Antianginal – late sodium current inhibitor
Brand names: Ranolazina Cinfa
Updated · Methodology
Second line
Second-line for stable angina per 2024 in patients with inadequate symptom control on β-blockers and/or calcium antagonists, or with intolerance. Dose 375–750 mg twice daily. Particularly useful in patients with bradycardia, hypotension, or heart failure where β-blockers and nitrates are limited. ERICA showed 30% reduction in angina episodes and improved exercise tolerance.
Sources
ICD-10: I20.8 · ICD-11: BA40.1
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Ranolazine is an antianginal drug with a metabolic mechanism of action (a late sodium current inhibitor). It is prescribed for stable angina as add-on therapy to β-blockers or CCBs when symptom control is inadequate ( 2024, AEMPS Ficha Técnica). In anti-aging regimens, ranolazine is positioned as a metabolic modulator for anti-aging of the myocardium in healthy adults. In people without angina, no clinical studies of prophylactic use exist. The drug causes constipation, nausea, dizziness, QT-interval prolongation, and CYP3A4-mediated drug interactions. If ranolazine was prescribed to a person without angina, consider seeking a second opinion.
A selective inhibitor of the late sodium current (late INa) in cardiomyocytes. Reduces intracellular sodium and calcium overload in ischemic myocardial cells, improving relaxation and reducing cardiac workload without effects on HR or BP. Principally different from β-blockers, calcium antagonists, and nitrates. CYP3A4-metabolized – significant interactions with CYP3A4 inhibitors and inducers.
Limited data. In pregnant angina patients, decisions are made with the cardiologist.
Not used during lactation.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Ranolazine is broken down by CYP3A4. The Ranexa SmPC contraindicates strong inhibitors of this enzyme and classes grapefruit juice as one of them. More ranolazine in the blood means more dose-dependent reactions, such as nausea and dizziness, and a longer QT interval. Grapefruit juice is avoided during treatment.
Source: EMA: Ficha técnica de Ranexa 375 mg comprimidos de liberación prolongada (ranolazina) (2023)
3 pairs found. Sorted from critical to minor.
Mechanism
The gut and liver break down ranolazine mainly through the enzyme CYP3A4, and clarithromycin strongly inhibits this enzyme. The labels give no figures for this exact pair. The closest guide is ketoconazole 200 mg twice daily, another strong CYP3A4 inhibitor. It raised the ranolazine area under the curve (AUC) 3.0–3.9-fold. As ranolazine levels rise, so do its dose-dependent adverse effects and QT interval prolongation on the electrocardiogram. Clarithromycin prolongs the QT interval on its own. The ranolazine prescribing information warns that combining ranolazine with such drugs may in theory raise the risk of ventricular arrhythmias.
Symptoms
Excess ranolazine causes dizziness, nausea and vomiting, and at high concentrations double vision, lethargy, confusion and fainting. Reported effects of oral ranolazine overdose include low blood pressure, slow heart rate, QT interval prolongation on the electrocardiogram, severe tremor, unsteady gait and hallucinations. Clarithromycin also prolongs the QT interval. Torsade de pointes and deaths have been reported in patients taking it.
Management
The combination is contraindicated (clarithromycin summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS; ranolazine SmPC, European Medicines Agency, ; ranolazine label, US Food and Drug Administration, ). None of these documents sets a dose condition, so the contraindication covers any dose of either drug. Ranolazine is used for stable angina (ranolazine SmPC, EMA). In coronary artery disease, weigh the benefit of clarithromycin against a rare risk of arrhythmia, myocardial infarction and cardiovascular death (clarithromycin SmPC, AEMPS). Also weigh it against higher all-cause mortality one year or more after the course (clarithromycin label, FDA). Clarithromycin is contraindicated in patients with low blood potassium or magnesium and in those with a history of QT interval prolongation or ventricular arrhythmia (clarithromycin SmPC, AEMPS). If a patient has taken both drugs and develops dizziness, vomiting, double vision or fainting, observe the patient closely and give symptomatic and supportive care (ranolazine SmPC, EMA). Monitor the electrocardiogram continuously if needed (ranolazine label, FDA).
Sources
Mechanism
Ranolazine is a substrate of two proteins: the enzyme CYP3A4, which breaks it down in the gut and liver, and the transport protein P-glycoprotein (P-gp). Ketoconazole strongly inhibits both CYP3A4 and P-gp. At 200 mg twice daily, it raised the ranolazine area under the curve (AUC) 3.0–3.9-fold. In the European Union, ketoconazole tablets are used for Cushing's syndrome at 400–1200 mg a day. The European ketoconazole prescribing information warns that interactions may be stronger at doses above 200 mg. Both drugs prolong the QT interval on the electrocardiogram. The ketoconazole documents base the contraindication on the risk of serious cardiovascular events, up to life-threatening ventricular arrhythmias.
Symptoms
Excess ranolazine causes dizziness, nausea and vomiting, and at high concentrations double vision, lethargy, confusion and fainting. Reported effects of oral ranolazine overdose include low blood pressure, slow heart rate, QT interval prolongation on the electrocardiogram, severe tremor, unsteady gait and hallucinations. When ketoconazole is combined with QT-prolonging drugs, ventricular arrhythmias can occur, including life-threatening torsade de pointes.
Management
The combination is contraindicated (ketoconazole summary of product characteristics, SmPC, European Medicines Agency, ; ranolazine SmPC, EMA; labels of both drugs, US Food and Drug Administration, ). Do not give ranolazine during the week after ketoconazole is stopped (ketoconazole label, FDA). Review all concomitant medicines before starting ketoconazole (ketoconazole SmPC, EMA). Ketoconazole is contraindicated in documented congenital or acquired QT interval prolongation. Record an electrocardiogram before treatment, within the first week and then as clinically indicated (ketoconazole SmPC, EMA). If the patient also takes other QT-prolonging drugs, continue electrocardiogram monitoring (ketoconazole SmPC, EMA). The contraindication concerns oral ketoconazole. After adults applied ketoconazole gel to the scalp or skin, no measurable ketoconazole was found in plasma (ketoconazole gel SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). If a patient has taken both drugs and develops dizziness, vomiting, double vision or fainting, observe the patient closely and give symptomatic and supportive care (ranolazine SmPC, EMA). Monitor the electrocardiogram continuously if needed (ranolazine label, FDA).
Sources
Mechanism
The liver breaks down ranolazine mainly through the enzyme CYP3A4, and ritonavir strongly inhibits this enzyme. The labels give no figures for this exact pair. The closest guide is ketoconazole, another strong CYP3A4 inhibitor, which raised the ranolazine area under the curve 3.0–3.9-fold. As ranolazine levels rise, so do its dose-dependent adverse effects and QT interval prolongation.
Symptoms
Excess ranolazine causes dizziness, nausea and vomiting. At high concentrations, double vision, lethargy and fainting are possible. In ranolazine overdose, low blood pressure, slow heart rate, QT prolongation on the electrocardiogram, severe tremor, unsteady gait and hallucinations have been reported.
Management
The combination is contraindicated (ritonavir and ranolazine SmPCs, European Medicines Agency, ; US labels of both drugs, US Food and Drug Administration, ). The contraindication includes low-dose ritonavir used to boost other human immunodeficiency virus (HIV) protease inhibitors. All HIV protease inhibitors are on the ranolazine contraindication list (ranolazine SmPC, EMA), and the ritonavir documents contraindicate ranolazine at any ritonavir dose (ritonavir SmPC, EMA; ritonavir label, FDA). When ritonavir boosts another protease inhibitor, check that drug's prescribing information for contraindications as well (ritonavir SmPC, EMA). If a patient has taken both and develops dizziness, vomiting, double vision or fainting, observe the patient closely and give symptomatic and supportive care (ranolazine SmPC, EMA). Monitor the electrocardiogram continuously if needed (ranolazine label, FDA).
Sources
Verbatim lines from the interaction sections, in the language of the label
«Effects of Other Drugs on Ranolazine: CYP3A Inducers Do not use ranolazine extended-release tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin…»FDA, section 7 · Open on DailyMed
«Administración concomitante de inhibidores potentes del CYP3A4 (p.ej. itraconazol, ketoconazol, voriconazol, posaconazol, inhibidores de la proteasa del VIH, claritromicina, telitromicina…»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4 , 7.1)»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) (4 , 7.1)»FDA, section 4 · Open on DailyMed
«Administración concomitante de antiarrítmicos de clase Ia (p.ej. quinidina) o clase III (p.ej. dofetilida, sotalol) distintos de la amiodarona.»AEMPS, section 4.3 · Open on CIMA
«Administración concomitante de inhibidores potentes del CYP3A4 (p.ej. itraconazol, ketoconazol, voriconazol, posaconazol, inhibidores de la proteasa del VIH, claritromicina, telitromicina…»AEMPS, section 4.3 · Open on CIMA
«Effects of Other Drugs on Ranolazine: Strong CYP3A Inhibitors Do not use ranolazine extended-release tablets with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin…»FDA, section 7 · Open on DailyMed
«Administración concomitante de inhibidores potentes del CYP3A4 (p.ej. itraconazol, ketoconazol, voriconazol, posaconazol, inhibidores de la proteasa del VIH, claritromicina, telitromicina…»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4 , 7.1)»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) (4 , 7.1)»FDA, section 4 · Open on DailyMed
«Effects of Other Drugs on Ranolazine: CYP3A Inducers Do not use ranolazine extended-release tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin…»FDA, section 7 · Open on DailyMed
«Administración concomitante de inhibidores potentes del CYP3A4 (p.ej. itraconazol, ketoconazol, voriconazol, posaconazol, inhibidores de la proteasa del VIH, claritromicina, telitromicina…»AEMPS, section 4.3 · Open on CIMA
«Administración concomitante de antiarrítmicos de clase Ia (p.ej. quinidina) o clase III (p.ej. dofetilida, sotalol) distintos de la amiodarona.»AEMPS, section 4.3 · Open on CIMA
«Effects of Other Drugs on Ranolazine: CYP3A Inducers Do not use ranolazine extended-release tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin…»FDA, section 7 · Open on DailyMed
«Effects of Other Drugs on Ranolazine: Strong CYP3A Inhibitors Do not use ranolazine extended-release tablets with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin…»FDA, section 7 · Open on DailyMed
«Administración concomitante de antiarrítmicos de clase Ia (p.ej. quinidina) o clase III (p.ej. dofetilida, sotalol) distintos de la amiodarona.»AEMPS, section 4.3 · Open on CIMA
«Administración concomitante de inhibidores potentes del CYP3A4 (p.ej. itraconazol, ketoconazol, voriconazol, posaconazol, inhibidores de la proteasa del VIH, claritromicina, telitromicina…»AEMPS, section 4.3 · Open on CIMA
«Administración concomitante de antiarrítmicos de clase Ia (p.ej. quinidina) o clase III (p.ej. dofetilida, sotalol) distintos de la amiodarona.»AEMPS, section 4.3 · Open on CIMA
«Inductores del CYP3A4: La rifampicina (600 mg una vez al día) disminuye las concentraciones de ranolazina en el estado estacionario en aproximadamente un 95%. Se debe evitar iniciar un tratamiento…»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4 , 7.1)»FDA, section 4 · Open on DailyMed
«Effects of Other Drugs on Ranolazine: Moderate CYP3A Inhibitors Limit the dose of ranolazine extended-release tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including…»FDA, section 7 · Open on DailyMed
«Effects of Other Drugs on Ranolazine: Moderate CYP3A Inhibitors Limit the dose of ranolazine extended-release tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including…»FDA, section 7 · Open on DailyMed
«Effects of Other Drugs on Ranolazine: Moderate CYP3A Inhibitors Limit the dose of ranolazine extended-release tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including…»FDA, section 7 · Open on DailyMed
«Inductores del CYP3A4: La rifampicina (600 mg una vez al día) disminuye las concentraciones de ranolazina en el estado estacionario en aproximadamente un 95%. Se debe evitar iniciar un tratamiento…»AEMPS, section 4.5 · Open on CIMA
«Administración concomitante de inhibidores potentes del CYP3A4 (p.ej. itraconazol, ketoconazol, voriconazol, posaconazol, inhibidores de la proteasa del VIH, claritromicina, telitromicina…»AEMPS, section 4.3 · Open on CIMA
«Effects of Ranolazine on Other Drugs: Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of ranolazine extended-release tablets to 20 mg once daily, when ranolazine is…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with ranolazine extended-release tablets 1000 mg twice daily. Doses of other OCT2 substrates may require…»FDA, section 7 · Open on DailyMed
«Inductores del CYP3A4: La rifampicina (600 mg una vez al día) disminuye las concentraciones de ranolazina en el estado estacionario en aproximadamente un 95%. Se debe evitar iniciar un tratamiento…»AEMPS, section 4.5 · Open on CIMA
«Inductores del CYP3A4: La rifampicina (600 mg una vez al día) disminuye las concentraciones de ranolazina en el estado estacionario en aproximadamente un 95%. Se debe evitar iniciar un tratamiento…»AEMPS, section 4.5 · Open on CIMA
«Inductores del CYP3A4: La rifampicina (600 mg una vez al día) disminuye las concentraciones de ranolazina en el estado estacionario en aproximadamente un 95%. Se debe evitar iniciar un tratamiento…»AEMPS, section 4.5 · Open on CIMA
«Effects of Ranolazine on Other Drugs: Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of ranolazine extended-release tablets to 20 mg once daily, when ranolazine is…»FDA, section 7 · Open on DailyMed
«Effects of Ranolazine on Other Drugs: Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of ranolazine extended-release tablets to 20 mg once daily, when ranolazine is…»FDA, section 7 · Open on DailyMed
«La administración concomitante con ticagrelor, ivabradina o ranolazina está contraindicada.»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Antianginal: ranolazine»FDA, section 4 · Open on DailyMed
«amiodarona, bepridilo, dronedarona, ivabradina, quinidina, ranolazina»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: • Alpha 1-adrenoreceptor antagonist: alfuzosin • Anti-gout: colchicine, in patients with renal and/FDA, section 4 · Open on DailyMed
«Drug Interactions: Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine…»FDA, section 4 · Open on DailyMed
«Aumento o disminución de los niveles del medicamento concomitante: Ranolazina»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Antianginal: ranolazine»FDA, section 4 · Open on DailyMed
«Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin: Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed simvastatin 10 mg…»FDA, section 7 · Open on DailyMed
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Ranolazine is evaluated for the following indications with varying evidence strength: Stable angina (evidence tier B), Anti-aging and longevity (evidence tier F). See the full indication matrix with dosing and citations above on this page.
Common side effects of Ranolazine (≥ 1 in 100): Dizziness, Constipation, Nausea, Fatigue, Headache. See the Safety section for uncommon and serious reactions.
Limited data. In pregnant angina patients, decisions are made with the cardiologist.
Not used during lactation.
Ranolazine is contraindicated in: Ranolazine hypersensitivity; Severe hepatic impairment; Severe renal impairment (eGFR under 30); Concomitant strong CYP3A4 inhibitors; Concomitant class Ia and III antiarrhythmics. Full list in the Safety section.
Direct links to regulator labels. Open in a new tab.
Amiodarone, Ubidecarenone (coenzyme Q10), Digoxin, Disopyramide, Dronedarone, Isosorbide mononitrate, Meldonium, Dofetilide