Schedule H

Oral

• Tablets: 5 mg, 7.5 mg

Note: Ivabradine selectively inhibits the If (funny) current in the sinoatrial node, reducing heart rate without affecting myocardial contractility, blood pressure, or atrioventricular conduction. It is effective ONLY in patients in sinus rhythm.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Heart Failure with Reduced Ejection Fraction (HFrEF)

Eligibility Criteria:

• LVEF ≤35%

• Sinus rhythm with resting heart rate ≥70 bpm

• On maximally tolerated dose of beta-blocker OR beta-blocker contraindicated/not tolerated

• Symptomatic heart failure (NYHA class II–IV) despite optimal medical therapy

Parameter Dose Clinical Notes

Starting dose 5 mg orally twice daily with meals If age >75 years or bradycardia risk: start at 2.5 mg twice daily

Titration Reassess at 2 weeks based on resting heart rate See algorithm below

Usual maintenance dose 5–7.5 mg twice daily Target resting HR 50–60 bpm

Maximum dose 7.5 mg twice daily

Dose Titration Algorithm:

Resting Heart Rate Action

60 bpm Increase dose by 2.5 mg twice daily (up to maximum 7.5 mg twice daily)

50–60 bpm Maintain current dose

<50 bpm OR symptomatic bradycardia Reduce dose by 2.5 mg twice daily; if already on 2.5 mg twice daily, discontinue

Critical: Use ONLY in patients in sinus rhythm. Ivabradine does NOT control ventricular rate in atrial fibrillation.

1. Chronic Stable Angina Pectoris

Eligibility:

• Patients with chronic stable angina who cannot tolerate or have contraindication to beta-blockers

• OR insufficient symptom control with beta-blockers alone

• Must be in sinus rhythm with resting HR ≥70 bpm

Parameter Dose Clinical Notes

Starting dose 5 mg orally twice daily with meals Take with food to improve absorption

Titration Adjust after 3–4 weeks based on heart rate and symptom control

Usual maintenance dose 5–7.5 mg twice daily

Maximum dose 7.5 mg twice daily

Titration based on response:

• If resting HR remains >60 bpm and angina not controlled: increase to 7.5 mg twice daily

• If resting HR <50 bpm or symptoms of bradycardia: reduce dose or discontinue

• If persistent HR <50 bpm on lowest dose: discontinue ivabradine

Secondary Indications — Adults (Off-label, if any)

1. Inappropriate Sinus Tachycardia — OFF-LABEL

Parameter Details

Indication Symptomatic inappropriate sinus tachycardia (IST) unresponsive to or intolerant of beta-blockers

Starting dose 2.5 mg orally twice daily

Titration Increase by 2.5 mg twice daily every 2 weeks based on HR and symptoms

Usual dose 5–7.5 mg twice daily

Maximum dose 7.5 mg twice daily

Duration Long-term; reassess periodically

Specialist only Yes — Cardiology/Electrophysiology

Evidence basis Case series; international expert consensus; used in Indian cardiac autonomic clinics

1. Postural Orthostatic Tachycardia Syndrome (POTS) — OFF-LABEL

Parameter Details

Indication POTS with persistent tachycardia and symptom burden despite non-pharmacological measures

Starting dose 2.5 mg orally twice daily

Titration Increase gradually based on standing HR and symptoms

Usual dose 2.5–5 mg twice daily

Maximum dose 7.5 mg twice daily

Duration Long-term symptom management

Specialist only Yes — Cardiology/Autonomic disorder specialist

Evidence basis International case series; specialist practice in Indian tertiary centres

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

NOT APPROVED for paediatric use in India.

• No paediatric-specific formulation available in India

• Safety and efficacy not established in children

Secondary Indications — Paediatrics (Off-label, if any)

Paediatric Dilated Cardiomyopathy with Heart Failure — OFF-LABEL

Parameter Details

Indication Dilated cardiomyopathy with reduced EF and persistent sinus tachycardia despite optimal therapy

Age ≥6 months (specialist only)

Starting dose 0.02–0.05 mg/kg/dose orally twice daily

Titration Increase by 0.02–0.05 mg/kg/dose every 2 weeks based on HR response

Usual maintenance dose 0.05–0.1 mg/kg/dose twice daily

Maximum dose 0.2 mg/kg/dose twice daily OR 7.5 mg twice daily (whichever is lower)

Specialist only Yes — Paediatric cardiology

Monitoring Heart rate, ECG, blood pressure, symptom assessment

Evidence basis Small paediatric series; international paediatric cardiology protocols; used in Indian paediatric cardiac centres

Weight-Based Dosing Guide:

Body Weight Starting Dose Usual Maintenance Maximum Dose

10–20 kg 0.5–1 mg twice daily 1–2 mg twice daily 2.5 mg twice daily

20–40 kg 1–2 mg twice daily 2–4 mg twice daily 5 mg twice daily

40 kg 2.5 mg twice daily 5 mg twice daily 7.5 mg twice daily

Note: May require compounding/tablet splitting for accurate paediatric dosing. Tablets are NOT scored.

Not recommended below 6 months of age. Use in infants 6 months to 1 year only under specialist paediatric cardiology supervision in tertiary centres with ECG monitoring capability.

Ivabradine is primarily hepatically metabolised; renal impairment has minimal effect on pharmacokinetics but may increase sensitivity to adverse effects.

Ivabradine undergoes extensive hepatic metabolism via CYP3A4; severe hepatic impairment significantly increases drug exposure.

• Resting heart rate <60 bpm prior to treatment initiation (increased bradycardia risk)

• Severe hypotension (<90/50 mmHg)

• Acute decompensated heart failure

• Cardiogenic shock

• Sick sinus syndrome

• Sinoatrial block

• Third-degree (complete) AV block

• Pacemaker-dependent patients (heart rate imposed exclusively by pacemaker)

• Unstable angina or acute myocardial infarction

• Severe hepatic impairment (Child-Pugh C)

• Concurrent use with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, nelfinavir)

• Concurrent use with verapamil or diltiazem (CYP3A4 inhibition + additive HR-lowering)

• Known hypersensitivity to ivabradine or any excipient

• Pregnancy and women of childbearing potential not using effective contraception

• Atrial fibrillation or atrial flutter — ivabradine is ineffective; do not initiate; discontinue if AF develops

• Frequent ventricular ectopy or non-sustained VT

• Congenital QT prolongation or concurrent QT-prolonging drugs — may increase arrhythmia risk

• Chronic atrial fibrillation or frequent PACs — assess rhythm before initiating

• Resting HR 60–70 bpm — start at lower dose; close monitoring

• Retinitis pigmentosa — ivabradine may worsen visual symptoms

• Moderate hepatic impairment — slower titration

• Hypotension — may exacerbate symptoms

• Elderly — increased bradycardia risk

• Moderate CYP3A4 inhibitors (fluconazole, erythromycin, grapefruit juice) — use with caution

• Abrupt discontinuation in angina — may worsen symptoms; taper if possible

Aspect Recommendation

Risk category Contraindicated — teratogenic and embryotoxic in animal studies

Human data Insufficient; presumed harmful based on mechanism and animal data

Use in pregnancy Avoid; use only if absolutely no alternative and benefit clearly outweighs risk

Preferred alternatives Beta-blockers (metoprolol, labetalol) for heart rate control in pregnancy

Contraception Women of childbearing potential must use effective contraception during treatment

If exposure occurs Discontinue immediately; specialist referral for fetal monitoring

Monitoring If unavoidable use: fetal heart rate, fetal growth, amniotic fluid

Aspect Recommendation

Compatibility Not recommended during breastfeeding

Drug levels in milk Expected moderate levels (lipophilic drug; animal data shows excretion in milk)

Preferred alternatives Beta-blockers (metoprolol, propranolol) if maternal heart rate control needed

Recommendations Avoid breastfeeding during ivabradine therapy; if essential, consider pump and discard

Infant monitoring (if inadvertent exposure) Bradycardia, poor feeding, lethargy, poor weight gain

Aspect Recommendation

Starting dose 2.5 mg orally twice daily

Titration Slower titration; reassess at 2–4 week intervals

Special considerations Elderly patients (especially >75 years) are more susceptible to bradycardia

Extra risks Symptomatic bradycardia; dizziness; visual disturbances; falls; syncope

Monitoring Heart rate, blood pressure (sitting and standing); symptom assessment; fall risk evaluation

Drug Interaction Management

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, nelfinavir) Markedly increased ivabradine levels → severe bradycardia Contraindicated

Verapamil Dual mechanism: CYP3A4 inhibition + additive HR-lowering → severe bradycardia Contraindicated

Diltiazem Dual mechanism: CYP3A4 inhibition + additive HR-lowering → severe bradycardia Contraindicated

QT-prolonging drugs (amiodarone, sotalol, quinidine, erythromycin, haloperidol) Ivabradine-induced bradycardia + QT prolongation → increased torsades de pointes risk Avoid combination if possible; if essential, close ECG monitoring

Grapefruit juice CYP3A4 inhibition → increased ivabradine exposure Avoid — counsel patients

Drug Interaction Management

Beta-blockers (metoprolol, carvedilol, bisoprolol) Additive heart rate reduction → increased bradycardia risk Often used together in HFrEF (therapeutic); start ivabradine at lower dose; monitor HR closely

Digoxin Additive bradycardia risk Monitor heart rate and ECG; dose adjustment rarely needed

Moderate CYP3A4 inhibitors (fluconazole, erythromycin) Increased ivabradine levels Reduce ivabradine starting dose to 2.5 mg twice daily; monitor HR

CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St. John's Wort) Reduced ivabradine efficacy May need higher ivabradine dose; monitor therapeutic response

Non-dihydropyridine CCBs (low-dose) Additive HR-lowering Use with caution; avoid high doses

Antihypertensives Additive BP-lowering (modest with ivabradine) Monitor blood pressure

• Phosphenes (luminous phenomena — transient brightness in visual field, usually triggered by sudden light intensity changes) — 15–20% incidence; usually transient

• Bradycardia (symptomatic in 2–5%)

• Headache

• Dizziness

• Blurred vision

• Fatigue

• Atrial fibrillation (3–5% in HFrEF trials)

• First-degree AV block

Note: Phosphenes are benign, transient visual symptoms related to retinal If channel effects; usually resolve with continued treatment; not associated with retinal damage.

Adverse Effect Clinical Notes

Severe symptomatic bradycardia May cause syncope, hypotension, worsening heart failure; reduce dose or discontinue; pacemaker may be needed

Atrial fibrillation May develop during treatment (~5%); discontinue ivabradine if sustained AF develops

Ventricular arrhythmias Rare; reported in association with bradycardia and QT prolongation

Syncope Usually related to bradycardia; evaluate and reduce dose or discontinue

Torsades de pointes Rare; increased risk with concurrent QT-prolonging drugs

Visual impairment (prolonged) Rare; evaluate if persistent visual symptoms; consider discontinuation

Action: Discontinue ivabradine if sustained atrial fibrillation develops, severe symptomatic bradycardia occurs, or persistent visual disturbance not related to phosphenes.

After initiation/dose change Heart rate and blood pressure at 2 weeks; ECG if bradycardia or rhythm concerns; assess for visual symptoms

During stable therapy Heart rate at each visit (every 2–3 months); periodic ECG (every 6 months or if symptoms); monitor for AF development; reassess visual symptoms

Long-term Periodic rhythm assessment (annual Holter if history of arrhythmia); reassess indication and response; echocardiography as per HF guidelines

• Coralan (Serdia/Servier) — originator brand

• Ivabrad (Abbott)

• Ivabeat (Sun Pharma)

• Ivabid (Cipla)

• Ivacard (Torrent)

• Ivanor (Glenmark)

• Bradia (Zydus)

• Cardibrade (Alkem)

• Multiple generic manufacturers

FDC Note: Some FDCs with carvedilol or metoprolol are marketed but NOT routinely recommended; use individual titration of each component.

• Not listed in NLEM 2022

• Not under NPPA price control

• Limited availability in government supply; increasingly available under PM-JAY and state cardiac programmes in some states

1. Sinus rhythm is mandatory — ivabradine works ONLY on the sinus node; it is completely ineffective for rate control in atrial fibrillation. Always confirm sinus rhythm before initiating and discontinue if AF develops.

1. Not a beta-blocker substitute — in HFrEF, ivabradine is added to maximally tolerated beta-blockers, not used instead of them. Only use as alternative when beta-blockers are truly contraindicated or not tolerated.

1. Target HR 50–60 bpm — the SHIFT trial showed maximum benefit when HR was reduced to 50–60 bpm; titrate to this target while avoiding symptomatic bradycardia.

1. Phosphenes are benign — reassure patients that visual brightness/flashing (phosphenes) are common, harmless, and usually diminish over time. They are NOT indicative of retinal damage.

1. Take with food — ivabradine absorption increases ~20–30% with food; consistent dosing with meals is recommended.

1. Watch for AF — approximately 5% of HFrEF patients develop atrial fibrillation on ivabradine; educate patients about irregular pulse and palpitations; discontinue if sustained AF develops.

1. Drug interaction vigilance — ivabradine is metabolised by CYP3A4; avoid strong inhibitors (azole antifungals, macrolides like clarithromycin, HIV protease inhibitors) and counsel patients to avoid grapefruit juice.

ivabradine; If channel inhibitor; heart failure; HFrEF; stable angina; sinus node; heart rate control; SHIFT trial; bradycardia; phosphenes; CYP3A4; Schedule H

RxIndia v1.0 — 26 May 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia

• API Textbook of Medicine

• AIIMS Heart Failure Management Guidelines

• ICMR Guidelines on Heart Failure

• Cardiological Society of India (CSI) Position Statement on Heart Failure Management

• SHIFT Trial (Lancet 2010) — for HFrEF indication

• BEAUTIFUL Trial (Lancet 2008) — for angina indication

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (supportive)