Usage
Carvedilol + Ivabradine is prescribed as a substitution therapy in adult patients with normal sinus rhythm who are already stabilized on carvedilol and ivabradine taken concomitantly at the same doses. It’s indicated for:
- Symptomatic treatment of chronic stable angina pectoris in patients with coronary artery disease.
- Treatment of chronic heart failure (NYHA Class II-IV) with systolic dysfunction.
Pharmacological Classification:
This combination drug falls under the following classifications:
- Beta-blocker (carvedilol): Carvedilol is a non-selective beta-blocker with alpha-1 blocking properties.
- Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker (ivabradine): Ivabradine selectively inhibits the If current in the sinoatrial node, slowing the heart rate.
Mechanism of Action:
Carvedilol reduces peripheral vascular resistance through alpha-1 blockade and suppresses the renin-angiotensin system through beta-blockade. Ivabradine works by selectively inhibiting the If current in the sinoatrial node, which slows the heart rate and reduces myocardial oxygen demand. The combination provides synergistic effects in managing angina and heart failure.
Alternate Names
International Nonproprietary Name (INN): Carvedilol/Ivabradine
Brand Names: Carivalan
How It Works
Pharmacodynamics:
- Carvedilol: Reduces heart rate, blood pressure, and myocardial contractility. It also improves myocardial oxygen supply/demand balance.
- Ivabradine: Reduces heart rate without affecting myocardial contractility, blood pressure or ventricular repolarization.
Pharmacokinetics:
- Carvedilol: Well absorbed orally, extensively metabolized in the liver (primarily by CYP2D6 and CYP2C9), and excreted in bile and urine.
- Ivabradine: Well absorbed orally, metabolized in the liver and intestine (primarily by CYP3A4), and excreted in urine and feces.
Mode of Action:
- Carvedilol: Blocks beta-adrenergic receptors and alpha-1 adrenergic receptors.
- Ivabradine: Selectively inhibits the If current in the sinoatrial node, slowing diastolic depolarization.
Receptor Binding/Enzyme Inhibition:
- Carvedilol: Beta-1, Beta-2, and Alpha-1 adrenergic receptor blocker.
- Ivabradine: HCN channel blocker.
Elimination Pathways:
- Carvedilol: Primarily hepatic metabolism and biliary excretion, some renal excretion.
- Ivabradine: Hepatic and intestinal metabolism (CYP3A4), renal and fecal excretion.
Dosage
Standard Dosage
Adults:
The recommended dose of Carvedilol + Ivabradine is one tablet twice daily, once in the morning and once in the evening, with food. It’s crucial that patients are already stabilized on individual components at their optimal doses before switching to the fixed-dose combination.
Children:
Carvedilol + Ivabradine is not recommended for use in children.
Special Cases:
- Elderly Patients: For patients aged 75 or older, a lower starting dose of ivabradine (2.5mg twice daily) as a separate component should be considered before up-titration if necessary. Carvedilol dose adjustments may be required based on renal function and response.
- Patients with Renal Impairment: No dose adjustment is required for ivabradine for patients with creatinine clearance above 15 mL/min. Ivabradine should be used with caution in patients with creatinine clearance below 15 mL/min. Carvedilol dose should be reduced in patients with severe renal impairment.
- Patients with Hepatic Dysfunction: Carvedilol + Ivabradine is contraindicated in patients with severe hepatic impairment. Carvedilol should be used with caution in mild to moderate hepatic impairment. Ivabradine dosage should be reduced in patients with moderate hepatic impairment.
- Patients with Comorbid Conditions: Dose adjustment may be necessary for patients with diabetes, other cardiovascular diseases, and respiratory conditions.
Clinical Use Cases
Carvedilol + Ivabradine is not typically used in acute clinical settings like intubation, surgical procedures, mechanical ventilation, or emergency situations. Its primary use is for chronic stable angina pectoris and chronic heart failure.
Dosage Adjustments
Dose adjustments are based on heart rate, blood pressure, and individual patient tolerance. If heart rate falls below 50 bpm at rest, or if the patient experiences symptoms of bradycardia (e.g., dizziness, fatigue, hypotension), down-titration of the individual components is necessary. Any dosage adjustments should be made with the individual components (carvedilol and ivabradine), not the fixed combination pill.
Side Effects
Common Side Effects
Dizziness, headache, fatigue, bradycardia, visual disturbances (phosphenes), low blood pressure, diarrhea.
Rare but Serious Side Effects
Severe bradycardia, symptomatic hypotension, worsening heart failure, atrioventricular block, sick sinus syndrome.
Long-Term Effects
Potential long-term effects include worsening of pre-existing heart conditions if not adequately monitored.
Adverse Drug Reactions (ADR)
Angioedema, severe allergic reactions, acute heart failure exacerbation.
Contraindications
- Hypersensitivity to carvedilol, ivabradine, or any component of the formulation.
- Severe hepatic impairment.
- Acute or unstable/decompensated heart failure.
- Unstable angina.
- Prinzmetal’s angina.
- Second or third-degree atrioventricular block.
- Sick sinus syndrome.
- Symptomatic bradycardia (<50 bpm).
- Cardiogenic shock.
- Pacemaker dependence.
- Severe peripheral vascular disease.
- Severe hypotension.
- Chronic obstructive pulmonary disease with bronchial obstruction.
- Bronchospasm or asthma.
- Metabolic acidosis.
- Untreated pheochromocytoma.
- Concomitant use with verapamil, diltiazem, or strong CYP3A4 inhibitors.
- Pregnancy and breastfeeding.
Drug Interactions
Carvedilol and ivabradine are both metabolized by hepatic enzymes, making them prone to drug interactions. Clinically significant interactions can occur with:
- CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, erythromycin): Can increase ivabradine levels, leading to severe bradycardia.
- CYP3A4 Inducers (e.g., rifampin, St. John’s Wort): Can decrease ivabradine levels, reducing its efficacy.
- Calcium Channel Blockers (e.g., verapamil, diltiazem): Can exacerbate bradycardia.
- Digoxin: Can enhance bradycardic effects.
- Other Beta-Blockers: Additive effects on heart rate and blood pressure.
Pregnancy and Breastfeeding
Carvedilol + Ivabradine is contraindicated during pregnancy and breastfeeding due to potential risks to the fetus and neonate. Carvedilol is classified as Pregnancy Category C, and ivabradine is contraindicated in pregnancy. Both drugs can be excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Carvedilol: Non-selective beta-blocker with alpha-1 blocking properties. Ivabradine: HCN channel blocker.
- Side Effects: Dizziness, headache, fatigue, bradycardia, hypotension, phosphenes, diarrhea.
- Contraindications: See the detailed “Contraindications” section above.
- Drug Interactions: See the detailed “Drug Interactions” section above.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: One tablet twice daily for adults already stabilized on individual components.
- Monitoring Parameters: Heart rate, blood pressure, ECG, signs and symptoms of heart failure exacerbation.
Popular Combinations
Since this is a fixed-dose combination, additional combinations should be approached with caution due to the potential for drug interactions and additive effects. If additional medications are required, it is recommended to titrate using the individual components.
Precautions
- Monitor heart rate and blood pressure closely.
- Assess liver and kidney function before and during treatment.
- Evaluate for signs and symptoms of heart failure exacerbation.
- Caution in patients with asthma or COPD.
- Avoid abrupt discontinuation.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Carvedilol + Ivabradine?
A: One tablet twice daily for adults already stabilized on individual components. The fixed combination is not suitable for initial therapy.
Q2: Can Carvedilol + Ivabradine be used in patients with acute heart failure?
A: No, it is contraindicated in acute or unstable/decompensated heart failure.
Q3: What are the common side effects?
A: Dizziness, headache, fatigue, bradycardia, phosphenes, hypotension, and diarrhea.
Q4: Are there any significant drug interactions?
A: Yes, with CYP3A4 inhibitors and inducers, calcium channel blockers, and digoxin. See the “Drug Interactions” section above.
Q5: Can this combination be used during pregnancy or breastfeeding?
A: No, it is contraindicated.
Q6: How should dosage be adjusted in elderly patients?
A: For patients 75 or older, a lower starting dose of the ivabradine component (2.5mg twice daily) should be considered before up-titration if necessary. Carvedilol dosing should be individualized according to renal function and clinical response.
Q7: What should be done if a patient develops bradycardia?
A: Down-titrate the individual components, carvedilol and ivabradine. The fixed-dose combination is not used for dose titration. Closely monitor heart rate and symptoms.
Q8: What are the key monitoring parameters for patients on Carvedilol + Ivabradine?
A: Heart rate, blood pressure, ECG, and signs and symptoms of heart failure exacerbation.
Q9: Can Carvedilol + Ivabradine be used to initiate therapy for angina or heart failure?
A: No, this fixed-dose combination is for substitution therapy only in patients already stabilized on both components individually. Initial therapy should be titrated using the individual components.
