Vernakalant Hydrochloride

Registered South African indications:

• Rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe aortic stenosis
• Systolic blood pressure <100mmHg
• Heart failure class NYHA III and NYHA IV
• Prolonged QT at baseline (uncorrected >440msec)
• Severe bradycardia
• Sinus node dysfunction
• Second degree and third degree heart block in the absence of a pacemaker
• Acute coronary syndrome (including myocardial infarction) within the last 30 days
• Coadministration with intravenous rhythm control antiarrhythmics (class I and class III) within 4 hours prior to, as well as in the first 4 hours after, vernakalant hydrochloride administration

Cautions

• Pregnancy
• Breastfeeding
• Severe hepatic impairment
• Congestive heart failure
• Heart failure class NYHA I and NYHA II
• Previously documented LVEF ≤35%
• Typical primary atrial flutter
• Valvular heart disease
• Clinically meaningful valvular stenosis
• Hypertrophic obstructive cardiomyopathy
• Restrictive cardiomyopathy
• Constrictive pericarditis
• Patients with pacemakers
• Patients on a controlled sodium diet
• May impair ability to drive and operate machinery

See additional prescribing points

Forms avail. in SA and covered in this monograph: inj

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

For patients weighing <113kg

• IV: Initial: 3mg/kg, as an infusion over 10 minutes; If conversion to sinus rhythm does not occur within 15 minutes, second dose: 2mg/kg an infusion over 10 minutes

For patients weighing ≥113kg

• IV: Initial: 3mg/kg, an infusion over 10 minutes; Max: 339mg (84.7ml of 4mg/ml solution); If conversion to sinus rhythm does not occur within 15 minutes, second dose: 2mg/kg an infusion over 10 minutes; Max: 226mg (56.5ml of 4mg/ml solution)

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 hydrochloride

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

Vernakalant hydrochloride should not be administered as an intravenous push or bolus

See additional prescribing points

Not established for use in South Africa for children below 18 years

Pregnancy

• Caution
• There are no data from the use of vernakalant hydrochloride in pregnant women. Animal studies have shown malformations after repeated oral exposure. As a precautionary measure, it is preferable to avoid the use of vernakalant during pregnancy

Breastfeeding

• Caution
• It is unknown whether vernakalant/metabolites are excreted in human milk. There is no information on the excretion of vernakalant/metabolites in animal milk. A risk to the breastfed child cannot be excluded. Caution should be exercised when used in breastfeeding women

Renal impairment

• No dose adjustment recommended

Hepatic impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Elderly

• No dose adjustment recommended

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Paraesthesia
• Dizziness
• Headache
• Hypoaesthesia
• Burning sensation
• Parosmia
• Somnolence
• Vasovagal syncope
• Fatigue

Cardiovascular Disorders

• Bradycardia
• Atrial flutter
• Sinus arrest
• Complete AV block
• First degree AV block
• Left bundle branch block
• Right bundle branch block
• Ventricular extrasystoles
• Palpitations
• Sinus bradycardia
• Ventricular tachycardia
• ECG QRS complex prolonged
• ECG QT prolonged
• Cardiogenic shock
• Hypotension

Respiratory Disorders

• Sneezing
• Cough
• Nasal discomfort
• Dyspnoea
• Suffocation feeling
• Rhinorrhoea
• Throat irritation
• Choking sensation
• Nasal congestion
• Chest discomfort

Gastrointestinal Disorders

• Nausea and vomiting
• Paraesthesia oral
• Diarrhoea
• Defecation urgency
• Dry mouth
• Hypoaesthesia oral

Musculoskeletal Disorders

• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Hyperhidrosis
• Generalised pruritus
• Cold sweat
• Pallor

Immune, Blood and Lymphatic System Disorders

• Flushing
• Hot flush

Sensory Disorders

• Eye irritation
• Lacrimation increased
• Visual impairment
• Dysgeusia

Others

• Infusion site pain
• Feeling hot
• Infusion site irritation
• Infusion site hypersensitivity
• Infusion site paraesthesia

• Class I and III antiarrhythmic drugs

See additional prescribing points

• Serum potassium
• ECG
• Blood pressure
• Heart rate
• Vital signs
• QT prolongation

Additional directions for use

• Vernakalant hydrochloride should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion. Only a well-qualified healthcare professional should administer vernakalant hydrochloride 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
• The initial infusion of vernakalant hydrochloride 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, a 2 mg/kg second infusion should be administered 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 first dose, the second dose of vernakalant hydrochloride may be administered as patients may convert to sinus rhythm
• Vernakalant hydrochloride vials are for single use only. Vernakalant hydrochloride must be diluted prior to administration. Vernakalant hydrochloride should only be administered by intravenous infusion

Administration directions

• Step 1: Vernakalant hydrochloride vials are for single use only and must be diluted prior to administration
  Vials should be visually inspected for particulate matter and discoloration before administration.
  Do not use any vials exhibiting particulate matter or discoloration
• Step 2: Dilution of concentrate
  To ensure proper administration, a sufficient amount of vernakalant hydrochloride 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 vernakalant hydrochloride 20 mg/ml is added to 100 ml of diluent
  Patients > 100 kg: 30 ml of vernakalant hydrochloride 20 mg/ml is added to 120 ml of diluent
  Recommended diluents are 0,9 % Sodium Chloride for Injection, Lactated Ringers for Injection, or 5 % Dextrose for Injection
• Step 3: Inspect the solution
  The diluted sterile concentrate should be a clear, colourless to pale yellow solution. Visually reinspect the solution for particulate matter and discoloration before administering
  The diluted sterile concentrate is chemically and physically stable for 12 hours at 15°C to 30°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
• Step 4: Administration of the initial infusion
  The initial infusion of vernakalant hydrochloride is administered as a 3mg/kg dose over 10 minutes. During this period the patient should be carefully monitored for any signs or symptoms of a rapid drop in blood pressure or heart rate. If such signs develop, with or without symptomatic hypotension or bradycardia, the infusion should be stopped immediately
• 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
  Discard any unused product or waste material used in the preparation of the admixture in accordance with regulations. Vernakalant hydrochloride does not contain a preservative. Do not save any unused product for later administration

Precautions for use

If any of the following signs or symptoms occurs, the administration of vernakalant hydrochloride 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)

Hypotension

• Cases of serious hypotension have been reported during and immediately following vernakalant hydrochloride 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

Congestive heart failure (CHF)

• 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 medicinal product discontinuation occurred in CHF patients following exposure to vernakalant hydrochloride in 2.9% of these patients compared to 0% in placebo

Use of antiarrhythmic drugs (AADs) prior to or after vernakalant hydrochloride

• Vernakalant hydrochloride cannot be recommended in patients previously administered intravenous AADs (class I and III) 4-24 hours prior to vernakalant due to lack of data. Vernakalant hydrochloride must not be administered in patients who received intravenous AADs (class I and III) within 4 hours prior to vernakalant
• Vernakalant hydrochloride 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
• There is limited experience with the use of intravenous rhythm control antiarrhythmics (class I and class III) in the first 4 hours after vernakalant hydrochloride administration, therefore these agents must not be used within this period
• Resumption or initiation of oral maintenance antiarrhythmic therapy can be considered starting 2 hours after vernakalant administration

Vernakalant acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow impulse conduction. These anti-fibrillatory actions on refractoriness and conduction are potentiated in the atria during atrial fibrillation and are thought to suppress re-entry. The relative selectivity of vernakalant on atrial versus ventricular refractoriness is postulated to result from the block of currents that are expressed in the atria, as well as the unique electrophysiologic condition of the fibrillating atria. However, blockade of cationic currents, including hERG channels and cardiac voltage-dependent sodium channels, which are present in the ventricles has been documented.

Injection (per ml) 20mg

• Brinavess (Pharmacare) originator