Ranolazine
Sprinkle granules: 500 mg, 1000 mg
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Treatment of chronic angina | Adults; may be used with beta-blockers, nitrates, CCBs, antiplatelets, lipid-lowering agents, ACEi or ARBs | Monotherapy or adjunctive | FDA Approved |
Ranolazine carries a single FDA-approved indication: the treatment of chronic angina. Originally approved in 2006 as second-line therapy after other antianginals, the labelling was updated in 2012 to remove the second-line restriction, making ranolazine a first-line antianginal option per the FDA label. Current 2023 AHA/ACC chronic coronary disease guidelines, however, still position ranolazine as an add-on agent when symptoms persist on beta-blocker, calcium channel blocker, or long-acting nitrate therapy. Its differentiating feature is anti-ischemic activity that does not depend on changes in heart rate or blood pressure — a useful property in normotensive or bradycardic patients in whom further haemodynamic suppression is undesirable.
Microvascular angina (INOCA / coronary microvascular dysfunction) — small randomised trials and observational data suggest ranolazine improves anginal frequency in patients with non-obstructive coronary artery disease. (Evidence quality: low–moderate)
Atrial fibrillation — adjunctive rhythm or rate control — late INa blockade reduces atrial triggered activity. Combination with low-dose dronedarone (HARMONY) and amiodarone-augmenting protocols have shown signal of benefit in paroxysmal AF, but ranolazine is not FDA-approved for this indication. (Evidence quality: low–moderate)
Diabetic glycemic control — modest reductions in HbA1c were observed in CARISA and TERISA, attributed to inhibition of glucagon secretion. Ranolazine should NOT be used as a glucose-lowering agent. (Evidence quality: moderate; not a treatment indication)
Long QT syndrome type 3 (SCN5A gain-of-function) — late INa blockade is mechanistically rational and has been used in selected paediatric and adult cases. (Evidence quality: very low — case series)
Stable ventricular arrhythmias — adjunctive use in select refractory ventricular tachycardia, particularly in ischaemic substrates. (Evidence quality: very low)
Dosing
Ranolazine is dosed twice daily, initially 500 mg PO BID, with up-titration to the maximum recommended 1000 mg PO BID guided by symptom response. Doses above 1000 mg BID are poorly tolerated and not approved. Tablets must be swallowed whole — they cannot be crushed, broken, or chewed; the Aspruzyo Sprinkle granule formulation is available for patients with swallowing difficulty.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Chronic angina — standard initiation, no relevant interactions | 500 mg BID | 1000 mg BID | 1000 mg BID | Up-titrate after several days based on symptom response Steady state reached within 3 days; allow ≥1 week before judging efficacy of a dose |
| On concomitant moderate CYP3A inhibitor (diltiazem, verapamil, erythromycin, fluconazole) | 500 mg BID | 500 mg BID | 500 mg BID (capped) | Do not exceed 500 mg BID per FDA label Diltiazem 180 mg/day raises ranolazine AUC ~1.5-fold |
| On concomitant P-gp inhibitor (e.g., cyclosporine) | 500 mg BID | Down-titrate by clinical response | Per response | Increased absorption via P-gp inhibition Monitor closely for adverse effects, ECG QTc |
| Aspruzyo Sprinkle (granules) — alternative formulation | 500 mg BID | 1000 mg BID | 1000 mg BID | Sprinkle on tablespoonful of soft food (applesauce, yoghurt) and consume immediately; do not chew May be administered via NG/G-tube per product label |
Population-Specific Considerations
| Population | Recommendation | Rationale |
|---|---|---|
| Pediatric (<18 y) | Not recommended — safety and efficacy not established | No supporting trial data; angina extremely rare in this group |
| Elderly ≥65 y | Standard dosing; clinical caution at the low end of dose range | Pharmacokinetics not significantly altered by age |
| Elderly ≥75 y | Higher rates of adverse events, serious adverse events, and discontinuations per FDA label; cautious titration advised | Greater susceptibility to dizziness, neurologic effects, and acute kidney injury |
| Mild renal impairment (CrCl 60–89 mL/min) | No dose adjustment | Modest exposure increase without clinical sequelae |
| Moderate renal impairment (CrCl 30–59 mL/min) | Initiate at lower end of range; monitor renal function periodically | Cmax up to 50% higher; increased risk of acute renal failure |
| Severe renal impairment (CrCl <30 mL/min) | Use with extreme caution; some sources avoid | Acute renal failure reported in PK study at 1000 mg BID; PK study halted prematurely |
| Mild hepatic impairment (Child-Pugh A) | Contraindicated per FDA label (cirrhotic patients) | Cmax increased ~30%; 3-fold greater QT prolongation than in non-cirrhotic patients |
| Moderate–severe hepatic impairment (Child-Pugh B/C) | Contraindicated | Cmax increased ~80% in Child-Pugh B |
| Heart failure (NYHA I–IV) | No dose adjustment | Pharmacokinetics unaffected; minimal effect on heart rate and blood pressure |
Ranolazine is unique among antianginals in that it does not lower heart rate or blood pressure to any clinically meaningful degree. This makes it especially useful in patients with chronic angina whose symptom control is incomplete despite first-line beta-blocker or calcium channel blocker therapy at maximum tolerated doses, in patients already at the haemodynamic floor (e.g., resting bradycardia or borderline hypotension), and in those whose comorbidities (heart failure, COPD) preclude further beta-blockade.
Pharmacology
Mechanism of Action
Ranolazine selectively inhibits the late inward sodium current (late INa) in cardiac myocytes. Under ischaemic conditions, late INa is pathologically enhanced, allowing excessive sodium entry that drives reverse-mode Na⁺/Ca²⁺ exchanger activity and cytosolic calcium overload. Calcium overload increases left ventricular diastolic wall tension, raises myocardial oxygen demand, and impairs coronary perfusion of the subendocardium. By blunting late INa, ranolazine lowers diastolic tension, restores diastolic perfusion, and reduces ischaemia-driven anginal symptoms — without affecting heart rate or systemic blood pressure to any clinically meaningful degree. A secondary, dose-related effect on the rapid delayed-rectifier potassium current (IKr) explains the modest QT-interval prolongation observed at therapeutic doses.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability 35–50% (IR); ER tablets 76% relative to solution; Tmax 2–5 h; food has no significant effect on Cmax/AUC | Take without regard to meals; high inter-individual variability in exposure |
| Distribution | Vd at steady state 85–180 L; ~62% protein-bound (mainly to α₁-acid glycoprotein, weakly to albumin) | Lipophilic with extensive tissue distribution; not removed by haemodialysis |
| Metabolism | Hepatic — predominantly CYP3A4, with minor CYP2D6 contribution; ranolazine is also a P-glycoprotein substrate. Weak CYP3A inhibitor; partial CYP2D6 inhibitor; P-gp inhibitor | The locus of nearly every clinically important interaction; strong CYP3A inhibitors and inducers are contraindicated |
| Elimination | ~73% urinary excretion (predominantly metabolites); <5% unchanged drug; true elimination t½ 1.4–1.9 h, but apparent t½ ~7 h with ER formulation due to flip-flop kinetics; steady state in 3 days | Twice-daily dosing produces a trough:peak ratio of 0.3–0.6; renal failure increases AUC up to two-fold |
Side Effects
The adverse-effect profile is dominated by mild central nervous system and gastrointestinal symptoms, all of which are dose-related and most common during titration to 1000 mg BID. Incidences below are taken from the integrated FDA Ranexa pivotal-trial dataset (2,018 patients across CARISA, MARISA, ERICA, and the long-term open-label extensions).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 6.2% | Dose-related; most prominent during titration. Counsel against driving until response is known. |
| Headache | 5.5% | Generally mild and self-limited; rarely a reason for discontinuation. |
| Constipation | 4.5% | Anticipate at initiation, particularly in elderly and bedbound patients; recommend hydration and a stimulant or osmotic laxative as needed. |
| Nausea | 4.4% | Usually mild; food may improve tolerance but is not required for absorption. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Asthenia, peripheral edema | 0.5–4% | Asthenia is a recognised reason for discontinuation; peripheral edema is generally mild. |
| Bradycardia, palpitations | 0.5–4% | Despite minimal heart-rate effect on average, individual cases occur — especially with concomitant beta-blockade or QT-prolonging drugs. |
| Hypotension, orthostatic hypotension | 0.5–4% | Less frequent than with traditional antianginals; usually mild. |
| Vomiting, abdominal pain, dry mouth, dyspepsia | 0.5–4% | GI effects often improve over weeks of therapy. |
| Anorexia | 0.5–4% | Monitor weight, particularly in elderly patients. |
| Tinnitus, vertigo | 0.5–4% | Class as ear/labyrinth disorder; usually self-resolving. |
| Blurred vision | 0.5–4% | Counsel against driving until visual response is known. |
| Dyspnea | 0.5–4% | Generally mild; differentiate from anginal-equivalent symptoms. |
| Confusional state, vasovagal syncope | 0.5–4% | More common in elderly; consider dose reduction. |
| Hyperhidrosis, hematuria | 0.5–4% | Hematuria warrants urinalysis to exclude alternative causes. |
| Serum creatinine elevation (~0.1 mg/dL) | Class effect Per FDA label | Per FDA label, an artefactual rise from inhibition of tubular creatinine secretion — true GFR is unchanged in healthy volunteers. Distinguish from genuine acute kidney injury (which is also reported and requires discontinuation). |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| QT interval prolongation | Dose-related; mean +6 ms at 1000 mg BID | Within days of initiation or dose increase | Baseline ECG; reassess after dose escalation; avoid in known/family long-QT syndrome and concurrent QT-prolonging drugs. Torsades not observed at therapeutic doses in the 6,560-patient MERLIN-TIMI 36 trial. |
| Acute renal failure | <0.5% Higher in CrCl <30 mL/min | Days to weeks after initiation | Check renal function at baseline and periodically in CrCl <60 mL/min. Differentiate from artefactual creatinine rise (no BUN change). Discontinue immediately if AKI develops. |
| Severe neurologic syndrome (myoclonus, abnormal coordination, tremor, paresthesia, hallucinations) | Rare (post-marketing) | Often after dose increase or with renal/hepatic impairment | Reduce dose or discontinue; symptoms typically resolve. Particular vigilance in CrCl <30 mL/min and the very elderly. |
| Angioedema | <0.5% | Variable | Discontinue immediately and treat per standard angioedema protocols; do not rechallenge. |
| Hypoglycaemia in diabetics on antidiabetic therapy | Post-marketing reports | Variable | Reinforce home glucose monitoring; consider down-titration of insulin or sulfonylurea if hypoglycaemia emerges. |
| Pulmonary fibrosis, hematologic cytopenias (thrombocytopenia, leukopenia, pancytopenia), eosinophilia | <0.5% | Variable; often after prolonged exposure | Investigate persistent dyspnea, unexplained cytopenia, or new infiltrates; discontinue if confirmed. |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Dizziness | 1.3% vs 0.1% placebo | Single most common cause of withdrawal; correlates with peak ranolazine plasma levels and the 1000 mg BID dose. |
| Nausea | 1.0% vs 0% placebo | Often improves with continued therapy; consider 500 mg BID for ≥1 week before escalation. |
| Asthenia, constipation, headache | ~0.5% each vs 0% placebo | Each accounts for a small but distinct withdrawal cohort. |
Patients with CrCl <30 mL/min are at highest risk for the two distinctive ranolazine toxicities — acute renal failure and the dose-dependent neurologic syndrome (myoclonus, ataxia, hallucinations). Both are typically reversible on discontinuation but can be misattributed to other causes in elderly patients on polypharmacy. Any new-onset neurologic symptoms, particularly involuntary movements or coordination disturbance, in a patient on ranolazine should prompt immediate dose reduction or withdrawal pending evaluation.
Drug Interactions
Ranolazine has a complex interaction profile because it is both a substrate and an inhibitor of multiple pathways: extensively metabolised by CYP3A4 (with a smaller CYP2D6 contribution) and a substrate of P-glycoprotein, while itself acting as a partial CYP2D6 inhibitor and a P-gp inhibitor. Strong CYP3A inhibitors and strong CYP3A inducers are absolute contraindications. Moderate CYP3A inhibitors mandate a 500 mg BID dose cap. QT-prolonging drugs require additive caution.
Monitoring
Monitoring is a balance of routine baseline assessments before initiation and trigger-based laboratory work directed at the two distinctive ranolazine toxicities — QT prolongation and acute kidney injury.
-
12-lead ECG (QTc)
Baseline; after each dose escalation; with new QT-prolonging co-medication
Routine Mean QTc increase is approximately 6 ms at 1000 mg BID. Avoid ranolazine if baseline QTc >500 ms; reassess if QTc rises >60 ms above baseline or exceeds 500 ms on therapy. -
Serum creatinine, BUN, electrolytes
Baseline; periodically in CrCl <60 mL/min
Routine An artefactual ~0.1 mg/dL creatinine rise occurs from inhibition of tubular secretion (no BUN change). Progressive creatinine rise with concurrent BUN/potassium increase indicates true AKI — discontinue. -
Blood pressure & heart rate
Baseline and at each visit
Routine Ranolazine has minimal haemodynamic effect on average; new tachycardia or hypotension should prompt reassessment of contributors. -
Anginal frequency & severity
Baseline and at follow-up; patient diary helpful
Routine Allow at least 1–2 weeks at 1000 mg BID before judging full response. Tolerance does not develop over 12 weeks. -
Drug interaction reconciliation
At every encounter
Routine Ask explicitly about new prescriptions of azole antifungals, macrolides, anticonvulsants, antiretrovirals, herbal St John’s wort, and grapefruit ingestion at every visit. -
Glucose / HbA1c in diabetics
If hypoglycaemia symptoms
Trigger-based Modest HbA1c reductions are well-described; rare hypoglycaemia reported with concomitant insulin or sulfonylurea. Reinforce home glucose monitoring at initiation. -
Neurologic examination
If new tremor, ataxia, myoclonus, or confusion
Trigger-based Neurologic syndromes are dose- and exposure-related; consider dose reduction or discontinuation. Particular vigilance in renal impairment and the very elderly. -
Digoxin level
7–10 days after ranolazine initiation/dose change in patients on digoxin
Trigger-based Anticipate ~1.5-fold rise; consider empirical 50% digoxin dose reduction at ranolazine initiation.
Contraindications & Cautions
Absolute Contraindications
- Liver cirrhosis of any Child-Pugh class — 3-fold greater QT prolongation reported in cirrhotic patients.
- Concurrent strong CYP3A inhibitors — ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, ritonavir-boosted antiretrovirals, cobicistat.
- Concurrent strong CYP3A inducers — rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, St John’s wort.
- Hypersensitivity to ranolazine or any tablet excipient.
Relative Contraindications (Specialist Input Recommended)
- Pre-existing QT prolongation — congenital long QT syndrome, family history of LQTS, baseline QTc >500 ms, or potassium-channel variants associated with QT prolongation.
- Severe renal impairment (CrCl <30 mL/min) — high risk of acute renal failure and neurotoxicity in pharmacokinetic study at 1000 mg BID; some clinicians avoid altogether.
- Concomitant Class IA or Class III antiarrhythmic therapy — additive QT prolongation; cardiology co-management essential.
- Acute coronary syndromes / acute MI — MERLIN-TIMI 36 did not demonstrate reduction in major cardiovascular events when ranolazine was added to standard ACS care; benefit limited to recurrent ischaemia and angina-related endpoints.
Use with Caution
- Patients ≥75 years — higher rates of adverse events, serious adverse events, and discontinuation per FDA label.
- Moderate renal impairment (CrCl 30–59 mL/min) — initiate at 500 mg BID and monitor renal function periodically.
- Diabetics on insulin or sulfonylurea — risk of hypoglycaemia.
- Concomitant digoxin or simvastatin — anticipate dose adjustment of the partner drug.
- Pregnancy — limited human data; animal toxicity at supratherapeutic exposures only. Use only if clearly needed.
The FDA Ranexa label highlights dose-related QTc prolongation as a class warning. Mean QTc increase at therapeutic doses is on the order of a few milliseconds (approximately 6 ms at 1000 mg BID in steady-state plasma exposure analyses) but can be markedly larger in patients with hepatic impairment (where the labelled contraindication applies) or with concomitant QT-prolonging drugs. Although torsades de pointes was not observed in MERLIN-TIMI 36 (n = 6,560 NSTE-ACS patients), the FDA warns that there is little experience with high doses, prolonged exposure, or co-administration with other QT-prolonging drugs in patients with congenital or acquired long QT syndromes.
Clinicians should obtain a baseline ECG, reassess after dose escalation to 1000 mg BID, correct potassium and magnesium before initiation, and avoid ranolazine in patients with baseline QTc >500 ms or known long QT syndrome.
Patient Counselling
Purpose of Therapy
Explain that ranolazine is a daily preventive medicine for chronic chest pain (angina). It works through a different mechanism than other heart medications and does not lower blood pressure or heart rate to any meaningful degree, which is why it is often added to existing treatment rather than replacing it. It is not a rescue medication — patients should continue to carry sublingual nitroglycerin for breakthrough chest pain.
How to Take
Take one tablet by mouth twice daily, approximately 12 hours apart, with or without food. Tablets must be swallowed whole — do not crush, break, or chew them, as this destroys the extended-release coating and changes how the medicine is absorbed. The Aspruzyo Sprinkle granule formulation is available for patients with swallowing difficulty: empty one packet onto a tablespoon of soft food (applesauce or yoghurt) and consume immediately. If a dose is missed, skip it and take the next dose at the regular time — never double up.
Sources
- U.S. Food and Drug Administration. Ranexa® (ranolazine) extended-release tablets — full prescribing information. Gilead Sciences. DailyMed — Ranexa label Definitive U.S. label and source for adverse-event incidence rates (dizziness 6.2%, headache 5.5%, constipation 4.5%, nausea 4.4%; 6% overall discontinuation) and dosing rules used in this monograph.
- U.S. Food and Drug Administration. Ranexa NDA 21-526 approval and supplements — historical labelling and pharmacokinetic data. accessdata.fda.gov Source for the 3.2-fold ranolazine AUC increase with ketoconazole, the 1.5-fold AUC rise with diltiazem 180 mg/day, and other labelled drug-interaction quantification.
- Chaitman BR, Skettino SL, Parker JO, et al; MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43(8):1375–1382. doi.org/10.1016/j.jacc.2003.11.045 Dose-response monotherapy trial (n = 191) establishing antianginal efficacy across 500–1500 mg BID without clinically meaningful haemodynamic change.
- Chaitman BR, Pepine CJ, Parker JO, et al; CARISA Investigators. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291(3):309–316. doi.org/10.1001/jama.291.3.309 Pivotal combination trial (n = 823) demonstrating reduced angina frequency and increased exercise duration when ranolazine was added to standard antianginal therapy.
- Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. 2006;48(3):566–575. doi.org/10.1016/j.jacc.2006.05.044 Combination trial (n = 565) showing reduced anginal frequency and nitroglycerin consumption when ranolazine 1000 mg BID was added to amlodipine 10 mg/day.
- 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. doi.org/10.1001/jama.297.16.1775 Largest ranolazine trial (n = 6,560) — neutral on the composite primary endpoint in NSTE-ACS but reassured on safety and showed reduced recurrent ischaemia, with no excess of arrhythmia or sudden death.
- Kosiborod M, Arnold SV, Spertus JA, et al; TERISA Investigators. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial. J Am Coll Cardiol. 2013;61(20):2038–2045. doi.org/10.1016/j.jacc.2013.02.011 Randomised trial in chronic angina with diabetes; ranolazine reduced angina frequency and sublingual nitroglycerin use compared with placebo.
- 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. Circulation. 2023;148(9):e9–e119. doi.org/10.1161/CIR.0000000000001168 Current U.S. guideline positioning ranolazine as an add-on antianginal agent in chronic coronary disease, particularly for patients on maximum tolerated first-line therapy.
- Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407–477. doi.org/10.1093/eurheartj/ehz425 European framework supporting ranolazine as a second-line antianginal agent and recognising its specific value in patients with low heart rate or low blood pressure.
- Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113(20):2462–2472. doi.org/10.1161/CIRCULATIONAHA.105.597500 Authoritative mechanistic and clinical review of ranolazine’s late INa blockade, antianginal effects, and electrophysiological profile.
- Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110(8):904–910. doi.org/10.1161/01.CIR.0000139333.83620.5D Foundational electrophysiology paper characterising ranolazine’s selective late INa blockade and its modest IKr effect.
- Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006;45(5):469–491. doi.org/10.2165/00003088-200645050-00003 Definitive pharmacokinetic review establishing the bioavailability range, ~62% protein binding, 85–180 L volume of distribution, and the flip-flop kinetics that account for the apparent 7-hour half-life with the ER formulation.
- Wilson SR, Scirica BM, Braunwald E, et al. Efficacy of ranolazine in patients with chronic angina: observations from the MERLIN-TIMI 36 trial. J Am Coll Cardiol. 2009;53(17):1510–1516. doi.org/10.1016/j.jacc.2009.01.037 Largest analysis of ranolazine in patients with established coronary artery disease (n = 3,565); confirmed antianginal efficacy with reassuring safety in a broader population than the original phase III trials.
- Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non–ST-segment elevation acute coronary syndrome: results from MERLIN-TIMI 36. Circulation. 2007;116(15):1647–1652. doi.org/10.1161/CIRCULATIONAHA.107.724880 Pre-specified arrhythmia analysis from MERLIN-TIMI 36 showing reduced ventricular and supraventricular arrhythmia on continuous Holter — the foundation for ongoing off-label investigation in atrial fibrillation.