Ranexa (Ranolazine)
Late Sodium Current Inhibitor for Chronic Stable Angina
Quick Facts About Ranexa
Key Takeaways About Ranexa
- Novel mechanism: Ranolazine is the only widely available antianginal that selectively inhibits the late sodium current, reducing cardiac ischaemia without lowering heart rate or blood pressure
- Add-on therapy: Indicated for chronic stable angina when beta-blockers or calcium channel blockers fail or are not tolerated – not a replacement for first-line treatment
- Not for acute attacks: Ranexa does not relieve acute chest pain; sublingual nitroglycerin remains the treatment of choice for breakthrough angina
- QT-prolonging: Dose-dependent QT prolongation can occur; avoid concurrent strong CYP3A4 inhibitors, grapefruit juice, and other QT-prolonging drugs
- Swallow whole: Prolonged-release tablets must never be crushed, split, or chewed – rapid release can cause dangerous plasma peaks
What Is Ranexa and What Is It Used For?
Ranexa (ranolazine) is a prolonged-release antianginal medication prescribed to adults with chronic stable angina pectoris whose symptoms are not adequately controlled by, or who cannot tolerate, first-line treatments such as beta-blockers, calcium channel blockers, and long-acting nitrates.
Ranolazine belongs to a unique pharmacological class known as late sodium current (late INa) inhibitors. It is classified under the Anatomical Therapeutic Chemical (ATC) system as C01EB18, within the group of “other cardiac preparations.” Ranexa was first approved by the U.S. Food and Drug Administration (FDA) in 2006 and received marketing authorisation from the European Medicines Agency (EMA) in 2008 for the symptomatic treatment of chronic stable angina.
In chronic stable angina, narrowed coronary arteries reduce the oxygen supply to the heart muscle, causing chest pain, pressure, or discomfort during exertion or stress. The goal of antianginal therapy is to rebalance oxygen supply and demand in the heart, reducing the frequency and severity of angina episodes. Most traditional antianginal drugs achieve this by lowering heart rate (beta-blockers, non-dihydropyridine calcium channel blockers), reducing afterload (dihydropyridine calcium channel blockers), or dilating coronary vessels (nitrates). Ranolazine, by contrast, acts inside the cardiac myocyte by correcting a pathological sodium and calcium imbalance that develops during ischaemia.
Ranexa is not used to treat acute angina attacks. It is a preventive, long-term medicine taken twice daily. For breakthrough chest pain, short-acting nitrates such as sublingual glyceryl trinitrate (nitroglycerin) remain the standard of care. Ranexa also does not replace cardiovascular risk-factor management: patients require continued lipid-lowering therapy, antiplatelet treatment (e.g. aspirin or clopidogrel), blood-pressure control, smoking cessation, and regular physical activity to reduce cardiovascular events.
Large randomised trials including MARISA, CARISA, ERICA, and MERLIN-TIMI 36 have demonstrated that ranolazine added to optimal medical therapy increases exercise duration, delays the onset of angina during treadmill testing, and reduces weekly angina frequency and nitroglycerin consumption. The MERLIN-TIMI 36 trial (involving over 6,500 patients with non-ST-elevation acute coronary syndrome) did not show a reduction in cardiovascular death or myocardial infarction but confirmed the antianginal and antiarrhythmic benefits and did not increase mortality.
Current European Society of Cardiology (ESC) 2024 guidelines for chronic coronary syndromes and joint American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend ranolazine as a second-line option for patients who remain symptomatic on beta-blockers or calcium channel blockers, or as first-line therapy when bradycardia, hypotension, or other haemodynamic concerns limit conventional drugs. It is particularly valuable in patients with diabetes, as it has a neutral or modestly favourable effect on HbA1c.
Ranolazine is unusual among antianginals in that it does not lower heart rate or blood pressure to any clinically meaningful extent. This makes it particularly useful in patients with resting bradycardia, hypotension, or heart failure with preserved ejection fraction, where further haemodynamic reduction would be poorly tolerated. It can be combined safely with beta-blockers, calcium channel blockers, nitrates, ACE inhibitors, and statins as part of a multidrug regimen.
What Should You Know Before Taking Ranexa?
Before starting Ranexa, tell your doctor about all your medical conditions, particularly kidney or liver disease, heart rhythm problems, and every medicine you take (including herbal products). Ranexa is contraindicated in severe renal impairment, moderate-to-severe hepatic impairment, and when combined with strong CYP3A4 inhibitors or Class Ia/III antiarrhythmics.
Contraindications
You must not take Ranexa if any of the following apply to you:
- Hypersensitivity to ranolazine or any of the tablet excipients
- Severe renal impairment (creatinine clearance < 30 mL/min) – ranolazine and its metabolites accumulate, increasing the risk of QT prolongation and other side effects
- Moderate or severe hepatic impairment (Child-Pugh B or C) – impaired liver metabolism markedly raises plasma levels
- Concurrent strong CYP3A4 inhibitors – including itraconazole, ketoconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and HIV protease inhibitors (ritonavir, nelfinavir, indinavir)
- Concurrent Class Ia antiarrhythmics (quinidine, procainamide, disopyramide) or Class III antiarrhythmics other than amiodarone (sotalol, dofetilide, ibutilide) – risk of additive QT prolongation and life-threatening arrhythmia
Warnings and Precautions
Talk to your doctor or pharmacist before taking Ranexa if any of the following apply to you:
- Mild or moderate renal impairment (creatinine clearance 30–80 mL/min) – starting dose should remain 375 mg twice daily; careful up-titration with blood pressure monitoring is required because plasma ranolazine exposure can be up to 1.7-fold higher than in patients with normal renal function
- Mild hepatic impairment (Child-Pugh A) – caution and monitoring are recommended
- Elderly patients (≥ 75 years) – higher plasma levels and more side effects, especially dizziness, constipation, and weakness, have been reported
- Low body weight (≤ 60 kg) – adverse reactions occur more frequently; cautious dose titration is required
- Moderate-to-severe heart failure (New York Heart Association Class III–IV) – limited safety data; use with caution
- Congenital or acquired long QT syndrome, known QTc prolongation, uncorrected electrolyte disturbances (hypokalaemia, hypomagnesaemia), or bradycardia
- History of ventricular tachycardia or torsades de pointes
Periodic review of the benefit-risk balance is advisable, especially in patients with multiple risk factors. Your doctor may obtain a baseline and follow-up electrocardiogram (ECG) to monitor the QT interval, particularly when you start Ranexa, after dose increases, or after introducing new interacting medications.
Use in Children and Adolescents
The safety and efficacy of Ranexa in children and adolescents under 18 years of age have not been established. No paediatric data are available, and the medicine is not recommended in this age group.
Pregnancy and Breastfeeding
The use of ranolazine during pregnancy has not been adequately studied in humans. Animal reproduction studies have shown some developmental toxicity at high doses. As a precaution, Ranexa is not recommended during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus. Women of childbearing potential should use effective contraception while on treatment and inform their doctor if they become pregnant or plan a pregnancy.
It is not known whether ranolazine or its metabolites are excreted in human breast milk. Because of the potential for serious adverse reactions in a breastfed infant, and to avoid any unnecessary infant drug exposure, breastfeeding is not recommended during Ranexa therapy.
Driving and Operating Machinery
Ranexa can cause dizziness, blurred vision, diplopia (double vision), confusional state, coordination disturbances, and occasionally hallucinations. These effects are more likely at the start of treatment, after dose increases, or in elderly patients. If you experience any of these symptoms, do not drive or operate machinery until the effect resolves and you have discussed it with your doctor.
Food and Drink Interactions
You should avoid grapefruit, grapefruit juice, and Seville oranges during treatment with Ranexa. These inhibit intestinal and hepatic CYP3A4, the primary enzyme responsible for ranolazine metabolism. Even small amounts can meaningfully increase plasma concentrations and raise the risk of QT prolongation, dizziness, and syncope. Ranexa tablets can be taken with or without food, but should be taken at approximately the same two times each day (roughly 12 hours apart) to maintain steady plasma levels.
How Does Ranexa Interact with Other Drugs?
Ranolazine is metabolised mainly by CYP3A4 and is also a substrate and inhibitor of P-glycoprotein. It interacts with many commonly prescribed drugs, including certain antifungals, antibiotics, HIV medicines, antiarrhythmics, statins, and digoxin. Always give your doctor and pharmacist a complete list of all your prescription, non-prescription, and herbal products before starting treatment.
Ranolazine has a complex interaction profile because it is simultaneously a substrate of the CYP3A4 and P-glycoprotein pathways and a moderate inhibitor of CYP3A4, CYP2D6, and P-glycoprotein. Concurrent administration of other drugs affecting these pathways can substantially increase or decrease ranolazine exposure, or alter the plasma levels of partner drugs. The tables below summarise the most clinically important interactions.
Major Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Ketoconazole / Itraconazole / Voriconazole | Azole antifungals | Strong CYP3A4 inhibitors – increase ranolazine exposure up to 3-fold, prolonging QT interval | Contraindicated – do not combine |
| Clarithromycin / Telithromycin | Macrolide antibiotics | Strong CYP3A4 inhibition – marked rise in ranolazine levels and QT prolongation | Contraindicated – use azithromycin instead |
| Ritonavir / Nelfinavir / Indinavir | HIV protease inhibitors | Strong CYP3A4 and P-gp inhibition – substantial increase in plasma ranolazine | Contraindicated |
| Quinidine / Procainamide / Disopyramide | Class Ia antiarrhythmics | Additive QT prolongation; increased risk of torsades de pointes | Contraindicated |
| Sotalol / Dofetilide / Ibutilide | Class III antiarrhythmics (except amiodarone) | Additive QT prolongation; ventricular arrhythmia risk | Contraindicated |
| Diltiazem / Verapamil | Non-dihydropyridine CCBs (moderate CYP3A4 inhibitors) | Increase ranolazine plasma concentration up to 2-fold | Limit Ranexa to 500 mg twice daily; monitor ECG and blood pressure |
| Simvastatin | HMG-CoA reductase inhibitor (statin) | Ranolazine roughly doubles simvastatin and simvastatin-acid exposure – risk of myopathy / rhabdomyolysis | Limit simvastatin to 20 mg daily; consider alternative statin (e.g. atorvastatin at adjusted dose) |
| Digoxin | Cardiac glycoside | Ranolazine inhibits P-glycoprotein – increases digoxin plasma concentration by approximately 1.5-fold | Monitor digoxin levels; reduce digoxin dose if needed |
Moderate and Minor Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Rifampicin / Rifabutin | Antimycobacterial (CYP3A4 inducers) | Reduce ranolazine exposure by up to 95% – loss of efficacy | Avoid concurrent use; alternative antianginal may be required |
| Carbamazepine / Phenytoin / Phenobarbital | Antiepileptics (CYP3A4 inducers) | Decrease ranolazine plasma concentration, reducing antianginal effect | Monitor angina control; dose adjustment usually impractical |
| St. John's Wort (Hypericum perforatum) | Herbal supplement (CYP3A4 inducer) | Reduces ranolazine exposure | Avoid concurrent use |
| Metformin | Oral antidiabetic | Ranolazine increases metformin exposure up to 1.8-fold at Ranexa 1,000 mg twice daily | Limit metformin to 1,700 mg/day when Ranexa dose exceeds 500 mg twice daily; monitor for lactic acidosis |
| Atorvastatin / Lovastatin | HMG-CoA reductase inhibitors | Modest increases in statin exposure | Consider lower statin starting dose; monitor for muscle symptoms |
| Cyclosporine / Tacrolimus / Sirolimus | Immunosuppressants (CYP3A4 and P-gp substrates) | Potentially increased plasma levels of immunosuppressants | Monitor trough concentrations; adjust dose as needed |
| Metoprolol / Propafenone / Tricyclic antidepressants | CYP2D6 substrates | Ranolazine moderately inhibits CYP2D6 – can increase their plasma concentrations | Consider dose reduction of CYP2D6 substrates; monitor clinically |
| Warfarin | Vitamin K antagonist | Small, clinically non-significant interaction reported in most studies | Standard INR monitoring recommended when starting or stopping Ranexa |
| Other QT-prolonging drugs | e.g. erythromycin, certain antipsychotics, methadone, ondansetron | Additive QT prolongation | Use with caution; ECG monitoring may be required |
This list is not exhaustive. Always inform every healthcare professional you consult – including dentists, emergency physicians, and pharmacists – that you are taking Ranexa. Before starting any new medicine or supplement, ask your pharmacist to check compatibility with ranolazine.
What Is the Correct Dosage of Ranexa?
The recommended starting dose of Ranexa is 375 mg twice daily. After 2–4 weeks, your doctor may up-titrate to 500 mg twice daily and, if needed for symptom control, to a maximum of 750 mg twice daily. Tablets must be swallowed whole – never crushed, split, or chewed – with or without food.
Your doctor will individualise the Ranexa dose based on your response, tolerability, renal and hepatic function, body weight, and any concomitant medications. Adherence to twice-daily dosing (roughly every 12 hours) is essential to maintain steady plasma levels and full antianginal effect.
Adults
Chronic Stable Angina – Standard Titration
Starting dose: 375 mg twice daily
After 2–4 weeks, if required: 500 mg twice daily
Maximum dose: 750 mg twice daily
If a patient experiences treatment-related adverse effects (such as dizziness, nausea, or vomiting), down-titration to 500 mg or 375 mg twice daily is recommended. If symptoms persist after dose reduction, treatment may need to be discontinued.
Children and Adolescents (< 18 years)
Not Recommended
The safety and efficacy of Ranexa in children and adolescents under 18 years have not been established. There are no clinical data supporting use in this population, and the medicine should not be prescribed outside formal clinical trials.
Elderly Patients
Cautious Titration
Starting dose: 375 mg twice daily – with extra caution
Older adults (≥ 75 years) experience higher plasma ranolazine exposure and more frequent adverse reactions (notably dizziness, constipation, nausea, asthenia, and hypotension). Dose titration should be slower, and consideration should be given to concurrent renal impairment and polypharmacy, which frequently coexist in this age group.
Patients with Renal Impairment
Mild-to-Moderate (CrCl 30–80 mL/min)
Starting dose: 375 mg twice daily
Cautious up-titration is required. Monitor blood pressure, signs of fluid retention, and ECG for QT prolongation. Dose reductions may be needed if adverse reactions occur.
Severe (CrCl < 30 mL/min) or End-Stage Renal Disease
Contraindicated. Ranolazine and its metabolites accumulate to potentially dangerous levels.
Patients with Hepatic Impairment
Mild (Child-Pugh A)
Cautious dose titration recommended; start at 375 mg twice daily and monitor carefully.
Moderate-to-Severe (Child-Pugh B or C)
Contraindicated. Ranolazine metabolism is markedly impaired, increasing the risk of toxicity.
Patients with Low Body Weight
≤ 60 kg
Higher incidence of adverse drug reactions. Consider slower titration and closer monitoring of side effects.
How to Take the Tablet
Swallow the tablet whole with a glass of water. Do not crush, break, chew, or dissolve the tablet: doing so would disrupt the prolonged-release system and cause a rapid, potentially dangerous release of ranolazine. Tablets may be taken with or without food. Take them at approximately the same times each day (for example, 8 a.m. and 8 p.m.) to maintain consistent plasma concentrations.
Missed Dose
If you forget a dose, take it as soon as you remember – unless it is nearly time for your next scheduled dose. In that case, skip the missed dose and continue with your normal schedule. Do not take a double dose to make up for a forgotten tablet, as this can lead to peak plasma concentrations associated with a higher risk of QT prolongation and side effects.
Overdose
Symptoms of ranolazine overdose may include dizziness, nausea, vomiting, diplopia, confusion, syncope, and dose-dependent QT interval prolongation with potential for torsades de pointes. In severe cases, seizures and paroxysmal ventricular tachycardia have been reported. If an overdose is suspected, seek immediate medical attention. Contact your local emergency services or poison control centre without delay. Treatment is supportive: activated charcoal if administered promptly, continuous ECG monitoring, correction of electrolytes (especially potassium and magnesium), and symptomatic care. Haemodialysis does not remove ranolazine effectively because of high protein binding.
Stopping Ranexa
Do not stop taking Ranexa without consulting your doctor, even if you feel better. Discontinuation may cause a return of angina symptoms and can reduce exercise tolerance. No dose tapering is routinely required, but re-evaluation of angina therapy is essential. If Ranexa is stopped because of intolerable side effects, your doctor will typically optimise beta-blocker or calcium channel blocker therapy and consider alternative add-on agents such as ivabradine, nicorandil, or trimetazidine.
What Are the Side Effects of Ranexa?
The most common side effects of Ranexa are dizziness, headache, constipation, nausea, and weakness (asthenia), each affecting up to 1 in 10 patients. Most are mild, dose-dependent, and tend to resolve with dose reduction or continued therapy. Rare but serious effects include QT prolongation, syncope, hallucinations, and severe allergic reactions.
Like all medicines, Ranexa can cause side effects, although not everyone will experience them. Adverse reactions are generally dose-dependent and more common at 750 mg twice daily than at 500 mg or 375 mg twice daily. Elderly patients, those with low body weight, and patients with impaired renal function are more susceptible to side effects.
- Sudden fainting, near-fainting, or loss of consciousness
- Irregular, fast, or pounding heartbeat, especially with dizziness
- Severe rash, blistering, or peeling of the skin
- Swelling of the face, lips, tongue, or throat, or difficulty breathing (signs of angioedema or severe allergy)
- New or worsening confusion, hallucinations, or disorientation
- Severe muscle pain, tenderness, or weakness (especially with dark urine) – possible rhabdomyolysis, particularly if taking a statin
Very Common
May affect more than 1 in 10 people
- None typically observed at standard doses – no single reaction reaches this frequency in pivotal trials
Common
May affect up to 1 in 10 people
- Dizziness
- Headache
- Constipation
- Nausea
- Vomiting
- Asthenia (fatigue, weakness, loss of energy)
- Peripheral oedema (swelling of ankles and feet)
- Abdominal pain
- Dyspepsia (indigestion)
- Dry mouth
- Anorexia (decreased appetite)
Uncommon
May affect up to 1 in 100 people
- Anxiety, insomnia, confusional state
- Tremor, lethargy, somnolence
- Blurred vision, diplopia (double vision), visual disturbances
- Vertigo, tinnitus (ringing in the ears)
- Palpitations, hot flushes, hypotension
- Dyspnoea (shortness of breath), cough, epistaxis (nosebleed)
- Dysgeusia (taste disturbance)
- Flatulence, stomach discomfort, pancreatitis
- Pruritus, rash, hyperhidrosis (excessive sweating)
- Pain in limb, muscle cramp, joint swelling, muscular weakness
- Dysuria (painful urination), haematuria (blood in urine), chromaturia (altered urine colour)
- Erectile dysfunction
- Dehydration
- Elevated blood urea, creatinine, and hepatic enzymes
- Electrocardiogram QT prolongation
Rare and Very Rare
May affect up to 1 in 1,000 people or fewer
- Hyponatraemia (low sodium)
- Disorientation, hallucinations, amnesia
- Syncope (fainting), paraesthesia (pins and needles), impaired coordination, gait disturbance, parosmia (distorted sense of smell)
- Hearing impairment
- Reduced renal function, acute renal failure, urinary retention
- Cold peripheries, orthostatic hypotension
- Pharyngeal tightness, throat constriction
- Angioedema, allergic dermatitis, urticaria (hives), cold sweat
- Rash
- Torsades de pointes, ventricular tachycardia (isolated reports)
- Thrombocytopenia, leukopenia (reported post-marketing)
- Pancytopenia (very rare)
- Severe cutaneous adverse reactions – drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (reported post-marketing)
If you experience any side effects not listed here, or if any reaction becomes severe or persistent, contact your doctor or pharmacist. Reporting suspected side effects contributes to the ongoing monitoring of the medicine's benefit-risk profile. In the European Union, reports can be submitted through national pharmacovigilance schemes; in the United States, through the FDA MedWatch programme.
How Should You Store Ranexa?
Store Ranexa tablets below 30°C in the original blister pack to protect from moisture, out of the reach and sight of children. Do not use the tablets after the expiry date printed on the carton. Return any unused or expired tablets to your pharmacy for safe disposal.
Ranexa prolonged-release tablets do not require any specific temperature storage conditions beyond protection from excessive heat. Keep the tablets in their original blister packaging until the moment you take them – the packaging protects the tablet's coating and prolonged-release matrix from humidity, which could otherwise alter the release profile.
Always check the expiry date ("EXP" or "Use by") on the carton and blister before taking a tablet; the expiry date refers to the last day of the stated month. Do not transfer tablets into pill organisers for longer than one week, because prolonged exposure to air and moisture may affect the formulation.
Do not flush unused tablets down the toilet or pour them down the sink. Do not dispose of them in household waste. Take any expired or unused Ranexa tablets to your pharmacy, where they will be destroyed safely in accordance with environmental and pharmaceutical regulations. Correct disposal protects waterways and wildlife from pharmaceutical pollution.
What Does Ranexa Contain?
Each Ranexa prolonged-release tablet contains ranolazine as the active ingredient, together with inactive excipients that control the gradual release of the drug over 12 hours. The tablets are film-coated, oval-shaped, and colour-coded by strength.
Active Ingredient
The active substance is ranolazine. Each prolonged-release tablet contains either 375 mg, 500 mg, or 750 mg of ranolazine.
Inactive Ingredients (Excipients)
The tablet core typically contains: carnauba wax, hypromellose, magnesium stearate, methacrylic acid-ethyl acrylate copolymer (1:1), microcrystalline cellulose, sodium hydroxide, and titanium dioxide. The film coating contains hypromellose, titanium dioxide, polyethylene glycol 400, and iron oxide pigments (which provide the strength-specific colour). The 500 mg tablets also contain polyvinyl alcohol, talc, and lecithin (soya, E322) in some preparations. Patients with a known soya allergy should discuss this with their pharmacist or prescriber.
Tablet Appearance and Packaging
375 mg tablets: Oval-shaped, pale blue, film-coated tablets engraved with “375” on one side.
500 mg tablets: Oval-shaped, light orange, film-coated tablets engraved with “500”.
750 mg tablets: Oval-shaped, pale green, film-coated tablets engraved with “750”.
Ranexa is supplied in PVC/PVDC aluminium blister packs containing 20, 60, or 100 prolonged-release tablets. Not all pack sizes may be marketed in every country.
Marketing Authorisation Holder
Ranexa is marketed in the European Union by Menarini International Operations Luxembourg S.A., and in the United States by Gilead Sciences. Authorised generic ranolazine products are available in several markets, containing identical active ingredient but sometimes different excipients and tablet appearance.
How Does Ranexa Work in the Body?
Ranolazine selectively inhibits the late sodium current (late INa) in cardiac muscle cells. By reducing sodium overload during ischaemia, it prevents the secondary calcium overload that stiffens ventricular muscle, increases oxygen demand, and triggers arrhythmias. Unlike traditional antianginals, ranolazine does so without meaningful effects on heart rate, blood pressure, or coronary vasodilation.
Under normal conditions, sodium enters cardiac cells during the upstroke of each heartbeat through fast-acting sodium channels, which then close rapidly. A small residual “late” sodium current persists during the plateau phase of the action potential, but in healthy tissue this is minor. In the presence of ischaemia, heart failure, or genetic variants, the late sodium current is pathologically enhanced, causing intracellular sodium accumulation.
This sodium overload drives the sodium-calcium exchanger (NCX) in reverse, pulling calcium into the cell rather than removing it. The resulting intracellular calcium overload has several harmful effects: it impairs myocardial relaxation (diastolic dysfunction), increases myocardial stiffness and wall tension, increases oxygen demand, compresses small intramural coronary vessels, and triggers early after-depolarisations (a substrate for ventricular arrhythmias).
Ranolazine binds preferentially to the inactivated state of cardiac sodium channels, selectively blocking the abnormally prolonged late INa without affecting the fast peak sodium current required for normal conduction. By normalising intracellular sodium, it indirectly lowers intracellular calcium, restoring diastolic relaxation, reducing oxygen demand, improving myocardial perfusion in the ischaemic subendocardium, and suppressing arrhythmogenic after-depolarisations.
Crucially, ranolazine achieves these effects without significantly affecting heart rate, blood pressure, contractility, or coronary vasodilation. This “haemodynamically neutral” profile makes it valuable in patients who already have low blood pressure or bradycardia and cannot tolerate further cardiovascular compromise from additional beta-blockers or calcium channel blockers.
Pharmacokinetic Profile
After oral administration, ranolazine is slowly absorbed, with peak plasma concentrations (Cmax) reached 2–5 hours after dosing. Absolute bioavailability ranges from 35% to 50% due to first-pass metabolism. Food has only a minor effect on absorption and is not clinically significant. Plasma protein binding is approximately 62%, predominantly to α1-acid glycoprotein.
Ranolazine is extensively metabolised in the liver, primarily by CYP3A4 (> 70%) and, to a lesser extent, by CYP2D6. Multiple metabolites are produced, none of which is considered active at therapeutic levels. Excretion is mainly renal (75% of an oral dose) and faecal (25%), almost entirely as metabolites – less than 5% of the parent drug is excreted unchanged.
The mean terminal elimination half-life of ranolazine is approximately 7 hours, which together with the prolonged-release tablet formulation supports a twice-daily dosing regimen. Steady state is reached within about three days of consistent dosing. Exposure is increased in patients with renal or hepatic impairment, in older adults, and in those with low body weight, which drives the dose adjustments outlined earlier.
Frequently Asked Questions About Ranexa
Ranexa (ranolazine) is used as add-on therapy for adults with chronic stable angina pectoris who remain symptomatic despite first-line treatment with beta-blockers or calcium channel blockers, or who cannot tolerate these medicines. It reduces the frequency of angina episodes and increases exercise tolerance. Ranexa does not treat acute chest pain attacks and should not be used for acute angina or heart attack.
Unlike beta-blockers and calcium channel blockers, Ranexa does not significantly lower heart rate or blood pressure. It works by inhibiting the late sodium current (late INa) in ischaemic heart muscle, reducing calcium overload and improving myocardial function without changing haemodynamics. This makes it useful in patients who cannot tolerate further blood pressure or heart rate reduction.
The most common side effects are dizziness, headache, constipation, nausea, and weakness (asthenia). These usually appear at the start of treatment and often improve as the body adjusts. Dose-dependent QT interval prolongation can also occur. Contact your doctor if you experience fainting, palpitations, or severe dizziness, as these may indicate a more serious reaction.
Yes – Ranexa is specifically designed to be added on top of standard antianginal therapy such as beta-blockers, dihydropyridine calcium channel blockers, and long-acting nitrates. However, it should not be combined with Class Ia antiarrhythmics (e.g. quinidine, disopyramide) or most Class III antiarrhythmics (e.g. sotalol, dofetilide), because of the risk of additive QT prolongation. Combination with diltiazem or verapamil is allowed but requires a lower Ranexa dose ceiling. Doses of simvastatin and digoxin may also need adjustment.
Yes. Grapefruit and grapefruit juice are moderate-to-strong inhibitors of the CYP3A4 enzyme that metabolises ranolazine. Consuming them can substantially raise ranolazine blood levels, increasing the risk of QT prolongation and side effects such as dizziness, nausea, or syncope. Seville oranges act similarly and should also be avoided. Other citrus fruits (sweet oranges, lemons, limes) are safe.
No. Ranexa tablets are prolonged-release (depot) formulations that release ranolazine gradually over 12 hours. Splitting, crushing, or chewing them would release the full dose almost at once, leading to peak plasma levels high enough to cause dangerous QT prolongation or severe side effects. Always swallow the tablet whole with a glass of water. If you have difficulty swallowing tablets, speak with your doctor about alternative formulations or therapies.
Some patients notice fewer or milder angina episodes within the first week of treatment, but a full therapeutic effect typically requires 2–4 weeks of consistent twice-daily dosing. Ranexa reaches steady plasma concentrations in about three days, but benefits in exercise capacity and symptom frequency usually become clear after the first month. Your doctor will assess response at follow-up visits before considering dose escalation.
Yes, and in fact ranolazine may have small favourable effects on blood glucose and HbA1c in patients with type 2 diabetes, as shown in the MERLIN-TIMI 36 and TERISA trials. However, ranolazine can increase plasma levels of metformin, so the metformin dose should not exceed 1,700 mg/day when Ranexa doses above 500 mg twice daily are used. Monitor for symptoms of lactic acidosis (such as unusual tiredness, muscle pain, or breathing difficulty) and report them promptly.
References
This article is based on the following international medical guidelines and peer-reviewed sources. All medical claims have been assessed against evidence level 1A, the highest quality of evidence based on systematic reviews of randomised controlled trials, or on authoritative regulatory prescribing information.
- European Medicines Agency (EMA). Ranexa: Summary of Product Characteristics (SmPC). Amsterdam: EMA; 2024. Accessed January 2026.
- U.S. Food and Drug Administration (FDA). Ranexa (ranolazine) prolonged-release tablets: Full Prescribing Information. Silver Spring, MD: FDA; 2023.
- Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. European Heart Journal. 2024;45(36):3415–3537. doi:10.1093/eurheartj/ehae177
- Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease. Journal of the American College of Cardiology. 2023;82(9):833–955.
- Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina (MARISA). Journal of the American College of Cardiology. 2004;43(8):1375–1382.
- Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial (CARISA). JAMA. 2004;291(3):309–316.
- Stone PH, Gratsiansky NA, Blokhin A, et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA trial. Journal of the American College of Cardiology. 2006;48(3):566–575.
- Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non–ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297(16):1775–1783.
- Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial. Journal of the American College of Cardiology. 2013;61(20):2038–2045.
- Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006;92(Suppl 4):iv6–iv14.
- World Health Organization (WHO). ATC/DDD Index 2024 – C01EB18 ranolazine. WHO Collaborating Centre for Drug Statistics Methodology. Accessed January 2026.
- British National Formulary (BNF). Ranolazine. BNF/NICE Joint Formulary Committee. Accessed January 2026.
Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, a group of licensed specialist physicians with expertise in cardiology, clinical pharmacology, and internal medicine.
Medical Writers
Board-certified physicians specialising in cardiovascular medicine and clinical pharmacology with documented academic and clinical experience in ischaemic heart disease management.
Medical Reviewers
Independent review board ensuring clinical accuracy, adherence to international guidelines (ESC, AHA/ACC, EMA, FDA), and evidence level 1A standards.
All content follows the GRADE evidence framework and is reviewed against current international guidelines. We have no commercial funding or pharmaceutical sponsorship. For more information, see our editorial standards and medical team pages.