Corolan 5mg. 7.5mg Tablet

Symptomatic treatment of chronic stable angina pectoris: Coralan u00ae 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: Coralan u00ae 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.

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 Coralan u00ae 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 Coralan u00ae should be discontinued (see WARNINGS AND SPECIAL PRECAUTIONS).

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 WARNINGS AND SPECIAL PRECAUTIONS).

Treatment must be discontinued if the heart rate remains below 50 bpm or symptoms of bradycardia persist.

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 WARNINGS AND SPECIAL PRECAUTIONS).

Method of administration: Coralan u00ae tablets must be taken orally twice daily, i.e. once in the morning and once in the evening. Coralan u00ae tablets should be taken with food.

- Known hypersensitivity to ivabradine or any of the excipients of Coralan u00ae .

- 3 rd degree 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 WARNINGS AND SPECIAL PRECAUTIONS).

- In combination with strong cytochrome P450 inhibitors such as azole antifungals, macrolide antibiotics, HIV protease inhibitors (see INTERACTIONS).

- Concomitant use of St Johnu2019s Wort.

- Coralan u00ae 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 INTERACTIONS).

- Women of childbearing potential not using appropriate contraceptive measures (see PREGNANCY AND LACTATION).

- Concomitant use of grapefruit juice is not recommended (see section INTERACTIONS).

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 Coralan u00ae should be avoided since QT-prolongation may be exacerbated by heart rate reduction.

- Coralan u00ae 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 Coralan u00ae is not recommended immediately after a stroke since no data is available in these situations.

Use in patients with AV-block of 2 nd degree: Coralan u00ae is not recommended in patients with AV-block of 2 nd degree.

Coralan u00ae treatment should be discontinued if the symptoms of angina pectoris do not improve with 3 months of Coralan u00ae treatment.

Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris: Coralan u00ae is indicated only for symptomatic treatment of chronic stable angina pectoris, because Coralan u00ae 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 Coralan u00ae treatment and in patients on treatment with Coralan u00ae when titration is considered. This also applies to patients who develop a low heart rate on treatment with Coralan u00ae, in particular when heart rate decreases below 50 bpm, or after dose reduction (see DOSAGE AND DIRECTIONS FOR USE).

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

Use in patients with a low heart rate: Coralan u00ae must not be initiated in patients with a pre-treatment resting heart rate below 70 beats per minute (see CONTRAINDICATIONS). If, during Coralan u00ae 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 DOSAGE AND DIRECTION FOR USE).

Combination with other anti-angina medications: Concomitant use of Coralan u00ae with heart rate reducing calcium channel blockers such as verapamil or diltiazem is contraindicated (see CONTRAINDICATIONS and INTERACTIONS). Additional efficacy of Coralan u00ae 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 Coralan u00ae 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 Coralan u00ae, may exacerbate QT-prolongation, which may give rise to severe dysrhythmias, in particular Torsade de pointes.

Cardiac dysrhythmias: Coralan u00ae 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). Coralan u00ae is not recommended in patients with atrial fibrillation or with other cardiac dysrhythmias that interfere with sinus node function. In patients treated with Coralan u00ae the risk of developing atrial fibrillation is increased (see SIDE EFFECTS). Atrial fibrillation has been more common in patients concomitantly using amiodarone or potent class I anti-dysrhythmics. It is recommended to regularly clinically monitor Coralan u00ae 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 doctor if these occur. If atrial fibrillation develops during treatment, the balance of benefits and risks of continued Coralan u00ae 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: Coralan u00ae has not been studied in patients with Wolf-Parkinson-White-syndrome (see CONTRAINDICATIONS).

Moderate to severe liver dysfunction: Coralan u00ae 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 CONTRAINDICATIONS).

Aortic and/or Mitral valvular disease: Due to the lack of data, Coralan u00ae is not recommended in patients with severe aortic and/or mitral valvular disease.

Concomitant use with cytochrome P450 3A4 (CYP3A4) inhibitors or inducers: - Strong CYP3A4 inhibitors: As these agents significantly increase Coralan u00ae plasma concentrations, their concomitant use with Coralan u00ae is contraindicated (see CONTRAINDICATIONS).

Pharmacokinetic interactions: Cytochrome P450 3A4 (CYP3A4): Coralan u00ae is metabolised by cytochrome P450 3A4 (CYP3A4) and is a weak inhibitor of this cytochrome. Therefore, Coralan u00ae is unlikely to influence the metabolism and plasma concentrations of other CYP3A4 substrates. CYP3A4 inhibitors and inducers are liable to interact with Coralan u00ae and to influence its metabolism and pharmacokinetics. Drug-drug interaction studies have established that CYP3A4 inhibitors increase Coralan u00ae plasma concentrations, while inducers decrease them. Increased plasma concentrations of Coralan u00ae may be associated with excessive bradycardia (see CONTRAINDICATIONS).

Concomitant use contraindicated: The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, ictraconozole), macrolide antibiotics (clarithromycin, erythromycin taken orally, josmycin, telithromycin), HIV protease inhibitors (including nelfinavir, ritonavrir) is contraindicated (see CONTRAINDICATIONS). The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased the mean plasma exposure of Coralan u00ae by 7 to 8 fold.

Moderate CYP3A4 inhibitors: Specific interaction studies in healthy volunteers and patients have shown that the combination of Coralan u00ae 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 CONTRAINDICATIONS).

Concomitant use not recommended: Grapefruit juice: Coralan u00c6 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 Coralan u00c6 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 agents with ivabradine may decrease ivabradine exposure and activity and therefore require an upward titration of the dose of Coralan u00ae. The combination of Coralan u00ae 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 CONTRAINDICATIONS).

Other concomitant use: Specific interaction studies have shown no clinically significant pharmacokinetic or pharmacodynamic interactions between Coralan u00ae 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 Coralan u00ae 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 agents.

Animal reproduction studies have shown embryotoxic and teratogenic effects at doses similar to those used in humans. Animal studies indicate that ivabradine is excreted in milk. Therefore, Coralan u00ae is contraindicated during pregnancy and lactation (see CONTRAINDICATIONS).

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

Coralan u00ae 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.

Coralan u00ae has been studied in clinical trials involving nearly 45 000 patients. The side effects associated with the use of Coralan u00ae are the following according to the MedDRA system organ class and frequencies: very common ( uf0b3 1/10); common ( uf0b3 1/100, < 1/10); uncommon ( uf0b3 1/1 000, < 1/100); rare ( uf0b3 1/10 000, < 1/1 000); very rare (< 1/10 000). The most common adverse events with Coralan u00ae, luminous phenomena (phosphenes) (u00b1 15 %) and bradycardia (u00b1 3,3 %), are dose dependant and are related to the pharmacological effect of the medicine.

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 Ear and labyrinth disorders Uncommon Vertigo Cardiac disorders Common Bradycardia AV 1 st degree block (ECG prolonged PQ interval) Atrial fibrillation Ventricular extrasystoles Uncommon Palpitations, supraventricular extrasystoles Very rare AV 2 nd degree block, AV 3 rd degree block Sick sinus syndrome Vascular disorders Common Increased blood pressure Respiratory, thoracic and mediastinal disorders Uncommon Dyspnoea Gastrointestinal disorders Uncommon Nausea Constipation Diarrhoea Musculoskeletal and connective tissue disorders Uncommon Muscle cramps Investigations Uncommon Elevated creatinine in blood ECG prolonged QT interval

The following adverse events were reported post marketing: Nervous system disorders Syncope, possibly related to bradycardia Eye disorders Visual impairment Diplopia Vascular disorders Hypotension, possibly related to bradycardia Gastrointestinal disorders Abdominal pain Skin and subcutaneous tissue disorders Angioedema Rash Erytema Pruritus Urticaria General disorders and administration site conditions Asthenia, possibly related to bradycardia Fatigue, possibly related to bradycardia Malaise, possibly related to bradycardia

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 (77,5 %) resolved during treatment. Less 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 and 0,5 % of patients experienced a severe bradycardia below or equal to 40 bpm.

In patients with angina pectoris, atrial fibrillation developed in about 5 % of patients treated with Coralan u00ae. 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.

Symptoms: In overdose, side effects will be exacerbated and exaggerated (see SIDE EFFECTS). 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 agents such as dobutamine may be considered. Temporary cardiac electrical pacing may be instituted if required.