Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
Ivabradine has been studied in clinical trials involving nearly 45,000 participants.

The most common adverse reactions with ivabradine, luminous phenomena (phosphenes) and bradycardia, are dose dependent and related to the pharmacological effect of the medicinal product.

Tabulated list of adverse reactions
The following adverse reactions have been reported during clinical trials and are ranked using the following frequency: 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); very rare (<1/10,000); not known (cannot be estimated from the available data).

System Organ Class             Frequency           Preferred Term
Blood and lymphatic system     Uncommon            Eosinophilia disorders
Metabolism and nutrition       Uncommon            Hyperuricaemia disorders
Nervous system disorders       Common              Headache, generally during the first month of treatment
Dizziness, possibly related to bradycardia
Uncommon*           Syncope, possibly related to bradycardia
Eye disorders                  Very common         Luminous phenomena (phosphenes) Common              Blurred vision
Uncommon*           Diplopia
Visual impairment
Ear and labyrinth disorders    Uncommon            Vertigo
Cardiac disorders              Common              Bradycardia
AV 1st degree block (ECG prolonged
PQ interval)
Ventricular extrasystoles
Atrial fibrillation
Uncommon            Palpitations, supraventricular extrasystoles
Very rare           AV 2nd degree block, AV 3rd degree block
Sick sinus syndrome
Vascular disorders             Common              Uncontrolled blood pressure Uncommon*           Hypotension, possibly related to bradycardia
Respiratory, thoracic and      Uncommon            Dyspnoea mediastinal disorders
Gastrointestinal disorders     Uncommon            Nausea
Constipation
Diarrhoea
Abdominal pain*
Skin and subcutaneous tissue   Uncommon*           Angioedema disorders                                          Rash
Rare*               Erythema
Pruritus
Urticaria
Musculoskeletal and            Uncommon            Muscle cramps connective tissue disorders
General disorders and          Uncommon*               Asthenia, possibly related to administration site conditions                         bradycardia
Fatigue, possibly related to bradycardia
Rare*                  Malaise, possibly related to bradycardia
Investigations                  Uncommon               Elevated creatinine in blood ECG prolonged QT interval
* Frequency calculated from clinical trials for adverse events detected from spontaneous report

Description of selected adverse reactions
Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), coloured bright lights, or multiple image (retinal persistency). The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.

Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.

In the SIGNIFY study atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinical trials with a duration of at least 3 months including more than 40,000 patients, the incidence of atrial fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding to a hazard ratio of 1.26, 95% CI [1.15-1.39].

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Ministry of Health according to the National Regulation by using an online form (http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).