Ivabradine

Ivabradine slows the heart rate by blocking the funny current in the sinoatrial node, without lowering blood pressure or contractility. It treats heart failure with reduced ejection fraction in sinus rhythm when the heart rate stays at 70 beats/minute or more despite the highest tolerated beta blocker dose, and stable angina when a beta blocker is not tolerated. It is not effective in atrial fibrillation. It is expensive and limited in East Africa.

Classification. Sinus node inhibitor; If channel blocker.

Mechanism. Selectively and dose dependently inhibits the hyperpolarisation activated cyclic nucleotide gated channel (the If current) in sinoatrial node cells, slowing diastolic depolarisation and reducing the heart rate. It has no effect on atrioventricular or ventricular conduction and no negative inotropic effect.

Pharmacodynamics. Reduces resting and exercise heart rate by about 10 to 15 beats/minute. Effect is dose dependent and maximal within 3 to 4 hours of a dose. Lengthens diastole and improves coronary perfusion. Reduces heart failure admission and cardiovascular death in heart failure with reduced ejection fraction.

Pharmacokinetics. Oral bioavailability about 40%; food delays absorption by 1 hour and raises exposure by 20 to 30%, so give with meals. Half life 2 hours (effective half life 11 hours). Metabolised by CYP3A4 in the liver and gut; excreted in urine and faeces.

Heart failure with reduced ejection fraction, adult.

• Condition: sinus rhythm, heart rate 70 beats/minute or more at rest, on the maximum tolerated beta blocker dose (or a contraindication).

• Start 5 mg twice daily (2.5 mg twice daily in patients over 75 years).

• After 2 weeks, adjust: heart rate above 60 beats/minute: increase by 2.5 mg a dose (maximum 7.5 mg twice daily); 50 to 60 beats/minute: keep the dose; below 50 beats/minute or symptoms of bradycardia: reduce by 2.5 mg a dose; stop if the rate stays below 50 beats/minute.

• Maximum 7.5 mg twice daily.

Chronic stable angina, adult (heart rate 70 beats/minute or more). Start 5 mg twice daily; after 3 to 4 weeks, increase to 7.5 mg twice daily if the heart rate remains above 60 beats/minute. After the first review, keep the dose if the rate is 50 to 60 beats/minute, and reduce by 2.5 mg a dose if it is below 50 beats/minute or bradycardia symptoms appear. Stop if no symptom benefit after 3 months.

Children aged 6 months and over with dilated cardiomyopathy and heart failure (specialist, where licensed). Weight based oral dosing from 0.02 mg/kg twice daily in the youngest, titrated every 2 weeks by heart rate; the lowest and highest weight bands use oral solution; maximum 0.2 mg/kg twice daily (7.5 mg).

Contraindications. Resting heart rate below 70 beats/minute before treatment; cardiogenic shock; acute myocardial infarction; unstable or acute heart failure; severe hypotension (below 90/50 mmHg); sick sinus syndrome; sinoatrial block; third degree atrioventricular block; pacemaker dependence; severe hepatic impairment; strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir); concurrent verapamil or diltiazem; pregnancy and breastfeeding.

Warnings. Atrial fibrillation (increased risk by about 15%; check pulse regularly and stop if it develops); bradycardia and atrioventricular block; luminous phenomena (phosphenes), usually transient; QT prolongation; hypotension. Avoid with QT prolonging drugs.

Adverse effects. Luminous phenomena (visual brightness), bradycardia, atrial fibrillation, headache, dizziness, blurred vision, first degree atrioventricular block, ventricular extrasystoles, hypertension.

Interactions. Strong CYP3A4 inhibitors: contraindicated. Verapamil and diltiazem: contraindicated (bradycardia and raised ivabradine levels). CYP3A4 inducers (rifampicin, carbamazepine, St John's wort): lower levels. QT prolonging drugs (for example some antimalarials, macrolides): additive effect. Amiodarone: bradycardia. Grapefruit juice raises exposure.

Special groups.

• Pregnancy: contraindicated; foetal cardiac and other abnormalities in animals.

• Breastfeeding: contraindicated.

• Patients of African ancestry: no dose change.

• Older adults: start 2.5 mg twice daily if over 75 years.

• Kidney impairment: creatinine clearance above 15 mL/min: no change; below 15 mL/min: little data, use with caution.

• Liver impairment: moderate: use with caution; severe: contraindicated.

Formulations. Tablets 5 mg and 7.5 mg; oral solution in some markets.

Administration. Oral twice daily with meals (morning and evening).

Baseline. Resting heart rate (at least 70 beats/minute), ECG for rhythm, blood pressure, liver function, pregnancy status.

Monitoring. Heart rate and rhythm after 2 weeks and with each dose change, then at every visit; pulse check for irregularity. Stop if atrial fibrillation develops or if the rate stays below 50 beats/minute. Review visual symptoms.

Stopping. No taper.

Common prescribing errors. Starting in atrial fibrillation or with a resting heart rate below 70 beats/minute; not titrating by heart rate; combining with verapamil or diltiazem; ignoring a clarithromycin or azole antifungal course; prescribing to women who are pregnant or not on contraception.