Brinavess · 4.1 Therapeutic indications · 1

HOS-095660 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most commonly reported adverse reactions (> 5 %) seen in the first 24 hours after receiving vernakalant were dysgeusia (taste disturbance) (17.9 %), sneezing (12.5 %), and paraesthesia (6.9 %). These reactions occurred around the time of infusion, were transient and were rarely treatment limiting. Tabulated list of adverse reactions The adverse reaction profile presented below is based on the analysis of pooled clinical trials, a post-authorisation safety study and spontaneous reporting. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000). Table 1: Adverse reactions a Nervous system Very common: Dysgeusia disorders Common: Paraesthesia; dizziness Uncommon: Hypoaesthesia; burning sensation; parosmia; syncope; somnolence Eye disorders Uncommon: Lacrimation increased; eye irritation; visual impairment Cardiac disorders Common: Bradycardia b; atrial flutter b Uncommon: Sinus arrest; ventricular tachycardia; palpitations; bundle branch block left; ventricular extrasystoles; AV block first degree; AV block complete; bundle branch block right; sinus bradycardia; ECG QRS complex prolonged; cardiogenic shock, blood pressure diastolic increased Rare: Atrial flutter with 1:1 atrioventricular conduction b, c Vascular disorders Common: Hypotension Uncommon: Flushing; hot flush; pallor 7  Respiratory, thoracic and Very common: Sneezing mediastinal disorders Common: Cough; nasal discomfort Uncommon: Dyspnoea; throat irritation; oropharyngeal pain; nasal congestion; suffocation feeling; choking sensation; rhinorrhoea Gastrointestinal disorders Common: Nausea; paraesthesia oral; vomiting Uncommon: Dry mouth; diarrhoea; hypoaesthesia oral; defecation urgency Skin and subcutaneous Common: Pruritus; hyperhidrosis tissue disorders

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HOS-095656 · has-contraindication-information · PDF-Seite 3

• 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 ms), or severe bradycardia, sinus node dysfunction or second degree and third degree heart block in the absence of a pacemaker. 3 • 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, vernakalant administration. • Acute coronary syndrome (including myocardial infarction) within the last 30 days.

HOS-095655 · has-indication-information · PDF-Seite 2

Brinavess is indicated in adults for rapid conversion of recent onset atrial fibrillation to sinus rhythm -For non-surgery patients: atrial fibrillation ≤ 7 days duration -For post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration

HOS-095658 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed. Vernakalant 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 vernakalant 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 AUC0-90min) 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 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.

HOS-095659 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no data from the use of vernakalant hydrochloride in pregnant women. Studies in animal have shown malformations after repeated oral exposure (see section 5.3). As a precautionary measure, it is preferable to avoid the use of vernakalant during pregnancy. Breast-feeding 6 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 newborns/infants cannot be excluded. Caution should be exercised when used in breast-feeding women. Fertility Vernakalant was not shown to alter fertility in animal studies.

HOS-095657 · has-warning-information · PDF-Seite 4

Patient monitoring Cases of serious hypotension have been reported during and immediately following vernakalant 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 vernakalant 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 vernakalant, patients should not receive the second dose. The patient should be further monitored for 2 hrs after the start of infusion and until clinical and ECG parameters have stabilised. Precautions before infusion Prior to attempting pharmacological cardioversion, patients should be adequately hydrated and haemodynamically optimised and if necessary patients should be anticoagulated in accordance with treatment guidelines. In patients with uncorrected hypokalaemia (serum potassium of less than 3.5 mmol/l), potassium levels should be corrected prior to use of vernakalant. 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 it. Hypotension Hypotension can occur in a small number of patients (vernakalant 5.7 %, placebo 5.5 % in the first 2 hours post-dose). 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 th

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