RANOLAZINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RANOLAZINE (RANOLAZINE).
Ranolazine inhibits the late inward sodium current (late INa) in cardiac myocytes, reducing intracellular sodium and calcium overload, thereby improving myocardial relaxation and reducing oxygen demand without affecting heart rate or blood pressure.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Also a substrate of P-glycoprotein. |
| Excretion | Primarily hepatic metabolism (CYP3A4, CYP2D6) with <5% excreted unchanged in urine and feces. Renal excretion accounts for ~75% of total clearance of metabolites; fecal excretion ~25%. |
| Half-life | Terminal elimination half-life ~7-9 hours in healthy individuals; prolonged to 12-16 hours in mild-to-moderate hepatic impairment (Child-Pugh Class A/B). |
| Protein binding | Approximately 62% bound to human plasma proteins (mainly albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | ~1.1 L/kg (85–110 L in 70 kg adult); indicates extensive extravascular distribution. |
| Bioavailability | Oral bioavailability ~35–50% (due to extensive first-pass metabolism); enhanced with food (reduced CYP3A4 activity). |
| Onset of Action | Oral: 2–4 hours for anti-anginal effect (peak plasma concentration achieved at 4–6 hours). |
| Duration of Action | Approximately 12 hours; twice-daily dosing maintains therapeutic levels throughout the dosing interval. |
500 mg orally twice daily, may increase to 1000 mg twice daily based on tolerance.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | Contraindicated if eGFR < 30 mL/min/1.73m2. For eGFR 30-59 mL/min/1.73m2, limit dose to 500 mg twice daily. No adjustment required for eGFR ≥ 60 mL/min/1.73m2. |
| Liver impairment | Contraindicated in Child-Pugh class B or C. Use is not recommended in any degree of hepatic impairment due to increased exposure. |
| Pediatric use | Safety and efficacy not established. No specific dosing guidelines available. |
| Geriatric use | Older adults may be more sensitive to QT prolongation; consider starting at lower dose of 500 mg twice daily. Monitor renal function closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RANOLAZINE (RANOLAZINE).
| Breastfeeding | Excretion in human milk unknown; M/P ratio not established. Due to potential for adverse effects in infant, discontinue drug or breastfeeding. |
| Teratogenic Risk | Insufficient human data; animal studies show no teratogenicity at up to 2 times human exposure. FDA Pregnancy Category C. Risk cannot be ruled out; avoid in first trimester unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
None
| Common Effects | Nausea Vomiting Headache Dizziness Constipation Weakness |
| Serious Effects |
["Pre-existing QT prolongation (QTc > 500 msec)","Severe renal impairment (CrCl < 30 mL/min)","Severe hepatic impairment (Child-Pugh Class C)","Concurrent use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) or inducers"]
| Precautions | ["QT prolongation (dose-related; avoid in patients with pre-existing QT interval prolongation, on QT-prolonging drugs, or with electrolyte disturbances)","Renal impairment (dose reduction required for moderate to severe impairment)","Hepatic impairment (contraindicated in severe hepatic impairment)","Hypotension (use with caution in patients with low blood pressure)"] |
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| Monitor ECG for QT prolongation; monitor renal function due to accumulation; monitor hepatic function; assess for dizziness, syncope, or arrhythmias. |
| Fertility Effects | No human data; animal studies showed no effect on fertility. Theoretical possibility of reduced fertility due to drug's effects on ion channels, but not observed. |