Usage
Ivabradine is prescribed for:
- Chronic Stable Angina Pectoris: In adults with normal sinus rhythm and a heart rate ≥ 70 bpm, it’s used as an alternative to beta-blockers or in combination with them when beta-blockers alone are insufficient.
- Chronic Heart Failure: In adults with NYHA class II to IV heart failure, systolic dysfunction, sinus rhythm, and heart rate ≥ 75 bpm. It’s used in conjunction with standard therapy, including beta-blockers, or when beta-blockers are contraindicated or not tolerated.
Pharmacological Classification: Ivabradine is a selective and specific If current inhibitor, also classified as a cardiac metabolic modulator, and a sinus node inhibitor.
Mechanism of Action: Ivabradine selectively and specifically inhibits the If current in the sinoatrial node, which slows the heart rate and reduces oxygen demand by the heart. It doesn’t affect myocardial contractility or ventricular repolarization.
Alternate Names
Ivabradine is the generic name. A popular brand name is Corlanor. Procoralan is another brand name for this medication.
How It Works
Pharmacodynamics: Ivabradine’s primary effect is to reduce heart rate. It acts on the If current in the sinoatrial node, the heart’s natural pacemaker. By inhibiting this current, it slows the rate of diastolic depolarization, thereby decreasing heart rate. It does not affect intracardiac conduction, myocardial contractility, or ventricular repolarization.
Pharmacokinetics:
- Absorption: Ivabradine is rapidly absorbed after oral administration, reaching peak plasma concentrations within about 1 hour. Food slightly delays absorption but increases bioavailability.
- Metabolism: Extensively metabolized by the liver, primarily via CYP3A4. The primary metabolite is an N-desmethylated active metabolite.
- Elimination: Excreted in the urine and feces, with approximately 70% renal excretion and 30% fecal elimination. The half-life is about 2 hours.
Mode of Action: Ivabradine specifically inhibits the If current, also known as the “funny current,” in the sinoatrial node. This current plays a key role in the slow diastolic depolarization phase of pacemaker cells. By inhibiting the If current, Ivabradine reduces the slope of this depolarization, prolonging the time it takes to reach the threshold for action potential generation, and thus slows the heart rate.
Receptor Binding/Enzyme Inhibition: Ivabradine acts directly on the If channels, specifically binding to HCN4 channels. It primarily interacts through CYP3A4 enzyme for its metabolism.
Dosage
Standard Dosage
Adults:
- Chronic Stable Angina Pectoris: Initial dose: 5 mg twice daily with meals. After 3-4 weeks, the dose can be increased to 7.5 mg twice daily if the resting heart rate remains > 60 bpm and the patient is still symptomatic. Maximum dose: 7.5 mg twice daily.
- Chronic Heart Failure: Initial dose: 5 mg twice daily with meals. After 2 weeks, the dose can be increased to 7.5 mg twice daily if the resting heart rate is persistently > 60 bpm, or decreased to 2.5 mg twice daily if the heart rate is persistently < 50 bpm or if bradycardia symptoms occur.
Children (Chronic Heart Failure due to Dilated Cardiomyopathy):
- <40 kg (oral solution): Initial dose: 0.05 mg/kg twice daily with food. Adjust dose at 2-week intervals by 0.05 mg/kg to target a heart rate reduction of at least 20%, based on tolerability. Maximum dose: 0.2 mg/kg twice daily for children 6 months to <1 year; 0.3 mg/kg twice daily (up to a maximum of 7.5 mg twice daily) for children ≥1 year.
- ≥40 kg (tablets): Initial dose: 2.5 mg twice daily with food. Adjust dose at 2-week intervals by 2.5 mg to target a heart rate reduction of at least 20%, based on tolerability. Maximum dose: 7.5 mg twice daily.
Special Cases:
- Elderly Patients (≥75 years): Start with a lower dose (2.5 mg twice daily) and titrate upwards if necessary.
- Patients with Renal Impairment: No dose adjustment is necessary for mild to moderate renal impairment (creatinine clearance >15 mL/min). For severe renal impairment, dosage information is not available.
- Patients with Hepatic Dysfunction: No dose adjustment for mild to moderate impairment. Contraindicated in severe hepatic impairment.
- Patients with Comorbid Conditions: Consider lower initial doses in patients with conduction defects or those in whom bradycardia could cause hemodynamic compromise.
Clinical Use Cases
Ivabradine’s clinical use is primarily focused on chronic stable angina pectoris and chronic heart failure. It is not indicated for use in acute settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like cardiac arrest.
Dosage Adjustments
Adjustments should be made based on heart rate, tolerability, and individual patient characteristics like age, renal/hepatic function, and concomitant medications (especially CYP3A4 inhibitors/inducers).
Side Effects
Common Side Effects
- Bradycardia
- Luminous phenomena (phosphenes)
- Headache
- Dizziness
- Blurred vision
Rare but Serious Side Effects
- Atrioventricular block
- Severe bradycardia
- Syncope
- Angioedema
Long-Term Effects
Long-term effects are still being studied, but some potential concerns include chronic bradycardia, and visual disturbances.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe bradycardia, syncope, and atrioventricular block, requiring dose reduction or discontinuation.
Contraindications
- Sick sinus syndrome
- Sinoatrial block
- Pacemaker dependence
- Severe bradycardia (<50 bpm before treatment)
- Cardiogenic shock
- Acute myocardial infarction
- Severe hepatic impairment
- Hypersensitivity to ivabradine
Drug Interactions
- CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Increase ivabradine plasma levels. Reduce ivabradine dose to 2.5mg twice daily if co-administration with a strong inhibitor is needed.
- CYP3A4 Inducers (e.g., rifampicin, phenytoin, St. John’s Wort): Decrease ivabradine plasma levels. Dose adjustments may be needed.
- Grapefruit Juice: Increases ivabradine plasma levels. Avoid concomitant use.
Pregnancy and Breastfeeding
- Pregnancy: Use only if clearly needed. Data on use in pregnant women is limited.
- Breastfeeding: Ivabradine is excreted in breast milk. Discontinue breastfeeding or the drug, taking into account the importance of the drug to the mother.
Drug Profile Summary
- Mechanism of Action: Selective and specific If current inhibition, reducing heart rate.
- Side Effects: Bradycardia, luminous phenomena, headache, dizziness, blurred vision. Rarely: atrioventricular block, severe bradycardia, syncope.
- Contraindications: Sick sinus syndrome, pacemaker dependence, severe bradycardia, hepatic impairment, hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors, CYP3A4 inducers, grapefruit juice.
- Pregnancy & Breastfeeding: Use with caution. Excreted in breast milk.
- Dosage: Adults: 5 mg BID, titrated to 7.5 mg BID. Pediatrics: Dose by weight, maximum 7.5 mg BID. Elderly: Start lower, titrate up.
- Monitoring Parameters: Heart rate, blood pressure, ECG, symptoms of bradycardia.
Popular Combinations
Ivabradine may be used in combination with beta-blockers in chronic stable angina and chronic heart failure when beta-blocker monotherapy is insufficient.
Precautions
- General Precautions: Monitor heart rate and ECG. Assess liver and renal function.
- Specific Populations: Assess risks versus benefits in pregnant/breastfeeding women. Monitor closely in elderly patients. No dose adjustments in pediatric data for severe renal dysfunction.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ivabradine?
A: Adults: Initially 5 mg twice daily, titrated to 7.5 mg twice daily based on heart rate and tolerability. Pediatrics: Dose by weight (0.05 mg/kg BID initially), max 7.5 mg BID. Elderly: Start lower (2.5 mg BID) and titrate up.
Q2: What is Ivabradine’s mechanism of action?
A: Ivabradine selectively inhibits the If current in the sinoatrial node, slowing the heart rate.
Q3: What are the common side effects of Ivabradine?
A: Bradycardia, luminous phenomena (phosphenes), headache, dizziness, and blurred vision.
Q4: Is Ivabradine safe in pregnancy?
A: Use only if clearly needed. Data on use during pregnancy is limited.
Q5: How does Ivabradine interact with other medications?
A: It can interact with CYP3A4 inhibitors (increasing Ivabradine levels) and CYP3A4 inducers (decreasing Ivabradine levels). Avoid grapefruit juice.
Q6: Can Ivabradine be used with beta-blockers?
A: Yes, it can be combined with beta-blockers in both chronic stable angina and chronic heart failure when beta-blockers alone are not sufficiently effective.
Q7: When is Ivabradine contraindicated?
A: In sick sinus syndrome, sinoatrial block, pacemaker dependence, severe bradycardia, cardiogenic shock, acute MI, severe hepatic impairment, and hypersensitivity.
Q8: What should be monitored in patients taking Ivabradine?
A: Heart rate, blood pressure, ECG, and symptoms of bradycardia.
Q9: What are the potential long-term effects of Ivabradine?
A: Long-term effects are still under investigation, but chronic bradycardia and visual disturbances are potential concerns.
Q10: What is the difference between Ivabradine’s use in angina and heart failure?
A: In both cases, it slows the heart rate. However, in heart failure, the initial and target heart rate for dose adjustment might be different and determined by the physician in charge of the patient. For angina, the target heart rate is generally <60 bpm whereas in heart failure the target is between 50-60 bpm. Furthermore, Ivabradine is used in conjunction with standard heart failure therapy, while in angina it can be used as monotherapy or in combination with beta-blockers.
