Adult: As add-on therapy in patients who are inadequately controlled or intolerant to 1st-line antianginal therapies (e.g. β-blockers, Ca antagonists): Initially, 375 mg bid; after 2-4 weeks, may increase to 500 mg bid based on patient's response. Dose may be further increased up to Max of 750 mg bid if needed. Dose reduction may be required according to patient's tolerability. Treatment and dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Oral Chronic angina
Adult: May be used in combination with β-blockers, nitrates, Ca channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers: Initially, 500 mg bid, then increase to 1,000 mg bid based on patient's clinical symptoms. Max: 1,000 mg bid. Treatment and dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Special Patient Group
Patients taking moderate CYP3A inhibitors (e.g. diltiazem, erythromycin) or P-glycoprotein (P-gp) inhibitors: Dose adjustment may be required (refer to specific product guideline).
Pharmacogenomics:
Ranolazine is metabolised primarily by CYP3A4, and to a lesser extent by CYP2D6. Studies have shown that CYP2D6 poor metabolisers have a higher area under the curve (AUC) as compared to CYP2D6 extensive metabolisers, therefore the risk of increased exposure leading to adverse events is higher in CYP2D6 poor metabolisers than in CYP2D6 extensive metabolisers. Currently, there is insufficient evidence for a recommendation on genetic testing and no dosage adjustment has been recommended for specific CYP2D6 genotypes.
Renal Impairment
CrCl (mL/min)
Dosage
<30
Contraindicated.
Hepatic Impairment
Moderate to severe: Contraindicated.
Administration
May be taken with or without food.
Contraindications
Severe renal (CrCl <30 mL/min) and moderate to severe hepatic impairment. Concomitant use with CYP3A4 inducers, potent CYP3A4 inhibitors, or class Ia or class III antiarrhythmics other than amiodarone; St. John's wort.
Special Precautions
Patient with history of congenital or family history of long QT syndrome, known acquired QT interval prolongation, moderate to severe CHF (NYHA Class III-IV), low weight (≤60 kg). CYP2D6 poor metabolisers. Patients taking moderate CYP3A4 inhibitors or P-gp inhibitors. Mild to moderate renal and mild hepatic impairment. Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Prolonged QTc interval; acute renal failure (particularly in those with severe renal impairment). Ear and labyrinth disorders: Vertigo, tinnitus. Eye disorders: Diplopia, blurred vision, visual disturbance. Gastrointestinal disorders: Nausea, vomiting, constipation. General disorders and administration site conditions: Asthenia. Metabolism and nutrition disorders: Anorexia, decreased appetite, dehydration. Musculoskeletal and connective tissue disorders: Muscle cramp, pain in extremity, joint swelling, muscular weakness. Nervous system disorders: Headache, dizziness. Psychiatric disorders: Confusional state, insomnia, anxiety, hallucination. Renal and urinary disorders: Haematuria, chromaturia, dysuria. Respiratory, thoracic and mediastinal disorders: Cough, epistaxis, dyspnoea. Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritus. Vascular disorders: Hot flush, hypotension.
This drug may cause dizziness, blurred vision, diplopia, confusional state, hallucination and abnormal coordination; if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor renal function periodically (particularly in those with moderate to severe renal impairment); blood pressure and serum K. Evaluate QT interval at baseline and follow up with ECG.
Overdosage
Symptoms: Dizziness, nausea, vomiting, hypotension, QT prolongation, bradycardia, myoclonic activity, severe tremor, unsteady gait or incoordination, dysphasia and hallucinations. Management: Symptomatic and supportive treatment. Perform continuous ECG monitoring.
Drug Interactions
Increased serum concentration with moderate CYP3A4 inhibitors (e.g. diltiazem, erythromycin, fluconazole), P-gp inhibitors (e.g. ciclosporin, verapamil) and CYP2D6 inhibitors (e.g. paroxetine). May increase serum concentration of digoxin, metformin, sensitive CYP3A4 substrates (e.g. atorvastatin, simvastatin, lovastatin), CYP3A4 substrates with narrow therapeutic range (e.g. everolimus, tacrolimus, sirolimus), metoprolol and other CYP2D6 substrates (e.g. flecainide, propafenone, TCAs, antipsychotics). May increase risk of ventricular arrhythmias with certain antihistamines (e.g. astemizole, mizolastine, terfenadine). Potentially Fatal: Increased serum concentration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, HIV protease inhibitors). Enhanced QT prolongation with class Ia antiarrhythmics (e.g. disopyramide, procainamide, quinidine) or class III antiarrhythmics other than amiodarone (e.g. sotalol, dofetilide). Decreased serum concentration with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital).
Food Interaction
Decreased serum concentration with St. John's wort. Increased serum concentration with grapefruit juice.
Action
Description: Mechanism of Action: Ranolazine is a piperazine derivative that exerts its antianginal and anti-ischaemic effects without changing the haemodynamic parameters (e.g. heart rate or blood pressure). It is believed that ranolazine inhibits the late phase of the inward Na channel (late INa) in ischaemic cardiac myocytes during cardiac repolarisation, thereby decreasing the intracellular Na concentration and consequently reducing intracellular Ca overload. This results in improved myocardial relaxation and decreased left ventricular diastolic stiffness. Pharmacokinetics: Absorption: Bioavailability: 76%. Time to peak plasma concentration: 2-5 hours. Distribution: Plasma protein binding: Approx 62%, mainly to α1-acid glycoprotein. Metabolism: Rapidly and extensively metabolised in the gastrointestinal tract and liver. Metabolised in the liver mainly by CYP3A, and to a lesser extent by CYP2D6. Excretion: Mainly via urine (75% as active and inactive metabolites; <5% as unchanged drug); faeces (25% as active and inactive metabolites; <5% as unchanged drug). Terminal elimination half-life: 7 hours.
Chemical Structure
Ranolazine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 56959, Ranolazine. https://pubchem.ncbi.nlm.nih.gov/compound/Ranolazine. Accessed Nov. 23, 2023.
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