Gavrila

Each film-coated tablet contains: Ivabradine Hydrochloride equivalent to Ivabradine 7.5 mg.

Pharmacology: 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 the 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 mg/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 main t½ of 2 hrs (70-75% of the AUC) in plasma and an effective t½ 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.
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 of both Ivabradine and its main metabolite S 18982.
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.
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship: Pharmacokinetic/Pharmacodynamic relationship analysis has shown that heart rate decreases almost linearly with increasing Ivabradine and S18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional 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.

For 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; and 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 of dose: 5 mg twice daily in patients <75 years.
After 3-4 weeks of treatment, if the patient is still symptomatic, 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 testing 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 uptitrated 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.

Overdose may lead to severe and prolonged bradycardia. Severe bradycardia should be treated symptomatically in a specialized environment. In the event of bradycardia including IV β-stimulating agents e.g., isoprenaline may be considered. Temporary cardiac electrical pacing may be instituted if required.

Hypersensitivity to Ivabradine or to any excipients; 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 e.g., 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 reducing properties (see Interactions).

Ivabradine is indicated only for symptomatic treatment of chronic stable angina pectoris because Ivabradine has no benefits on cardiovascular outcomes.
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.
Cardiac Arrhythmias: Ivabradine is not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function.
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. If during treatment, resting heart rate decreases persistently <50 bpm or the patient experiences symptoms related to bradycardia e.g., dizziness, fatigue or hypotension, the dose must be titrated downward or treatment discontinued if heart rate is <50 bpm or symptoms of bradycardia persist.
Combination with Calcium Channel Blockers: Concomitant use of Ivabradine with heart rate-reducing calcium channel blockers e.g., Verapamil or Diltiazem is contraindicated. No safety issue has been raised on the combination of Ivabradine with nitrates and dihydropyridine calcium channel blockers e.g., Amlodipine.
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. To date, there is no evidence of a toxic effect of Ivabradine on the retina, but the effect 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 Ivabradine.

Ivabradine should not be given to patients with resting heart rate below 60 beats/minute, or to patients with cardiogenic shock, severe conduction defects, acute myocardial infarction, or unstable angina. Heart failure should be controlled before Ivabradine is started; it has not been studied in severe heart failure. Ivabradine should not be used in patients with congenital QT prolongation. Ivabradine is not recommended in atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function, and regular monitoring for such arrhythmias should be performed. If resting heart rate falls below 50 beats/minute, the dose should be reduced; treatment should be stopped if this rate persists. Ivabradine is contraindicated in severe hypotension and severe hepatic impairment, and should be used with caution in severe renal impairment. If unexpected deterioration in visual function occurs, stopping treatment may be considered. Caution should be observed in patients with retinitis pigmentosa. Studies in animals have shown that Ivabradine is embryotoxic and teratogenic, and is distributed into breast milk.
Patients with Hypotension: Ivabradine is contraindicated in patients with severe hypotension (blood pressure <90/50 mmHg).
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. 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. These episodes occurred most frequently shortly after blood pressure treatment was modified, were transient and did not effect 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.
Use in Patients with Moderate Hepatic Insufficiency: Caution should be exercised when using Ivabradine in patients with moderate hepatic insufficiency.
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).
Effects on the Ability to Drive or Operate Machinery: Ivabradine may cause transient luminous phenomena consisting mainly of phosphenes. 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. The potential risk for humans is unknown. Therefore, Ivabradine is contraindicated during pregnancy and breastfeeding women.

The most common adverse effects seen with Ivabradine are luminous phenomena in the visual field (phosphenes). Other adverse effects include blurred vision, bradycardia, which may be severe, and other cardiac arrhythmias, nausea, constipation, diarrhoea, headache, dizziness, dyspnoea, and muscle cramps. Hyperuricaemia, eosinophilia, and elevated blood-creatinine concentrations have been reported.

Pharmacodynamic Interactions: Concomitant Use not Recommended: QT Prolonging Medical Products: Cardiovascular QT prolonging medical products (e.g., Quinidine, Disopyramide, Bepridil, Sotalol, Ibutilide, Amiodarone). Noncardiovascular QT prolonging medicinal products (e.g., Pimozide, Ziprasidone, Sertindole, Mefloquine, Halofantrine, Pentamidine, Cisapride, Erythromycin IV). The concomitant use of cardiovascular and noncardiovascular QT prolonging medical 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.
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 if 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.
Contraindication Of Concomitant Use: The concomitant use of potent CYP3A4 inhibitors e.g., azole antifungals (ketoconazole, Itraconazole), macrolide antibiotics (Clarithromycin, oral Erythromycin, Josamycin, Telithromycin), HIV protease inhibitors (Nelfinavir, Ritonavir) and Nefazodone is contraindicated. The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and Josamycin (1 g twice daily) increased Ivabradine mean plasma exposure by 7-108-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.
Concomitant Use not Recommended: Grapefruit juice: Ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore, the intake of grapefruit juice should be avoided.
Concomitant Use With Precautions: Moderate CYP3A4 Inhibitors: The concomitant use of Ivabradine with other moderate CYP3A4 inhibitors (e.g., Fluconazole) may be considered at the starting dose of 2.5 mg twice if daily and if resting heart rate is >70 bpm, with monitoring of heart rate.
Cytochrome P450 3A4 (CYP3A4) Inducers: CYP3A4 inducers (e.g., Rifampicin, Barbiturates, Phenytoin, Hypericum perforatum (St. John's wort)) may decrease Ivabradine exposure and activity. The concomitant use of CYP3A4-inducing medicinal products may 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.

Store at temperatures not exceeding 30°C.
Shelf Life: 24 months.

Anti-Anginal Drugs

C01EB17 - ivabradine ; Belongs to the class of other cardiac preparations.

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