not be used in this population.
Method of administration
Intravenous use.
An infusion pump is the preferred delivery device. However, a syringe pump is acceptable provided that the calculated volume can be accurately given within the specified infusion time.
BRINAVESS should not be administered as an intravenous push or bolus.
BRINAVESS vials are for single use only and must be diluted prior to administration.
Recommended diluents are 0.9% Sodium Chloride for Injection, Lactated Ringers for Injection, or 5% Glucose for Injection.
For instructions on dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
• 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 < 100 mm Hg, and patients with heart failure class NYHA III and NYHA IV.
• Patients with prolonged QT at baseline (uncorrected > 440 msec), or severe bradycardia, sinus node dysfunction or second degree and third degree heart block in the absence of a pacemaker.
• Use of intravenous rhythm control antiarrhythmics (class I and class III) within 4 hours prior to, as well as in the first 4 hours after, BRINAVESS administration.
• Acute coronary syndrome (including myocardial infarction) within the last 30 days.
4.4 Special warnings and precautions for use
Cases of serious hypotension have been reported during and immediately following BRINAVESS 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 BRINAVESS 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 BRINAVESS, patients should not receive the second dose of BRINAVESS.
The patient should be further monitored for 2 hrs after the start of infusion and until clinical and ECG parameters have stabilised.
Direct-current cardioversion may be considered for patients who do not respond to therapy. There is no clinical experience with direct-current cardioversion under two hours postdose.
Prior to attempting pharmacological cardioversion, patients should be adequately hydrated and haemodynamically optimized and if necessary patients should be anticoagulated in accordance with treatment guidelines. In patients with uncorrected hypokalemia (serum potassium of less than
3.5 mmol/l), potassium levels should be corrected prior to use of BRINAVESS.
Hypotension
Hypotension can occur in a small number of patients (vernakalant 7.6%, placebo 5.1%). 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
(16.1% versus 4.7%, respectively). In patients without CHF the incidence of hypotension was not significantly different during the first 2 hours after dose in patients treated with vernakalant compared to patients receiving placebo (5.7% versus. 5.2%, respectively). Hypotension reported as a serious adverse experience or leading to medicine discontinuation occurred in CHF patients following exposure to BRINAVESS in 2.9% of these patients compared to 0% in placebo.
Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first two hours post dose (7.3% for BRINAVESS compared to 1.6% in placebo) . These arrhythmias typically presented as asymptomatic, monomorphic, non-sustained (average 3-4 beats) ventricular tachycardias. By contrast, ventricular arrhythmias were reported with similar frequencies in patients without a history of CHF who were treated with either BRINAVESS or placebo (3.2% for BRINAVESS versus 3.6% for placebo).
Due to the higher incidence of the adverse events 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).
Atrial flutter
BRINAVESS was not found to be effective in converting typical primary atrial flutter to sinus rhythm.
Patients receiving BRINAVESS 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 very rare cases of atrial flutter with 1:1 atrioventricular
conduction are observed.
Use of AADs (antiarrhythmic drugs) prior to or after BRINAVESS
BRINAVESS cannot be recommended in patients previously administered intravenous AADs (class I and III) 4-24 hours prior to vernakalant, due to lack of data. BRINAVESS must not be administered in patients who received intravenous AADs (class I and III) within 4 hours prior to vernakalant (see section 4.3).
BRINAVESS 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 BRINAVESS 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.
Valvular heart disease
In patients with valvular heart disease, there was a higher incidence of ventricular arrhythmia events in vernakalant patients. These patients should be monitored closely.
Other diseases and conditions not studied
BRINAVESS has been administered to patients with an uncorrected QT less than 440 msec without an increased risk of torsade de pointes.
Furthermore, BRINAVESS 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 BRINAVESS in patients with pacemakers.
As the clinical trial experience in patients with advanced hepatic impairment is limited, vernakalant is not recommended in these patients.
Sodium content
This medicinal product contains approximately 1.4 mmol (32 mg) sodium in each 200 mg vial. Each vial of 500 mg contains approximately 3.5 mmol (80 mg) of sodium. This should be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction No formal interaction studies have been undertaken with vernakalant injection.
BRINAVESS 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 BRINAVESS 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 (Cmax and
AUC0-90 min) 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 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.
6.6 Special precautions for disposal and other handling Read all steps before administration. Preparation of BRINAVESS for infusion
Step 1: BRINAVESS vials should be visually inspected for particulate matter and discolouration before administration. Any vials exhibiting particulate matter or discolouration should not be used. Note: BRINAVESS concentrate for solution for infusion ranges from colourless to pale yellow. Variations of colour within this range do not affect potency.
Step 2: Dilution of concentrate
To ensure proper administration, a sufficient amount of BRINAVESS 20 mg/ml should be prepared at the outset of therapy to deliver the initial and second infusion should it be warranted.
Create a solution with a concentration of 4 mg/ml following the dilution guidelines below:
Patients ≤100 kg: 25 ml of BRINAVESS 20 mg/ml is added to 100 ml of diluent.
Patients >100 kg: 30 ml of BRINAVESS 20 mg/ml is added to 120 ml of diluent.
Step 3: Inspection of the solution
The diluted sterile solution should be clear, colourless to pale yellow. The solution should be visually re-inspected for particulate matter and discolouration before administering.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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