Ivabradine

Approved Indications:

• Chronic Heart Failure (CHF):
  Treatment of stable symptomatic chronic heart failure with reduced ejection fraction (HFrEF; LVEF ≤35%) in patients in sinus rhythm with resting heart rate ≥70 bpm, despite optimal standard therapy including beta-blockers or when beta-blockers are contraindicated or not tolerated.
• Chronic Stable Angina Pectoris:
  Symptomatic treatment of chronic stable angina in patients with normal sinus rhythm who are intolerant to or have contraindications for beta-blockers, or in combination with beta-blockers when additional heart rate reduction is desired.
• Off-label/Investigational Uses:
  Some use in inappropriate sinus tachycardia and certain cases of postural orthostatic tachycardia syndrome (POTS), though not widely approved.

Adults:

• Initial Dose: 5 mg orally twice daily.
• Dose Adjustment:
• After 2 weeks, dose may be adjusted based on resting heart rate.
• Increase to 7.5 mg twice daily if heart rate >60 bpm.
• Decrease to 2.5 mg twice daily if heart rate <50 bpm or if bradycardia symptoms occur.
• Maximum Dose: 7.5 mg twice daily.
• Administration: Take with meals to improve bioavailability.
• Duration: Chronic treatment; continuous use as prescribed.

Elderly:

• No dose adjustment required but monitor closely for bradycardia.

Pediatrics:

• Safety and efficacy not established; not recommended.

Special Populations:

• Renal Impairment: No dose adjustment required in mild to moderate impairment; avoid use in severe impairment unless benefits outweigh risks.
• Hepatic Impairment: Contraindicated in severe hepatic impairment (Child-Pugh class C). Use with caution in mild to moderate impairment.

Ivabradine selectively inhibits the If ("funny") current in the sinoatrial (SA) node, which is responsible for the spontaneous depolarization that regulates heart rate. By blocking these hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, ivabradine slows the pacemaker activity, reducing heart rate without affecting myocardial contractility or ventricular repolarization. This selective heart rate reduction decreases myocardial oxygen demand, improving symptoms in angina and reducing cardiac workload in heart failure.

• Absorption: Rapid oral absorption; peak plasma concentration at 1 hour post-dose.
• Bioavailability: Approximately 40% due to first-pass metabolism.
• Distribution: High plasma protein binding (~70%).
• Metabolism: Extensively metabolized in the liver and intestine via CYP3A4 to active metabolites.
• Half-life: Effective half-life approximately 11 hours.
• Elimination: Mainly fecal (~70%), with some renal excretion (~20%) as metabolites.

• Pregnancy:
  FDA Category C. Animal studies show potential fetal toxicity at high doses; no adequate human studies. Use only if potential benefit justifies potential risk.
• Lactation:
  Unknown if excreted in human milk; caution advised. Breastfeeding is generally not recommended during treatment.

• Primary Class: Cardiovascular Agent
• Subclass: Selective If Channel Inhibitor (Heart Rate Lowering Agent)

• Known hypersensitivity to ivabradine or excipients.
• Acute decompensated heart failure.
• Blood pressure <90/50 mmHg.
• Resting heart rate <60 bpm before treatment.
• Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block without a pacemaker.
• Severe hepatic impairment (Child-Pugh C).
• Concomitant use with strong CYP3A4 inhibitors (e.g., azole antifungals, macrolides, HIV protease inhibitors).
• Pacemaker dependence.

• Bradycardia: Monitor heart rate; dose reduction or discontinuation may be needed.
• Atrial Fibrillation: Ivabradine may increase risk; monitor for new-onset or worsening arrhythmias.
• Visual Disturbances: Phosphenes (transient enhanced brightness) reported; generally mild and reversible.
• Hypotension: Monitor blood pressure in susceptible patients.
• Use in Combination: Caution when combined with other negative chronotropes (beta-blockers, calcium channel blockers).
• Clinical Monitoring: Regular ECG and heart rate assessment recommended.

Common:

• Bradycardia.
• Visual phenomena (phosphenes).
• Headache.
• Dizziness.
• Fatigue.

Less Common:

• Atrial fibrillation.
• Hypotension.
• Nausea.

Serious/Rare:

• Severe bradycardia causing syncope.
• Heart block in susceptible patients.
• Allergic reactions.

Timing: Side effects often appear within days to weeks of treatment initiation and may resolve with dose adjustment.

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase ivabradine levels, risk of bradycardia; contraindicated.
• CYP3A4 inducers (e.g., rifampin): Decrease ivabradine efficacy.
• Other negative chronotropes (beta-blockers, verapamil, diltiazem): Additive bradycardia risk.
• QT-prolonging drugs: Caution due to potential arrhythmias.
• Food: High-fat meals may delay absorption but not clinically significant.

• Current heart failure guidelines (ACC/AHA, ESC) recommend ivabradine for HFrEF patients in sinus rhythm with elevated resting heart rate despite optimal medical therapy.
• No recent major changes in approved indications or dosing.
• Emphasis on careful patient selection and heart rate monitoring to optimize safety.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original packaging until use.
• No special reconstitution or refrigeration required.