4.1. Therapeutic indications

Symptomatic treatment of chronic stable angina pectoris.

Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated:

- in adults unable to tolerate or with a contraindication to the use of beta-blockers

- or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose.

Treatment of chronic heart failure

Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated (see section 5.1).

4.2. Posology and method of administration

Posology

For the different doses, film-coated tablets containing 5 mg and 7.5 mg ivabradine are available.

Symptomatic treatment of chronic stable angina pectoris.

It is recommended that the decision to initiate or titrate treatment takes place with the availability of serial heart rate measurements, ECG or ambulatory 24-hour monitoring.

The starting dose of ivabradine should not exceed 5 mg twice daily in patients aged below 75 years. After three to four weeks of treatment, if the patient is still symptomatic, if the initial dose is well tolerated and if resting heart rate remains above 60 bpm, the dose may be increased to the next higher dose in patients receiving 2.5 mg twice daily or 5 mg twice daily. The maintenance dose should not exceed 7.5 mg twice daily.

If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment of ivabradine should be discontinued.

In addition, discontinuation of treatment should be considered if there is only limited symptomatic response and when there is no clinically relevant reduction in resting heart rate within three months.

If, during treatment, heart rate decreases below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward including the lowest dose of 2.5 mg twice daily (one half 5 mg tablet twice daily). After dose reduction, heart rate should be monitored (see section 4.4). Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist despite dose reduction.

Treatment of chronic heart failure

The treatment has to be initiated only in patient with stable heart failure. It is recommended that the treating physician should be experienced in the management of chronic heart failure.

The usual recommended starting dose of ivabradine is 5 mg twice daily. After two weeks of treatment, the dose can be increased to 7.5 mg twice daily if resting heart rate is persistently above 60 bpm or decreased to 2.5 mg twice daily (one half 5 mg tablet twice daily) if resting heart rate is persistently below 50 bpm or in case of symptoms related to bradycardia such as dizziness, fatigue or hypotension. If heart rate is between 50 and 60 bpm, the dose of 5 mg twice daily should be maintained.

If during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia, the dose must be titrated downward to the next lower dose in patients receiving 7.5 mg twice daily or 5 mg twice daily. If heart rate increases persistently above 60 beats per minute at rest, the dose can be up titrated to the next upper dose in patients receiving 2.5 mg twice daily or 5 mg twice daily.

Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist (see section 4.4).

Special population

Elderly

In patients aged 75 years or more, a lower starting dose should be considered (2.5 mg twice daily i.e. one half 5 mg tablet twice daily) before up-titration if necessary.

Renal impairment

No dose adjustment is required in patients with renal insufficiency and creatinine clearance above 15 ml/min (see section 5.2).

No data are available in patients with creatinine clearance below 15 ml/min. Ivabradine should therefore be used with precaution in this population.

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercised when using ivabradine in patients with moderate hepatic impairment. Ivabradine is contraindicated for use in patients with severe hepatic insufficiency, since it has not been studied in this population and a large increase in systemic exposure is anticipated (see sections 4.3 and 5.2).

Paediatric population

The safety and efficacy of ivabradine in children aged below 18 years have not been established.

Currently available data for the treatment of chronic heart failure are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

No data for symptomatic treatment of chronic stable angina pectoris are available.

Method of administration

Tablets must be taken orally twice daily, i.e. once in the morning and once in the evening during meals (see section 5.2).

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Resting heart rate below 70 beats per minute prior to treatment

- Cardiogenic shock

- Acute myocardial infarction

- Severe hypotension (< 90/50 mmHg)

- Severe hepatic insufficiency

- Sick sinus syndrome

- Sino-atrial block

- Unstable or acute heart failure

- Pacemaker dependent (heart rate imposed exclusively by the pacemaker)

- Unstable angina

- AV-block of 3rd degree

- Combination with strong cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see sections 4.5 and 5.2)

- Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties (see section 4.5)

- Pregnancy, lactation and women of child-bearing potential not using appropriate contraceptive measures (see section 4.6)

4.4. Special warnings and precautions for use

Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris

Ivabradine is indicated only for symptomatic treatment of chronic stable angina pectoris because ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death) (see section 5.1).

Measurement of heart rate

Given that the heart rate may fluctuate considerably over time, serial heart rate measurements, ECG or ambulatory 24-hour monitoring should be considered when determining resting heart rate before initiation of ivabradine treatment and in patients on treatment with ivabradine when titration is considered. This also applies to patients with a low heart rate, in particular when heart rate decreases below 50 bpm, or after dose reduction (see section 4.2).

Cardiac arrhythmias

Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its efficacy when a tachyarrhythmia occurs (e.g. ventricular or supra- ventricular tachycardia). Ivabradine is therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function.

In patients treated with ivabradine the risk of developing atrial fibrillation is increased (see section 4.8). Atrial fibrillation has been more common in patients using concomitantly amiodarone or potent class I anti-arrhythmics. It is recommended to regularly clinically monitor ivabradine treated patients for the occurrence of atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse).

Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact their physician if these occur. If atrial fibrillation develops during treatment, the balance of benefits and risks of continued ivabradine treatment should be carefully reconsidered.

Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be monitored closely.

Use in patients with AV-block of 2nd degree

Ivabradine is not recommended in patients with AV-block of 2nd degree.

Use in patients with a low heart rate

Ivabradine must not be initiated in patients with a pre-treatment resting heart rate below 70 beats per minute (see section 4.3).

If, during treatment, resting heart rate decreases persistently below 50 bpm or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward or treatment discontinued if heart rate below 50 bpm or symptoms of bradycardia persist (see section 4.2).

Combination with calcium channel blockers

Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or diltiazem is contraindicated (see sections 4.3 and 4.5). No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established (see section 5.1).

Chronic heart failure

Heart failure must be stable before considering ivabradine treatment. Ivabradine should be used with caution in heart failure patients with NYHA functional classification IV due to limited amount of data in this population.

Stroke

The use of ivabradine is not recommended immediately after a stroke since no data is available in these situations.

Visual function

Ivabradine influences retinal function. There is no evidence of a toxic effect of long- term ivabradine treatment on the retina (see section 5.1). Cessation of treatment should be considered if any unexpected deterioration in visual function occurs.

Caution should be exercised in patients with retinitis pigmentosa.

Patients with hypotension

Limited data are available in patients with mild to moderate hypotension, and ivabradine should therefore be used with caution in these patients. Ivabradine is contraindicated in patients with severe hypotension (blood pressure < 90/50 mmHg) (see section 4.3).

Atrial fibrillation - Cardiac arrhythmias

There is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when pharmacological cardioversion is initiated in patients treated with ivabradine.

However, in the absence of extensive data, non-urgent DC-cardioversion should be considered 24 hours after the last dose of ivabradine.

Use in patients with congenital QT syndrome or treated with QT prolonging medicinal products

The use of ivabradine in patients with congenital QT syndrome or treated with QT prolonging medicinal products should be avoided (see section 4.5). If the combination appears necessary, close cardiac monitoring is needed.

Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise to severe arrhythmias, in particular Torsade de pointes.

Hypertensive patients requiring blood pressure treatment modifications.

When treatment modifications are made in chronic heart failure patients treated with ivabradine blood pressure should be monitored at an appropriate interval (see section 4.8).

Excipients

Since tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say it is essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Concomitant use not recommended

QT prolonging medicinal products

- Cardiovascular QT prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).

- Non cardiovascular QT prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).

The concomitant use of cardiovascular and non-cardiovascular QT prolonging medicinal products with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed (see section 4.4).

Concomitant use with precaution

Potassium-depleting diuretics (thiazide diuretics and loop diuretics): hypokalaemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalaemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced.

Pharmacokinetic interactions

Cytochrome P450 3A4 (CYP3A4)

Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with the risk of excessive bradycardia (see section 4.4).

Contraindication of concomitant use

Potent CYP3A4 inhibitors

The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, and telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see section 4.3). The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7 to 8-fold.

Moderate CYP3A4 inhibitors: specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with the heart rate reducing agents diltiazem or verapamil resulted in an increase in ivabradine exposure (2 to 3 fold increase in AUC) and an additional heart rate reduction of 5 bpm. The concomitant use of ivabradine with these medicinal products is contraindicated (see section 4.3).

Concomitant use not recommended

Grapefruit juice: ivabradine exposure was increased by 2-fold following the co- administration with grapefruit juice. Therefore, the intake of grapefruit juice should be avoided.

Concomitant use with precautions

- Moderate CYP3A4 inhibitors: the concomitant use of ivabradine with other moderate CYP3A4 inhibitors (e.g. fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is above 70 bpm, with monitoring of heart rate.

- CYP3A4 inducers: CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St John's Wort]) may decrease ivabradine exposure and activity. The concomitant use of CYP3A4 inducing medicinal products may re- quire an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice daily with St John's Wort was shown to reduce ivabradine AUC by half. The intake of St John's Wort should be restricted during the treatment with ivabradine.

Other concomitant use

Specific drug-drug interaction studies have shown no clinically significant effect of the following medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition, there was no clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.

In pivotal phase III clinical trials the following medicinal products were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, antialdosterone agents, short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet medicinal products.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of child-bearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).

Pregnancy

There are no or limited amount of data from the use of ivabradine in pregnant women. Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects (see section 5.3). The potential risk for humans is unknown. Therefore, ivabradine is contra-indicated during pregnancy (see section 4.3).

Breastfeeding

Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contra-indicated during breast-feeding (see section 4.3).

Women that need treatment with ivabradine should stop breast-feeding and choose for another way of feeding their child.

Fertility

Studies in rats have shown no effect on fertility in males and females (see section 5.3).

4.7. Effects on ability to drive and use machines

Ivabradine has no or negligible influence on the ability to use machines.

A specific study to assess the possible influence of ivabradine on driving performance has been performed in healthy volunteers where no alteration of the driving performance was evidenced. However, in post-marketing experience, cases of impaired driving ability due to visual symptoms have been reported. Ivabradine may cause transient luminous phenomena consisting mainly of phosphenes (see section 4.8). The possible occurrence of such luminous phenomena should be taken into account when driving or using machines in situations where sudden variations in light intensity may occur, especially when driving at night.

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 disorders

Uncommon

Eosinophilia

Metabolism and nutrition disorders

Uncommon

Hyperuricaemia

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, ECG prolonged QT interval

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 mediastinal disorders

Uncommon

Dyspnoea

Gastrointestinal disorders

Uncommon

Nausea

Constipation

Diarrhoea

Abdominal pain*

Skin and subcutaneous tissue disorders

Uncommon*

Angioedema

Rash

Rare*

Erythema

Pruritus

Urticaria

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasms

General disorders and administration site conditions

Uncommon*

Asthenia, possibly related to bradycardia

Fatigue, possibly related to bradycardia

Rare*

Malaise, possibly related to bradycardia

Renal and urinary disorders

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].

In the SHIFT trial more patients experienced episodes of increased blood pressure while treated with ivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred most frequently shortly after blood pressure treatment was modified, were transient, and did not affect the treatment effect of ivabradine.

Reporting of suspected adverse reactions

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 via: Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Overdose may lead to severe and prolonged bradycardia (see section 4.8).

Management

Severe bradycardia should be treated symptomatically in a specialised environment.

In the event of bradycardia with poor haemodynamic tolerance, symptomatic treatment including intravenous beta-stimulating medicinal products such as isoprenaline may be considered. Temporary cardiac electrical pacing may be instituted if required.