Bradhet 5 mg & 7,5 mg Tablets

Symptomatic treatment of chronic stable angina pectoris: BRADHET is indicated for the symptomatic treatment of chronic stable angina pectoris, in patients with normal sinus rhythm and heart rate u2265 70 bpm, as monotherapy or in combination with beta-blockers.

Treatment of chronic heart failure: BRADHET is indicated in adults in sinus rhythm with mild to moderate (NYHA II & III class) symptomatic heart failure whose heart rate is u2265 77 bpm to reduce cardiovascular events (cardiovascular mortality or hospitalisation for worsening heart failure), in combination with standard therapy including beta-blockers or when beta-blockers are contraindicated or not tolerated.

Posology

Symptomatic treatment of chronic stable angina pectoris: It is recommended that the decision to initiate or titrate treatment takes place using serial heart rate measurements, ECG or ambulatory 24-hour monitoring. The starting dose of BRADHET in patients below 75 years of age should not exceed 5 mg twice daily. After two 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 a maximum of 7,5 mg twice daily depending on the therapeutic response. If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment of BRADHET should be discontinued (see section 4.4). 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 bpm at rest or the patient experiences symptoms related to bradycardia, such as dizziness, fatigue or hypotension, the dosage 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 the heart rate remains below 50 bpm or symptoms of bradycardia persist, despite dose reduction.

Treatment of chronic heart failure: The recommended starting dose of ivabradine is 5 mg twice daily in patients below 75 years of age. After two weeks of treatment, the dose can be increased to a maximum of 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, the heart rate decreases persistently to 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 the heart rate increases persistently to above 60 beats per minute at rest, the dose can be up titrated to the next higher 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 populations

Elderly patients: 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.

Patients with renal impairment: No dose adjustment is required in patients with renal insufficiency and creatinine clearance above 15 ml/min (see section 5). No data are available in patients with creatinine clearance below 15 ml/min. BRADHET should therefore be used with precaution in this population.

Patients with hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. BRADHET is not recommended in patients with moderate hepatic insufficiency, since there is limited data and is contraindicated for use in patients with severe hepatic insufficiency, since it has not been studied in this population (see section 4.3).

Paediatric population: The safety and efficacy of BRADHET in children aged below 18 years have not yet been established.

Method of administration

BRADHET tablets must be taken orally twice daily, i.e. once in the morning and once in the evening. BRADHET tablets should be taken with food.

Pregnancy and lactation, as BRADHET has shown to be teratogenic in animal reproductive studies (see section 4.6).

• Known hypersensitivity to ivabradine or to any of the excipients of BRADHET (see section 6.1).
• 3rd degree atrioventricular (AV) Block.
• Pacemaker dependent (heart rate imposed exclusively by the pacemaker).
• Resting heart rate below 70 bpm prior to treatment.
• Severe hypotension (< 90/50 mmHg).
• Cardiogenic shock.
• Unstable or acute heart failure.
• Acute coronary syndrome.
• Unstable angina pectoris.
• Use in patients with congenital long QT syndrome or in patients treated with QT-prolonging medicines should be avoided (see section 4.4).
• In combination with strong cytochrome P450 inhibitors such as azole antifungals, macrolide antibiotics, HIV protease inhibitors (see section 4.5).
• Concomitant use of St Johnu2019s Wort.
• BRADHET is not recommended in patients with moderate liver dysfunction (limited data in these populations) and is contraindicated in severe liver dysfunction (no data).
• Combination with verapamil or diltiazem, which are moderate CYP3A4 inhibitors with heart-rate reducing properties (see section 4.5).
• Women of childbearing potential not using appropriate contraceptive measures (see section 4.6).
• Concomitant use of grapefruit juice is not recommended (see section 4.5).
• Concomitant use with QT-prolonging medicines: The concomitant use of cardiovascular (quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone) or non-cardiovascular (tricyclic antidepressant, antipsychotics, erythromycin IV, pentamidine, pimozide, mefloquine) QT-prolonging medicines with BRADHET should be avoided since QT-prolongation may be exacerbated by heart rate reduction.
• BRADHET has not been studied in patients with rapid conduction disorders i.e. WPW.
• Cardiac dysrhythmias:
• sick sinus syndrome.
• sino-atrial block.
• Stroke: The use of BRADHET is not recommended immediately after a stroke since no data are available in these situations.
• Use in patients with AV-block of 2nd degree: BRADHET is not recommended in patients with AV-block of 2nd degree.
• Acute myocardial infarction.

BRADHET treatment should be discontinued if the symptoms of angina pectoris do not improve with 3 months of BRADHET treatment. Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris: BRADHET is indicated only for symptomatic treatment of chronic stable angina pectoris, because BRADHET has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death).

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

Chronic heart failure: Heart failure must be stable before considering ivabradine treatment.

Use in patients with a low heart rate: BRADHET must not be initiated in patients with a pre-treatment resting heart rate below 70 beats per minute (see section 4.3). If, during BRADHET treatment, heart rate decreases below 50 bpm at rest or the patient experiences symptoms related to bradycardia, the dose must be titrated downward or discontinued. Treatment must be discontinued if heart rate below 50 bpm persists (see section 4.2).

Combination with other anti-angina medications: Concomitant use of BRADHET with heart rate reducing calcium channel blockers such as verapamil or diltiazem is contraindicated (see sections 4.3 and 4.5). Additional efficacy of BRADHET in combination with dihydropyridine calcium channel blockers has not been established.

Use in patients with congenital QT syndrome or in patients treated with QT-prolongation medicines: Since BRADHET reduces heart rate it should be avoided in patients with congenital QT syndrome or treated with QT-prolongations medicines. If the combination appears necessary, close cardiac monitoring is needed. Heart rate reduction, as caused by BRADHET, may exacerbate QT-prolongation, which may give rise to severe dysrhythmias, in particular Torsade de pointes.

Cardiac dysrhythmias: BRADHET is not effective in the treatment or prevention of cardiac dysrhythmias and likely loses its efficacy when a tachy-dysrhythmia occurs (i.e. ventricular or supra-ventricular tachycardia). BRADHET is not recommended in patients with atrial fibrillation or with other cardiac dysrhythmias that interfere with sinus node function. In patients treated with BRADHET the risk of developing atrial fibrillation is increased (see section 4.8). Atrial fibrillation has been more common in patients concomitantly using amiodarone or potent class I anti-dysrhythmics. It is recommended to regularly clinically monitor BRADHET treated patients for the occurrence of atrial fibrillation (sustained of paroxysmal), which should also include ECG monitoring if clinically indicated (i.e. in case of exacerbated angina, palpitations or irregular pulse). Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact their medical practitioner if these occur. If atrial fibrillation develops during treatment, the balance of benefits and risks of continued BRADHET treatment should be carefully reconsidered.

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

Visual function: Ivabradine influences on retinal function. To date, there is no evidence of a toxic effect of ivabradine on the retina, but the effects of long-term ivabradine treatment beyond one year on retinal function are currently not known. Cessation of treatment should be considered if any unexpected deterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa.

Wolf-Parkinson-White-syndrome: BRADHET has not been studied in patients with Wolf-Parkinson-White-syndrome (see section 4.3).

Moderate to severe liver dysfunction: BRADHET is not recommended in patients with moderate liver dysfunction since there is limited data in these populations and is contraindicated in severe liver dysfunction (see section 4.3).

Aortic and/or Mitral valvular disease: Due to the lack of data, BRADHET is not recommended in patients with severe aortic and/or mitral valvular disease.

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

Concomitant use with cytochrome P450 3A4 (CYP3A4) inhibitors or inducers: Strong CYP3A4 inhibitors: As these medicines significantly increase BRADHET plasma concentrations, their concomitant use with BRADHET is contraindicated (see section 4.3). Moderate CYP3A4 inhibitors: As these medicines increase ivabradine plasma concentrations, their concomitant use with BRADHET may require a downward titration of the dose of BRADHET depending on heartrate (see section 4.5). CYP3A4 inducers: As these medicines decrease ivabradine plasma concentrations, their prolonged concomitant use with BRADHET may require an upward titration of the dose of BRADHET depending on the therapeutic response. In this case, heart rate monitoring is recommended when discontinuing CYP3A4 inducers (see section 4.5).

Hypertension requiring blood pressure treatment modifications: As patients treated with BRADHET may experience episodes of increased blood pressure, blood pressure should be monitored at appropriate intervals (see section 4.8).

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

Lactose warning: BRADHET contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pharmacokinetic interactions: Cytochrome P450 3A4 (CYP3A4): Ivabradine is metabolised by cytochrome P450 3A4 (CYP3A4) and is a weak inhibitor of this cytochrome. Therefore, ivabradine is unlikely to influence the metabolism and plasma concentrations of other CYP3A4 substrates. CYP3A4 inhibitors and inducers are liable to interact with ivabradine and to influence its metabolism and pharmacokinetics. 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 excessive bradycardia (see section 4.3).

Concomitant use contraindicated: The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin taken orally, josmycin, telithromycin), HIV protease inhibitors (including nelfinavir, ritonavrir) is contraindicated (see section 4.3). The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased the mean plasma exposure of ivabradine by 7 to 8 fold.

Moderate CYP3A4 inhibitors: Specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with diltiazem and verapamil resulted in an increased ivabradine exposure (2 to 3 fold increase in AUC) with an additional heart rate reduction of 5 bpm. The concomitant use of ivabradine with these medicines 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 caution: The concomitant use of BRADHET with other moderate CYP3A4 inhibitors (i.e. fluconazole) may be considered at the starting dose of 2,5 mg twice daily and if resting heart rate is above 70 bpm, while monitoring heart rate. CYP3A4 metabolism inducers such as rifampicin, barbiturates, phenytoin and Hypericum perforatum (St Johnu2019s Wort): Prolonged concomitant use of these medicines with ivabradine may decrease ivabradine exposure and activity and therefore require an upward titration of the dose of BRADHET. The combination of BRADHET 10 mg twice daily with St Johnu2019s Wort was shown to reduce the area under the curve (AUC) of ivabradine by 50%. The intake of St Johnu2019s Wort is not recommended (see section 4.3).

Other concomitant use: Specific interaction studies have shown no clinically significant pharmacokinetic or pharmacodynamic interactions between BRADHET and any of the following: digoxin, HMG CoA reductase inhibitors (statins), proton pump inhibitors (e.g. omeprazole, lansoprazole), dihydropyridine calcium channel blockers (nifedipine, amlodipine, lacidipine), aspirin and warfarin. In pivotal phase III clinical trials the following medicines were frequently combined with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, anti-aldosterone, calcium channel blockers (e.g. nifidipine), short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics (including: biguanides, sulphonylureas, alpha-glucosidases inhibitors, DPP-4 inhibitors, glitazones (thiazolidinediones), aspirin and other anti-platelet medicines.

Pharmacodynamic interactions: Concomitant use not recommended: QT-prolonging medicines: u2022 Cardiovascular QT-prolonging medicines (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone). u2022 Non cardiovascular QT-prolonging medicines (e.g. pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin). The concomitant use of cardiovascular and non-cardiovascular QT-prolonging medicines with BRADHET should be avoided since QT-prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is required.

Concomitant use with precaution: Potassium-depleting diuretics (thiazide diuretics and loop diuretics): Hypokalaemia can increase the risk of dysrhythmia. As BRADHET may cause bradycardia, the resulting combination of hypokalaemia and bradycardia is a predisposing factor to the onset of severe dysrhythmias, especially in patients with long QT syndrome, whether congenital or substance induced (see section 4.3).

Paediatric population: Interaction studies have only been performed in adults.

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

Pregnancy: Animal reproduction studies have shown embryotoxic and teratogenic effects at doses similar to those used in humans.

Lactation: Animal studies indicate that ivabradine is excreted in milk. Therefore, BRADHET is contraindicated during pregnancy and lactation (see section 4.3).

BRADHET may cause transient visual symptoms consisting mainly of phosphenes. The possible occurrence of such visual symptoms should be taken into account when driving or using machines in situations where sudden variations in light intensity may occur. BRADHET may also cause headache, generally during the first month of treatment, and dizziness, possibly related to bradycardia (see section 4.8).

a) Summary of the safety profile: Ivabradine has been studied in clinical trials involving nearly 45 000 patients. The frequent adverse events with BRADHET, luminous phenomena (phosphenes) and bradycardia, are dose dependant and are related to the pharmacological effect of the medicine.

b) Tabulated summary of adverse reactions

Blood and lymphatic system disorders

Less frequent: Eosinophilia

Metabolism and nutrition disorders

Less frequent: Hyperuricaemia

Nervous system disorders

Frequent: Headache, generally during the first month of treatment, dizziness, possibly related to bradycardia

Less frequent: Syncope, possibly related to bradycardia

Eye disorders

Frequent: Luminous phenomena (phosphenes), blurred vision

Less Frequent: Visual impairment, diplopia

Ear and labyrinth disorders

Less frequent: Vertigo

Cardiac disorders

Frequent: Bradycardia, AV 1st degree block (ECG prolonged PQ interval), atrial fibrillation, ventricular extrasystoles

Less frequent: Palpitations, supraventricular extrasystoles, AV 2nd degree block, AV 3rd degree block, sick sinus syndrome

Vascular disorders

Frequent: Increased blood pressure

Frequency unknown: Hypotension, possibly related to bradycardia

Respiratory, thoracic and mediastinal disorders

Less frequent: Dyspnoea

Gastrointestinal disorders

Less frequent: Nausea, constipation, diarrhoea

Frequency unknown: Abdominal pain

Skin and subcutaneous tissue disorders

Less Frequent: Angioedema, rash, erythema, pruritus, urticaria

Musculoskeletal and connective tissue disorders

Less frequent: Muscle cramps

General disorders and administration site conditions

Less Frequent: Asthenia, possibly related to bradycardia, fatigue, possibly related to bradycardia, malaise, possibly related to bradycardia

Investigations

Less frequent: Elevated creatinine in blood, ECG prolonged QT interval

c) 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 and kaleidoscopic), coloured bright lights, or multiple images (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 resolved during treatment. Less than 1 % of patients changed their daily routine or discontinued the treatment in relation with phosphenes. Bradycardia was reported by patients particularly within the first 2 to 3 months of treatment initiation and patients experienced a severe bradycardia below or equal to 40 bpm. In patients with angina pectoris, artrial fibrillation developed in about 5 % of patients treated with ivabradine. 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 atrial fibrillation developed in 4,86 % of ivabradine treated patients compared to 4,08 % in controls.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za and to the Holder of certificate of registration through the mail: [email protected]

Symptoms: In overdose, side effects will be exacerbated and exaggerated (see section 4.8). Overdose may lead to severe and prolonged bradycardia, which should be treated symptomatically in a specialised environment.

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