CORALAN Ivabradine 5mg Film-Coated Tablet 1's

Symptomatic Treatment of Coronary Stable Angina Pectoris: Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥70 bpm. Indicated in adults unable to tolerate or with a contraindication to the use of β-blockers or in combination with β-blockers in patients inadequately controlled with an optimal β-blocker dose.
Treatment of Chronic Heart Failure: Ivabradine is indicated in chronic heart failure NYHA class II-IV with systolic dysfunction, in adult patients in sinus rhythm and whose heart rate is ≥75 bpm, in combination with standard therapy including β-blocker therapy or when β-blocker therapy is contraindicated or not tolerated.

Symptomatic Treatment of Chronic Stable Angina Pectoris: Starting Dose: 5 mg twice daily in patients <75 years. After 3-4 weeks of treatment, if the patient is still symptomatic, if the initial dose is well-tolerated and if resting heart rate remains >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. Maintenance Dose: 7.5 mg twice daily.
It is recommended that the decision to initiate or titrate treatment takes place with the availability of serial heart rate measurements, electrocardiogram (ECG) or ambulatory 24-hr monitoring.
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 3 months.
If, during treatment, heart rate decreases <50 bpm at rest or the patient experiences symptoms related to bradycardia eg, 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. Treatment must be discontinued if heart rate remains <50 bpm or symptoms of bradycardia persist despite dose reduction.
Treatment of Chronic Heart Failure: Usual Recommended Starting Dose: 5 mg twice daily. After 2 weeks of treatment, the dose can be increased to 7.5 mg twice daily if resting heart rate is persistently >60 bpm or decreased to 2.5 mg twice daily (one-half 5 mg tablet twice daily) if resting heart rate is persistently <50 bpm or in case of symptoms related to bradycardia eg, 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 <50 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 >60 bpm 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 <50 bpm or symptoms of bradycardia persist.
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.
Renal Insufficiency: No dose adjustment is required in patients with renal insufficiency and CrCl >15 mL/min (see Pharmacokinetics under Actions). No data are available in patients with CrCl <15 mL/min. Ivabradine should therefore be used with caution 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 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 Pharmacokinetics under Actions and Contraindications).
Children and Adolescents: Coralan is not recommended in children and adolescents as the efficacy and safety of ivabradine has not been studied in these populations.
Elderly: In patients ≥75 years, a lower starting dose should be considered for these patients (2.5 mg twice daily ie, ½ 5-mg tablet twice daily) before up-titration, if necessary.
Missed Dose: If a dose is missed, take the next dose at the usual time. Do not take a double dose to make up for the forgotten dose.
Administration: Tablets must be taken orally twice daily ie, once in the morning and once in the evening during meals (see Pharmacokinetics under Actions).

Should be taken with food: Take during meals. Avoid excessive consumption of grapefruit juice.

Hypersensitivity to ivabradine or to any excipients of Coralan; resting heart rate of <70 bpm prior to treatment; cardiogenic shock; acute myocardial infarction; severe hypotension (<90/50 mmHg); severe hepatic insufficiency; sick sinus syndrome; sino-atrial block; pacemaker-dependent; unstable angina; AV-block of 3rd degree, heart failure which has recently become worse.
Combination with strong cytochrome P450 3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see Pharmacokinetics under Actions and Interactions). Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties (see Interactions).
Use in pregnancy & lactation: Women of childbearing potential should use appropriate contraceptive measures during treatment. There are no adequate data concerning the use of ivabradine in pregnant women. Animal reproduction studies have shown embryotoxic and teratogenic effects (see Toxicology under Actions). The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.
Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated in breastfeeding women.

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 (eg, myocardial infarction or cardiovascular death) (see Pharmacology under Actions).
Measurement of Heart Rate: Given that the heart rate may fluctuate considerably over time, serial heart rate measurements, ECG or ambulatory 24-hr 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 <50 bpm or after dose reduction (see Dosage & Administration).
Cardiac Arrhythmias: Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its efficacy when a tachyarrhythmia occurs (eg, ventricular or supraventricular 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 Adverse Reactions). Atrial fibrillation has been more common in patients using concomitantly amiodarone or potent class I antiarrhythmics. 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 (eg, in case of exacerbated angina, palpitations, irregular pulse). Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact the 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 <70 bpm (see Contraindications). If during treatment, resting heart rate decreases persistently <50 bpm or the patient experiences symptoms related to bradycardia eg, dizziness, fatigue or hypotension, the dose must be titrated downward or treatment discontinued if heart rate is <50 bpm or symptoms of bradycardia persist (see Dosage & Administration).
Combination with Calcium Channel Blockers: Concomitant use of ivabradine with heart rate-reducing calcium channel blockers eg, verapamil or diltiazem is contraindicated (see Contraindications and Interactions). No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers eg, amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established. (See Pharmacology under Actions).
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 on retinal function (see Pharmacology under Actions). To date, there is no evidence of a toxic effect of ivabradine on the retina, but the effects of long-term ivabradine treatment beyond 1 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.
Excipients: Since tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Coralan.

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 Contraindications).
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 hrs 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 Interactions). 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: 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. When treatment modifications are made in chronic heart failure patients treated with ivabradine, blood pressure should be monitored at an appropriate interval (see Adverse Reactions).
Use in Patients with Moderate Hepatic Insufficiency: Caution should be exercised when using ivabradine in patients with moderate hepatic insufficiency (see Dosage & Administration).
Use in Patients with Severe Renal Insufficiency: Caution should be exercised when using ivabradine in patients with severe renal insufficiency (creatinine clearance <15 mL/min) (see Dosage & Administration).
Effects on the Ability to Drive or Operate Machinery: 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, ivabradine may cause transient luminous phenomena consisting mainly of phosphenes (see Adverse Reactions). 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. Ivabradine has no influence on the ability to use machines.

Women of childbearing potential should use appropriate contraceptive measures during treatment. There are no adequate data concerning the use of ivabradine in pregnant women. Animal reproduction studies have shown embryotoxic and teratogenic effects (see Toxicology under Actions). The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.
Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated in breastfeeding women.

Coralan has been studied in clinical trials involving nearly 45,000 participants. The most common undesirable effects with ivabradine are dose-dependent and related to the pharmacological effect of the medicinal product.
The following adverse effects or events have been reported during clinical trials.
Eye Disorders: Very Common (>1/10): Luminous Phenomena (Phosphenes): 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 2 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. Common (>1/100, <1/10): Blurred vision. Uncommon (>1/1,000, <1/100): Diplopia, visual impairment.
Cardiovascular Disorders: Common (>1/100, <1/10): Bradycardia: 3.3% of patients particularly within the first 2-3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia ≤40 bpm; AV 1st degree block; ventricular extrasystoles, atrial fibrillation. Uncommon (>1/1,000, <1/100): Palpitations, supraventricular extrasystoles. Very Rare (<1/10,000): AV 2nd degree block, 3rd degree block, sick sinus syndrome.
Gastrointestinal Disorders: Uncommon (>1/1,000, <1/100): Nausea, constipation, diarrhea and abdominal pain.
General Disorders: Common (>1/100, <1/10): Headache, generally during the 1st month of treatment; dizziness, possibly related to bradycardia, uncontrolled blood pressure. Uncommon (>1/1,000, <1/100): Vertigo, dyspnea, muscle cramps; syncope, possibly related to bradycardia; hypotension, possibly related to bradycardia; asthenia, possibly related to bradycardia; fatigue, possibly related to bradycardia. Rare (>1/10,000, <1/1,000): Malaise, possibly related to bradycardia.
Investigations: Uncommon (>1/1,000, <1/100): Hyperuricemia, eosinophilia, elevated creatinine in blood, ECG prolonged QT interval.
Skin and Subcutaneous Tissue Disorders: Uncommon (>1/1,000): Angioedema, rash. Rare (>1/10,000, <1/1,000): Erythema, pruritus, urticaria.

Pharmacodynamic Interactions: Concomitant Use Not Recommended: QT Prolonging Medicinal Products: Cardiovascular QT prolonging medicinal products (eg, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone). Noncardiovascular QT prolonging medicinal products (eg, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin IV).
The concomitant use of cardiovascular and noncardiovascular 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 Warnings and Precautions).
Concomitant Use with Precautions: Potassium-depleting diuretics (thiazide diuretics and loop diuretics): Hypokalemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalemia 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 metabolized 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 Warnings and Precautions.)
Contraindication of Concomitant Use: The concomitant use of potent CYP3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see Contraindications). 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 Contraindications).
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 (eg, fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is >70 bpm, with monitoring of heart rate.
Cytochrome P450 3A4 (CYP3A4) Inducers: CYP3A4 inducers (eg, rifampicin, barbiturates, phenytoin, Hypericum perforatum (St. John's wort) may decrease ivabradine exposure and activity. The concomitant use of CYP3A4-inducing medicinal products may require 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 ½. 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 not restricted and therefore were routinely combined with ivabradine with no evidence of safety concerns: Angiotensin-converting enzyme inhibitors, angiotensin II antagonists, β-blockers, diuretics, anti-aldosterone agents, short and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other antiplatelet agents.

Store at a temperature not exceeding 30°C.
Shelf-Life: 3 years.

Pharmacotherapeutic Group: Antiangina. Pure heart rate reduction.
Pharmacology: Pharmacodynamics: Ivabradine is a pure heart rate-lowering agent, acting by selective and specific inhibition of the cardiac pacemaker I_f current that controls the spontaneous diastolic depolarization in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarization.
Ivabradine can interact also with the retinal current I_h which closely resembles cardiac I_f. It participates in the temporal resolution of the visual system by curtailing the retinal response to bright light stimuli. Under triggering circumstances (eg, rapid changes in luminosity), partial inhibition of I_h by ivabradine underlies the luminous phenomena that may be occasionally experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field (see Adverse Reactions).
The main pharmacodynamic property of ivabradine in humans is a specific dose-dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect which is consistent with a reduced risk of severe bradycardia <40 beats/min (bpm) (see Adverse Reactions).
At usual recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac workload and myocardial oxygen consumption. Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarization: In clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT intervals; in patients with left ventricular dysfunction [left ventricular ejection fraction (LVEF) between 30% and 45%], ivabradine did not have any deleterious influence on LVEF.
The antianginal and anti-ischemic efficacy of Coralan was studied in 5 double-blind randomized trials (3 versus placebo, and 1 each versus atenolol and amlodipine). These trials included a total of 4111 patients with chronic stable angina pectoris, of whom 2617 received ivabradine.
Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3-4 weeks of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over 5 mg twice daily was established in a reference-controlled study versus atenolol: Total exercise duration at trough was increased by about 1 min after 1 month of treatment with 5 mg twice daily and further improved by almost 25 sec after an additional 3-month period with forced titration to 7.5 mg twice daily. In this study, the antianginal and anti-ischemic benefits of ivabradine were confirmed in patients ≥65 years. The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercise test parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about 70% in the rate of angina attacks. The twice-daily dosing regimen of ivabradine gave uniform efficacy over 24 hrs.
In a 889-patients randomized placebo-controlled study, ivabradine given on top of atenolol 50 mg once daily showed additional efficacy on all ETT parameters at the trough of drug activity (12 hrs after oral intake).
In a 725-patients randomized placebo-controlled study, ivabradine did not show additional efficacy on top of amlodipine at the trough of drug activity (12 hrs after oral intake) while an additional efficacy was shown at peak (3-4 hrs after oral intake).
Ivabradine efficacy was fully maintained throughout the 3-or 4-month treatment periods in the efficacy trials. There was no evidence of pharmacological tolerance (loss of efficacy) developing during treatment nor of rebound phenomena after abrupt treatment discontinuation. The antianginal and anti-ischemic effects of ivabradine were associated with dose-dependent reductions in heart rate and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and during exercise. The effects on blood pressure and peripheral vascular resistance were minor and not clinically significant.
A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least 1 year (n=713). No influence on glucose or lipid metabolism was observed.
The antianginal and anti-ischemic efficacy of ivabradine was preserved in diabetic patients (n=457) with a similar safety profile as compared to the overall population.
A large outcome study, BEAUTIFUL, was performed in 10,917 patients with coronary artery disease (CAD) and left ventricular dysfunction (LVEF <40%) on top of optimal background therapy with 86.9% of patients receiving β-blockers. The main efficacy criterion was the composite of cardiovascular death, hospitalization for acute MI or hospitalization for new onset or worsening heart failure. The study showed no difference in the rate of primary composite outcome in the ivabradine group by comparison to the placebo group (relative risk ivabradine:placebo 1, p=0.945).
In a post-hoc subgroup of patients with symptomatic angina at randomization (n=1507), no safety signal was identified regarding cardiovascular death, hospitalization for acute MI or heart failure (ivabradine 12% vs placebo 15.5%, p=0.05).
A large outcome study, SIGNIFY, was performed in 19,102 patients with coronary artery disease and without clinical heart failure (LVEF >40%), on top of optimal background therapy. A therapeutic scheme higher than the approved posology was used [starting dose 7.5 mg twice daily (5 mg twice daily, if age ≥75 years) and titration up to 10 mg twice daily]. The main efficacy criterion was the composite of cardiovascular death or nonfatal myocardial infarction (MI). The study showed no difference in the rate of the primary composite endpoint (PCE) in the ivabradine group by comparison to the placebo group (relative risk ivabradine/placebo 1.08, p=0.197). Bradycardia was reported by 17.9% of patients in the ivabradine group (2.1% in the placebo group). Verapamil, diltiazem or strong CYP3A4 inhibitors were received by 7.1% of patients during the study.
A small statistically significant increase in the PCE was observed in a pre-specified subgroup of patients with angina patients in CCS class II or higher at baseline (n=12,049) (annual rates 3.4% vs 2.9%, relative risk ivabradine/placebo 1.18, p=0.018), but not in the subgroup of the overall angina population in CCS class ≥I (n=14,286) (relative risk ivabradine/placebo 1.11, p=0.11).
The higher than approved dose used in the study did not fully explain these findings.
The SHIFT study was a large multicentre, international, randomized double-blind placebo controlled outcome trial conducted in 6505 adult patients with stable chronic CHF (for ≥4 weeks), NYHA class II-IV, with a reduced left ventricular ejection fraction (LVEF ≤35%) and a resting heart rate ≥70 bpm.
Patients received standard care including β-blockers (89%), ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%) and anti-aldosterone agents (60%). In the ivabradine group, 67% of patients were treated with 7.5 mg twice a day. The median follow-up duration was 22.9 months. Treatment with ivabradine was associated with an average reduction in heart rate of 15 bpm from a baseline value of 80 bpm. The difference in heart rate between ivabradine and placebo arms was 10.8 bpm at 28 days, 9.1 bpm at 12 months and 8.3 bpm at 24 months.
The study demonstrated a clinically and statistically significant relative risk reduction of 18% in the rate of the primary composite endpoint of cardiovascular mortality and hospitalization for worsening heart failure [hazard ratio: 0.82, 95%CI (0.75;0.9) - p<0.0001] apparent within 3 months of initiation of treatment. The absolute risk reduction was 4.2%. The results on the primary endpoint are mainly driven by the heart failure endpoints, hospitalization for worsening heart failure (absolute risk reduced by 4.7%) and deaths from heart failure (absolute risk by 1.1%). (See table.)

The reduction in the primary endpoint was observed consistently irrespective of gender, NYHA class, ischemic or non-ischemic heart failure etiology and of background history of diabetes or hypertension.
In the subgroup of patients with HR ≥75 bpm (n=4150), a greater reduction was observed in the primary composite endpoint of 24% [hazard ratio: 0.76, 95%Cl (0.68;0.85) - p<0.0001] and for other secondary endpoints, including all cause death [hazard ratio: 0.83, 95%Cl (0.72;0.96) - p=0.0109] and CV death [hazard ratio: 0.83, 95%Cl (0.71;0.97) - p=0.0166]. In this subgroup of patients, the safety profile of ivabradine is in line with the one of the overall population.
A significant effect was observed on the primary composite endpoint in the overall group of patients receiving β-blocker therapy [hazard ratio: 0.85, 95%Cl (0.76;0.94)]. In the subgroup of patients with HR ≥75 bpm and on the recommended target dose of β-blocker, no statistically significant benefit was observed on the primary composite endpoint [hazard ratio: 0.97, 95%Cl (0.74;1.28)] and other secondary endpoints, including hospitalization for worsening heart failure [hazard ratio: 0.79, 95%Cl (0.56;1.1)] or death from heart failure [hazard ratio: 0.69, 95%Cl (0.31;1.53)].
There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients on ivabradine improved versus 776 (24%) of patients on placebo (p=0.001).
Pediatric Population: The European Medicines Agency has waived the obligation to submit the results of studies with Coralan in all subsets of the pediatric population in the treatment of angina pectoris.
The European Medicines Agency has deferred the obligation to submit the results of studies with Coralan in 1 or more subsets of the pediatric population in the treatment of chronic heart failure (see Dosage & Administration).
Pharmacokinetics: Under physiological conditions, ivabradine is rapidly released from tablets and is highly water-soluble (>10 mg/mL). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.
Absorption and Bioavailability: Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hr under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver.
Food delayed absorption by approximately 1 hr and increased plasma exposure by 20-30%. The intake of the tablet during meals is recommended in order to decrease intraindividual variability in exposure (see Dosage & Administration).
Distribution: Ivabradine is approximately 70% plasma protein-bound and the volume of distribution at steady state is close to 100 L in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/mL (CV=29%). The average plasma concentration is 10 ng/mL (CV=38%) at steady state.
Biotransformation: Ivabradine is extensively metabolized by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma concentrations (see Interactions).
Elimination: Ivabradine is eliminated with a main t_½ of 2 hrs (70-75% of the AUC) in plasma and an effective t_½ of 11 hrs. The total clearance is about 400 mL/min and the renal clearance is about 70 mL/min. Excretion of metabolites occurs to a similar extent via feces and urine. About 4% of an oral dose is excreted unchanged in urine.
Linearity/Nonlinearity: The kinetics of ivabradine is linear over an oral dose range of 0.5-24 mg.
Special Populations: Elderly: No pharmacokinetic differences (AUC and C_max) have been observed between elderly (≥65 years) or very elderly patients (≥75 years) and the overall population (see Dosage & Administration).
Renal Insufficiency: The impact of renal impairment (creatinine clearance from 15-60 mL/min) on ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance (about 20%) to total elimination for both ivabradine and its main metabolite S 18982 (see Dosage & Administration).
Hepatic Impairment: In patients with mild hepatic impairment (Child Pugh score up to 7) unbound AUC of ivabradine and the main active metabolite were about 20% higher than in subjects with normal hepatic function. Data are insufficient to draw conclusions in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (see Dosage & Administration and Contraindications).
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship: Pharmacokinetic/Pharmacodynamic relationship analysis has shown that heart rate decreases almost linearly with increasing ivabradine and S 18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations and tends to reach a plateau. High exposures to ivabradine that may occur when ivabradine is given in combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate, although this risk is reduced with moderate CYP3A4 inhibitors (see Contraindications, Warnings, Precautions and Interactions).
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential.Reproductive toxicity studies showed no effect of ivabradine on fertility in male and female rats. When pregnant animals were treated during organogenesis at exposures close to therapeutic doses, there was a higher incidence of fetuses with cardiac defects in the rat and a small number of fetuses with ectrodactylia in the rabbit.
In dogs, given ivabradine (doses of 2, 7 or 24 mg/kg/day) for 1 year, reversible changes in retinal function were observed but were not associated with any damage to ocular structures. These data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarization-activated I_h currents in the retina, which share extensive homology with the cardiac pacemaker I_f current.
Other long-term repeat dose and carcinogenicity studies revealed no clinically relevant changes.

Anti-Anginal Drugs