Ranolazine

Ranolazine is an anti anginal drug that does not lower heart rate or blood pressure. It is added when angina persists on a beta blocker, calcium channel blocker or nitrate, or when these are not tolerated. It prolongs the QT interval slightly and has many interactions through CYP3A4 and P-glycoprotein. It is expensive and rarely available in East Africa.

Classification. Late sodium current inhibitor; anti anginal.

Mechanism. Inhibits the late inward sodium current in cardiac muscle, reducing intracellular sodium and calcium overload and diastolic wall tension, which improves oxygen balance without changing heart rate or blood pressure. It also inhibits the delayed rectifier potassium current, which prolongs the QT interval.

Pharmacodynamics. Effect builds over 1 to 2 weeks. Reduces angina frequency and nitrate use and increases exercise time. Little change in heart rate or blood pressure. Lowers HbA1c by about 0.5% in diabetes.

Pharmacokinetics. Oral bioavailability 30 to 55% and variable; food has no effect. Half life 7 hours (modified release). Metabolised mainly by CYP3A4 and partly CYP2D6; less than 5% excreted unchanged in urine. A substrate and inhibitor of P-glycoprotein and an inhibitor of CYP3A4 and CYP2D6.

Chronic stable angina (add on), adult.

• Start 375 mg twice daily.

• After 2 to 4 weeks, increase to 500 mg twice daily.

• Maximum 750 mg twice daily, based on response and tolerance.

• Use a lower starting dose and take extra care in older adults, low body weight (under 60 kg), heart failure of NYHA class III to IV, and mild to moderate kidney impairment.

• Limit to a maximum of 500 mg twice daily with moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin, fluconazole).

Children. Not established.

Contraindications. Liver cirrhosis (any grade); severe kidney impairment (creatinine clearance under 30 mL/min); concurrent strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, nefazodone); concurrent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort); congenital long QT syndrome or concurrent QT prolonging drugs; hypersensitivity.

Warnings. QT prolongation (dose related); dizziness and syncope; raised creatinine (reversible, from inhibition of tubular secretion); constipation. Not for acute angina. Older adults and low weight have higher exposure.

Adverse effects. Dizziness, constipation, nausea, vomiting, headache, asthenia, dry mouth, palpitations, QT prolongation, creatinine rise, rarely hallucinations or tremor.

Interactions. Strong CYP3A4 inhibitors and inducers: contraindicated. Moderate CYP3A4 inhibitors: maximum 500 mg twice daily. Simvastatin: limit to 20 mg daily. Metformin: limit to 1700 mg daily (with ranolazine 1000 mg twice daily). Digoxin: levels rise. Ciclosporin, tacrolimus, sirolimus: raised levels. Dronedarone, class I and III antiarrhythmics, antimalarials (for example artemether lumefantrine), macrolides, antipsychotics: QT prolongation. Paroxetine: raised ranolazine levels.

Special groups.

• Pregnancy: avoid unless essential; limited data.

• Breastfeeding: no data; avoid.

• Patients of African ancestry: no dose change.

• Older adults: start 375 mg twice daily; monitor for dizziness.

• Kidney impairment: avoid with creatinine clearance under 30 mL/min; use with caution and monitor creatinine when it is 30 to 80 mL/min.

• Liver impairment: contraindicated in cirrhosis.

Formulations. Modified release tablets 375, 500, 750 mg.

Administration. Oral twice daily with or without food. Swallow whole; do not crush, break or chew.

Baseline. ECG (QTc), creatinine and eGFR, liver function, potassium and magnesium, full drug history for CYP3A4 interactions.

Monitoring. Angina frequency and nitrate use at 2 to 4 weeks. ECG after dose increases if there are other QT prolonging factors. Creatinine in kidney impairment (at baseline, 1 month and then every 6 months). Dizziness and falls.

Stopping. No taper needed.

Common prescribing errors. Prescribing with clarithromycin, ketoconazole or rifampicin; exceeding 500 mg twice daily with diltiazem or verapamil; using in cirrhosis; leaving simvastatin above 20 mg; crushing tablets.