Usage
Ivabradine + Metoprolol Tartrate is prescribed for the symptomatic treatment of chronic stable angina pectoris in adult patients with normal sinus rhythm who are already controlled on stable doses of the individual components (Ivabradine and Metoprolol) given concurrently, with Metoprolol at the optimal dose. It belongs to the pharmacological class of cardiovascular agents, specifically a combination of a beta-blocker (Metoprolol) and a selective and specific If current inhibitor (Ivabradine).
The mechanism of action involves a dual approach: Metoprolol blocks beta-adrenergic receptors, reducing heart rate and myocardial contractility, while Ivabradine selectively inhibits the If current in the sinoatrial node, further slowing the heart rate. This combined effect reduces myocardial oxygen demand and improves myocardial perfusion, alleviating angina symptoms.
Alternate Names
This fixed-dose combination (FDC) medication doesn’t have an established International Nonproprietary Name (INN). It’s commonly referred to as the Ivabradine/Metoprolol combination or FDC. A brand name for this combination is Implicor.
How It Works
Pharmacodynamics: Metoprolol decreases heart rate, myocardial contractility, cardiac output, and blood pressure. Ivabradine selectively inhibits the If current in the sinoatrial node, slowing diastolic depolarization and thus reducing heart rate. It has no effect on myocardial contractility, intracardiac conduction, or repolarization.
Pharmacokinetics:
- Absorption: Both drugs are absorbed orally. Food increases Metoprolol exposure and delays Ivabradine absorption.
- Metabolism: Metoprolol is extensively metabolized by the liver, primarily by CYP2D6. Ivabradine is also extensively metabolized by the liver and gut wall, primarily by CYP3A4.
- Elimination: Both drugs are primarily eliminated renally, though some metabolites are excreted in feces.
Mode of Action: Metoprolol competitively blocks beta-1 adrenergic receptors in the heart, decreasing sympathetic stimulation. Ivabradine specifically inhibits the If current, a mixed Na+/K+ inward current in the sinoatrial node responsible for pacemaker activity. It does not affect other ionic currents or adrenergic/cholinergic activity.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Metoprolol binds to beta-1 adrenergic receptors. Ivabradine binds to the If channel. Neither drug directly modulates neurotransmitters or inhibits enzymes other than CYP involvement in metabolism.
Elimination Pathways: Metoprolol and its metabolites are primarily excreted renally. Ivabradine and its metabolites are also eliminated renally, with some fecal excretion.
Dosage
Standard Dosage
Adults:
The recommended dose of Ivabradine + Metoprolol Tartrate is one tablet twice daily, once in the morning and once in the evening, taken with meals. The combination should only be used in patients already stabilized on the individual components at equivalent doses. Titration should be done with the individual components.
Children:
The safety and efficacy in children and adolescents have not been established. No data are available.
Special Cases:
- Elderly Patients: Use with caution.
- Patients with Renal Impairment: Specific dose recommendations for this FDC aren’t available, though dosage adjustments may be necessary. Consult individual drug monographs.
- Patients with Hepatic Dysfunction: Specific dose recommendations for this FDC aren’t available, though dosage adjustments may be necessary. Consult individual drug monographs.
- Patients with Comorbid Conditions: Exercise caution in patients with diabetes, other cardiovascular diseases, and respiratory conditions. Consult individual drug monographs.
Clinical Use Cases
Specific dosage recommendations for intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not available for this FDC. Consult individual drug monographs for Metoprolol and Ivabradine.
Dosage Adjustments
Dose adjustments based on renal/hepatic function, metabolic disorders, or genetic polymorphisms should be based on the individual components. Consult individual drug monographs.
Side Effects
Common Side Effects
- Luminous phenomena (phosphenes)
- Bradycardia
- Dizziness
- Headache
- Blurred vision
- Fatigue
Rare but Serious Side Effects
- Severe bradycardia
- Atrioventricular block
- Hypotension
- Syncope
- Angioedema
- Bronchospasm
Long-Term Effects
Long-term effects of the combination have not been specifically studied. Consult individual drug monographs.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe bradycardia, hypotension, and angioedema, requiring immediate intervention.
Contraindications
- Sick sinus syndrome (unless paced)
- Sino-atrial block
- Third-degree atrioventricular block (unless paced)
- Severe bradycardia (<50 bpm before treatment)
- Severe hypotension (<90/50 mmHg)
- Acute heart failure
- Cardiogenic shock
- Severe hepatic impairment
- Concomitant use of strong CYP3A4 inhibitors
- Hypersensitivity to either drug
Drug Interactions
- CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors can significantly increase Ivabradine levels. Avoid co-administration.
- Bradycardic Drugs: Use with caution with other medications that lower heart rate (e.g., other beta-blockers, calcium channel blockers, digoxin).
- Grapefruit juice: Avoid grapefruit juice, which can increase Ivabradine levels.
- CYP2D6 Inhibitors/Inducers: Can affect Metoprolol metabolism.
Pregnancy and Breastfeeding
Ivabradine is contraindicated during pregnancy and breastfeeding. Metoprolol should be used with caution during pregnancy and breastfeeding. Use only if the potential benefit outweighs the risk.
Drug Profile Summary
- Mechanism of Action: Metoprolol: Beta-1 adrenergic receptor blocker; Ivabradine: If current inhibitor.
- Side Effects: Bradycardia, phosphenes, dizziness, headache, blurred vision.
- Contraindications: See Contraindications section above.
- Drug Interactions: CYP3A4 inhibitors, bradycardic drugs, grapefruit juice.
- Pregnancy & Breastfeeding: Ivabradine is contraindicated. Metoprolol use with caution.
- Dosage: One tablet twice daily with meals.
- Monitoring Parameters: Heart rate, blood pressure, ECG.
Popular Combinations
Ivabradine is sometimes used in combination with other antianginal agents like nitrates or calcium channel blockers if monotherapy or the combination with Metoprolol is inadequate.
Precautions
- Monitor heart rate, blood pressure, and ECG.
- Caution in patients with hepatic or renal impairment.
- Avoid grapefruit juice.
- Patients should report symptoms of bradycardia.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ivabradine + Metoprolol Tartrate?
A: One tablet twice daily with meals for adults. Not recommended for children.
Q2: How does this combination treat angina?
A: It reduces heart rate and myocardial oxygen demand through the dual action of beta-blockade and If current inhibition.
Q3: Can this combination be used in patients with heart failure?
A: No, acute heart failure is a contraindication. Ivabradine monotherapy can be used in chronic heart failure, but this FDC is not indicated.
Q4: What are the most common side effects?
A: Bradycardia, phosphenes, dizziness, headache, and blurred vision.
Q5: Are there any significant drug interactions?
A: Yes, with CYP3A4 inhibitors, bradycardic drugs, and grapefruit juice.
Q6: Can this FDC be used during pregnancy or breastfeeding?
A: Ivabradine is contraindicated during both pregnancy and breastfeeding. Metoprolol requires careful risk-benefit assessment if considered.
Q7: What should be monitored in patients taking this medication?
A: Heart rate, blood pressure, and ECG should be monitored.
Q8: What should patients do if they experience significant bradycardia?
A: They should contact their doctor immediately.
Q9: How should this medication be taken?
A: Orally, twice daily, with meals.
