BRINAVESS 20 mg/ml, concentrate for solution for infusion

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 fibrillationwhich has started recently (? 7 days) for non-surgery patients and ? 3 days for post-cardiac surgery patients . Your doctor will decide whether you should be treated with BRINAVESS.

You should not be given BRINAVESS if:

• you are allergic (hypersensitive) to vernakalant hydrochloride or any of the other ingredients of BRINAVESS (see 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 <100 mm Hgor advanced heart failure with symptoms at minimal exertion or at rest</li>
• 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 have been given certain otherintravenous medicines (anti-arrhythmics Class I and III) used to normalize an abnormal heart rhythm, 4 hours before BRINAVESS is to be given

You should not be given BRINAVESS if any of the above apply to you. If you are not sure, talk to your doctor before you are given this medicine.

Take special care with BRINAVESS

Check with your doctor before you are given 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 may stop your treatment.
Your doctor will consider if you need additional rhythm control medicine 4 hours after 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.

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.

Use in Children

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.

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription or herbal medicines and natural products.

Pregnancy and breast-feeding

• Talk to your doctor before having this medicine if you are pregnant or might become pregnant. This is because it is preferable to avoid the use of BRINAVESS during pregnancy.
• If you are breast-feeding or planning to breast-feed you should talk to your doctor before you are given BRINAVESS. This is because it should be used with care as it is not known whether BRINAVESS passes into the breast milk.

Ask your doctor for advice before taking any medicine, if you are pregnant or breast-feeding.

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 POSSIBLE SIDE EFFECTS.) If you get dizzy, you should avoid driving or operating machinery after receiving BRINAVESS.

Important information about some of the ingredients of BRINAVESS
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.
Take into consideration if you are on a controlled sodium diet.

• BRINAVESS will be given to you by a health care professional.
• 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. 26

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.

The following terms are used to describe how often side effects have been reported. very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000

Like all medicines, BRINAVESS can cause side effects, although not everybody gets them. Your doctor may decide to stop the infusion if your doctor observes any abnormal changes of:

• your heart beat
• your blood pressure
• the electrical activity of your heart Very common side effects seen within 24 hours of being given BRINAVESS include:
• taste disturbances
• sneezing These effects should pass quickly.

Other side effects include:
Common:

• numbness or pain at the infusion site, numbness or decreased skin sensation, tingling feelings or numbness
• nausea and vomiting
• feeling hot and tired
• low blood pressure, slow, fast or irregular heart beat,feeling dizzy
• headache
• coughing,dry mouth,sore nose
• sweating,itching

Uncommon:

• certain kinds of heart beat problems, (such as a short pause in the normal activity of your heart or a missed beat;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; itching
• urgency to have a bowel movement; diarrhoea
• shortness of breath or a tight chest
• irritation at the infusion site
• feeling light-headed or fainting;generally feeling unwell;feeling drowsy or sleepy
• runny nose; sore throat
• pale skin

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Keep out of the reach and sight of children.

Do not use BRINAVESS 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 medicinal product 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.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What BRINAVESS contains

• The active substance is vernakalant hydrochloride. Each ml of concentrate contains 20 mg vernakalant hydrochloride equivalent to 18.1 mg vernakalant free base.Each vial of 200 mg vernakalant hydrochloride is equivalent to 181 mg vernakalant free base. Each vial of 500 mg of vernakalant hydrochloride is equivalent to 452.5 mg of vernakalant free base.
• The other ingredients are citric acid, sodium chloride, sodium hydroxide and water for injection.

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

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder Manufacturer

Merck Sharp Dohme Ltd. Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom Merck Sharp Dohme B. V. Waarderweg 39, Postbus 581 NL-2003 PC Haarlem The Netherlands

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

LT Lietuva UAB Merck Sharp Dohme Tel. 370 5 278 02 47 msdlietuvamerck.com BELU Merck Sharp Dohme B.V. Succursale belgeBelgisch bijhuis TélTel 32 0 800 38693 MSDBelgiuminfomerck.com

BG . 359 2 819 3740 info-msdbgmerck.com HU MSD Magyarország Kft. Tel. 361 888 53 00 hungarymsdmerck.com

CS Merck Sharp Dohme IDEA, Inc., org. sl. Tel. 420 233 010 111 msdcrmerck.com MT Merck Sharp Dohme Cyprus Limited Tel 357 22866700 maltainfomerck.com

DK Merck Sharp Dohme Tlf 45 43 28 77 66 dkmailmerck.com NL Merck Sharp Dohme BV Tel 31 0 23 5153153 ms dbvnlmerck.com

DE MSD SHARP DOHME GMBH Tel 49 0 89 4561 2612 Infocentermsd.de NO MSD Norge AS Tlf 47 32 20 73 00 msdnorgemsd.no

EE Merck Sharp Dohme OÜ Tel. 372 613 9750 msdeestimerck.com AT Merck Sharp Dohme Ges.m.b.H. Tel 43 0 1 26 044 msd-medizinmerck.com

EL MSD 30 210 98 97 300 cora.greece.gragcmmerck.com PL MSD Polska Sp.z o.o. Tel. 48 22 549 51 00 msdpolskamerck.com

ES España Merck Sharp Dohme de España, S.A. Tel 34 91 321 06 00 BRINAVESSmsd.es PT Merck Sharp Dohme, Lda Tel 351 21 4465700 informacaodoentemerck.com

RO Merck Sharp Dohme Romania S.R.L. Tel 4021 529 29 00 msdromaniamerck.com FR France Laboratoires Merck Sharp Dohme Chibret Tél 33 0 1 47 54 87 00 contactmsd-france.com

SI Merck Sharp Dohme, inovativna zdravila d.o.o. Tel 386 1 5204201 msdsloveniamerck.com IE Merck Sharp and Dohme Ireland Human Health Limited Tel 353 01 2998700 medinfoirelandmerck.com

ÍS Icepharma hf. Sími 354 540 8000 ISmailmerck.com SK Merck Sharp Dohme IDEA, Inc. Tel. 421 2 58282010 msdskmerck.com

IT Merck Sharp Dohme Italia S.p.A. Tel 39 06 361911 doccenmerck.com FI MSD Finland Oy PuhTel 358 0 9 804650 infomsd.fi

CY Merck Sharp Dohme Cyprus Limited 357 22866700 cyprusinfomerck.com SE Merck Sharp Dohme Sweden AB Tel 46 0 8 626 1400 medicinskinfomerck.com

LV Latvija SIA Merck Sharp Dohme Latvija Tel 371 67364 224 msdlvmerck.com UK Merck Sharp and Dohme Limited Tel 44 0 1992 467272 medinfoukmerck.com

This leaflet was last approved in {MM/YYYY} .

The following information is intended for medical or 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, byqualified medical personnel in a monitored clinical setting appropriate for cardioversion.

Posology
BRINAVESS is dosed by patient body weight, with a maximum calculated dose based upon 113 kgs. The recommended initial infusion is 3 mg/kg to be infused over a 10 minute period. For patients weighing ? 113 kg, do not exceed the maximum initial dose of 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 2 mg/kg may be administered. For patients weighing ? 113 kg, do not exceed the maximum second infusion of 226 mg (56.5 ml of 4 mg/ml solution) .Cumulative doses of greater than 5 mg/kg should not be administered within 24 hours.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.

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.)

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.

Do not administer as an intravenous push or bolus.

Recommended diluents are 0.9% Sodium Chloride for Injection, Lactated Ringers for Injection, or 5% Glucose for Injection.

Read all steps before administration.

Preparation of BRINAVESS for infusion
Step 1: Visually inspect BRINAVESS vials for particulate matter and discolouration before administration. Do not use any vials exhibiting particulate matter or discolouration. 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: Inspect solution
The diluted sterile solution should be clear, colourless to pale yellow. Visually re-inspect the solution for particulate matter and discolouration before administering.

Method of administration
BRINAVESS vials are for single use only and must be diluted prior to administration.

Step 4: Administration of the initial infusion
The initial infusion of BRINAVESS is administered as a 3 mg/kg dose over 10 minutes.

Step 5: Patient observation
If conversion to sinus rhythm has not occurred, observe the patient?s vital signs and cardiac rhythm for an additional 15 minutes.

Step 6: Administration of second infusion
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.

Cumulative doses above 565 mg have not been evaluated.

Post-cardiac surgery patients:
No dose adjustment necessary.

Renal impairment:

No dose adjustment necessary (see section 5.2).

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 should not be used in this population.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients (see 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 anti-arrhythmics (class I and class III) within 4 hours prior to BRINAVESS administration.
• Acute coronary syndrome (including myocardial infarction) within the last 30 days.

4.4 Special warnings and precautions for use

Patients should be observed with assessment of vital signs and continuous cardiac rhythm monitoring during and after administration of BRINAVESS, 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, ensure that patients are 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.

During infusion of BRINAVESS, if patients develop clinically meaningful bradycardia and/or hypotension or develop 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), the administration of BRINAVESS should be discontinued and these patients should receive appropriate medical management. If these events occur during the first infusion of BRINAVESS, patients should not receive the second dose 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. Patients with congestive heart failure (CHF) have been identified as a population at higher risk for hypotension. (See section 4.8.)

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)

Use of AADs (anti-arrhythmic drugs) prior to or after BRINAVESS
BRINAVESS can not be recommended in patients previously administered intravenous AADs (class I and III) 4-24 hours prior to vernakalant, due to lack of data. BRINAVESS should 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 anti-arrhythmics (class I and class III) in the first 4 hours after BRINAVESS administration, therefore these agents should be used cautiously within this period. 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 can not 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.

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. 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

Any unused product or waste material should be disposed of in accordance with local requirements BRINAVESS does not contain a preservative.