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Refractory Stable Angina Pregnancy: Avoid — animal studies show fetal toxicity; no adequate human data

Ranolazine

Brand names: Ranexa

Adult dose

Dose: 375 mg twice daily initially; increase to 500 mg BD after 2-4 weeks; then 750 mg BD if needed
Route: Oral
Frequency: Twice daily (swallow whole — modified-release; do not crush/chew)
Max: 750 mg twice daily
Late sodium current inhibitor (INa blocker). Reduces intracellular calcium overload in ischaemic cardiomyocytes. Does NOT affect heart rate or blood pressure significantly — useful add-on when haemodynamic agents (beta-blockers, CCBs) limited by bradycardia/hypotension.

Paediatric dose

Route: Oral
Seek specialist opinion — not licensed in children

Dose adjustments

Renal

Caution in severe renal impairment (eGFR <30) — increased plasma levels. Use lowest dose (375 mg BD).

Hepatic

Contraindicated in severe hepatic impairment; caution in moderate impairment

Clinical pearls

  • MERLIN-TIMI 36 trial (Morrow et al. JAMA 2007): ranolazine vs placebo added to standard therapy in NSTEMI — did NOT reduce primary endpoint (death, MI, recurrent ischaemia) significantly, but significantly reduced recurrent ischaemia and new-onset HF. Safe in ACS.
  • Haemodynamically neutral: unlike beta-blockers and CCBs, ranolazine does not lower heart rate or blood pressure. This makes it valuable add-on therapy when further rate-reduction or pressure-lowering is limited or contraindicated.
  • Mechanism — late INa current: during myocardial ischaemia, the late sodium current (INa) increases dramatically, causing intracellular Na+ overload → Na+/Ca2+ exchanger dysfunction → intracellular Ca2+ overload → impaired diastolic relaxation and oxygen consumption. Ranolazine blocks this selectively.
  • Diltiazem interaction is important: diltiazem (moderate CYP3A4 inhibitor) increases ranolazine AUC ~2.4-fold. Use ranolazine 375 mg BD when combined with diltiazem; do not uptitrate above 500 mg BD.
  • QTc monitoring: ranolazine causes modest QTc prolongation (~6 ms at therapeutic levels). Clinically significant only when combined with other QTc-prolonging agents. Baseline ECG recommended.

Contraindications

  • Severe hepatic impairment
  • Concomitant strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) — markedly increase ranolazine levels
  • Concomitant Class Ia or III antiarrhythmics (except amiodarone) — QTc risk
  • QTc >500 ms at baseline

Side effects

  • Dizziness
  • Constipation
  • Nausea
  • Headache
  • QTc prolongation (modest — clinically significant interaction with other QTc-prolonging drugs)
  • Peripheral oedema

Interactions

  • Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) — CONTRAINDICATED (dramatically increase ranolazine levels)
  • Moderate CYP3A4 inhibitors (diltiazem, verapamil, fluconazole) — increase ranolazine levels; use lowest dose
  • Simvastatin — ranolazine increases simvastatin AUC 2-fold; max simvastatin 20 mg with ranolazine
  • Digoxin — ranolazine increases digoxin levels ~1.5-fold; monitor

Monitoring

  • ECG (QTc at baseline and if symptoms)
  • Blood pressure and heart rate
  • Angina frequency (efficacy assessment)
  • Renal function
  • Digoxin levels if co-prescribed

Reference: BNFc; BNF 90; MERLIN-TIMI 36 Trial (Morrow et al. JAMA 2007); ESC Stable CAD Guidelines 2019; NICE CG126; SPC Ranexa. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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