Each tablet contains ivabradine 5 and 7.5 mg equivalent to ivabradine HCl 5.39 and 8.085 mg, respectively. It also contains the following excipients: Lactose monohydrate, magnesium stearate (E 470 B), maize starch, maltodextrin, anhydrous colloidal silica (E 551), hypromellose (E 464), titanium dioxide (E 171), macrogol 6000, glycerol (E 422), yellow iron oxide (E 172) and red iron oxide (E 172).
Pharmacotherapeutic Group: Other cardiac preparations. ATC Code: C01EB17.
Pharmacology: Pharmacodynamics: Ivabradine is a pure heart rate-lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If 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 Ih which closely resembles cardiac If. 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 Ih 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 aged ≥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 o.d. showed additional efficacy on all ETT parameters at the trough of drug activity (12 hours 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.
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 1st-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 P-450 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 half-life of 2 hrs (70-75% of the AUC) in plasma and an effective half-life 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 Cmax) 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: PK/PD 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: 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 Ih currents in the retina, which share extensive homology with the cardiac pacemaker If current.
Other long-term repeat dose and carcinogenicity studies revealed no clinically relevant changes.
Treatment of coronary artery disease: Symptomatic treatment of chronic stable angina pectoris in coronary artery disease (CAD) adults with normal sinus rhythm who are contraindicated or have intolerance for β-blockers, or in combination in patients adequately controlled by β-blockers & whose heart rate is >60 beats/min.
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 beats/min, in combination with standard therapy including β-blocker therapy or when β-blocker therapy is contraindicated or not tolerated.
Treatment of coronary artery disease:
Usual Recommended Starting Dose: 5 mg twice daily. After 3-4 weeks of treatment, the dose may be increased to 7.5 mg twice daily depending on the therapeutic response. If, during treatment, heart rate decreases persistently <50 beats/min (bpm) at rest or the patient experiences symptoms related to bradycardia eg, dizziness, fatigue or hypotension, the dose must be titrated downward including the possible dose of 2.5 mg twice daily (½ 5-mg tab twice daily). Treatment must be discontinued if heart rate is <50 bpm or symptoms of bradycardia persist (see Warnings and Precautions).
Treatment of chronic heart failure:
The treatment has to be initiated only in patient with stable 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 decrease 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 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.
Renal Insufficiency: No dose adjustment is required in patients with renal insufficiency and creatinine clearance >15 mL/min (see Pharmacology: Pharmacokinetics under Actions).
No data are available in patients with creatinine clearance <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 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 Contraindications and Pharmacology: Pharmacokinetics under Actions).
Children and Adolescents: Coralan is not recommended in children and adolescents as the efficacy and safety of ivabradine have not been studied in these populations.
Elderly: Since ivabradine has been studied in a limited number of patients ≥75 years, a lower starting dose should be considered for these patients (2.5 mg twice daily ie, ½ 5-mg tab twice daily) before up-titration if necessary.
Administration: Tablets must be taken orally twice daily ie, once in the morning and once in the evening during meals (see Pharmaclogy: Pharmacokinetics under Actions).
Overdose may lead to severe and prolonged bradycardia (see Adverse Reactions). Severe bradycardia should be treated symptomatically in a specialized environment. In the event of bradycardia with poor hemodynamic tolerance, symptomatic treatment including IV β-stimulating agents eg, isoprenaline may be considered. Temporary cardiac electrical pacing may be instituted if required.
Hypersensitivity to ivabradine or to any excipients of Coralan; resting heart rate of <60 bpm prior to treatment; cardiogenic shock; acute myocardial infarction; severe hypotension (<90/50 mm Hg); severe hepatic insufficiency; sick sinus syndrome; sino-atrial block; heart failure patients with NYHA functional classification III-IV due to lack of data; pacemaker-dependent; unstable angina; AV-block of 3rd degree.
Combination with strong cytochrome P-450 3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see Interactions, Pharmacology: Pharmacokinetics under Actions).
Use in pregnancy & lactation: There are no adequate data concerning the use of ivabradine in pregnant women. Animal reproduction studies have shown embryotoxic and teratogenic effects (see Pharmacology: 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.
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.
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).
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 <60 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 Other Antianginal Therapies: Concomitant use of ivabradine with heart rate-reducing calcium channel blockers eg, verapamil or diltiazem is not recommended (see 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 appropriately controlled before considering ivabradine treatment. The use of ivabradine is contraindicated in heart failure patients with NYHA functional classification III-IV, due to a lack of data on clinical efficacy and safety (see Contraindications). Caution is needed in patients with asymptomatic left ventricular dysfunction, as well as in heart failure patients with NYHA functional classification II due to a limited number of patients studied.
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, 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.
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. Ivabradine has no influence on the ability to drive and use machines. 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.
There are no adequate data concerning the use of ivabradine in pregnant women. Animal reproduction studies have shown embryotoxic and teratogenic effects (see Pharmacology: 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 14,000 participants. The most common adverse reaction with ivabradine, luminous phenomena (phosphenes), bradycardia, 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 and ranked using the following frequency: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); not known (cannot be estimated from the available data.
Very Common: 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. 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: Blurred vision.
Common: 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. Uncommon: Palpitations, supraventricular extrasystoles.
The following events reported during clinical trials were of similar incidence than comparators and/or possibly related to the underlying disease: Sinus arrhythmia, unstable angina, aggravated angina pectoris, atrial fibrillation, myocardial ischaemia, myocardial infarction and ventricular tachycardia.
Uncommon: Nausea, constipation and diarrhea.
Common: Headache, generally during the 1st month of treatment, dizziness, possibly related to bradycardia. Uncommon: Vertigo, dyspnea, muscle cramps.
Uncommon: Hyperuricaemia, eosinophilia, elevated creatinine in blood.
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).
Pharmacokinetic Interactions: Cytochrome P-450 3A4 (CYP3A4): Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was not shown 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.
Concomitant Use Not Recommended: 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 not recommended (see Warnings and Precautions).
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 >60 bpm, with monitoring of heart rate.
Grapefruit Juice: Ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore, the intake of grapefruit juice should be restricted during the treatment with ivabradine.
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 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 not restricted and therefore were routinely combined with ivabradine with no evidence of safety concerns: Angiotensin-converting enzyme inhibitors, angiotensin II antagonists, diuretics, short and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton-pump inhibitors, oral antidiabetics, aspirin and other antiplatelet agents.
C01EB17 - ivabradine ; Belongs to the class of other cardiac preparations.
FC tab 5 mg (salmon-coloured, rod-shaped, engraved with "5" on one face and the company logo on the other face) x 56's. 7.5 mg (salmon-coloured, triangular, engraved with "7.5" on one face and the company logo on the other face) x 56's.