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ranolazine (Ranexa)

Indications: - adjuvant therapy of chronic angina pectoris after other options exhausted [3] - rhythm control in atrial fibrillation [5] - may accelerate chemical cardioconversion with amiodarone in patients with recent-onset atrial fibrillation [7] Contraindications: 1) pre-existing QT prolongation 2) hepatic insufficiency (Child-Pugh classes A,B,C) 3) coadministration of drugs that prolong QT interval 4) no benefit for acute onset coronary artery disease 5) no benefit for patients with incomplete revascularization after PCI [4] Pregnancy category: C Dosage: 1) start 500 mg PO BID 2) titrate to maximum dose of 1000 mg BID Tabs: 500 (orange) Pharmacokinetics: - metabolized by cyt P450 3A4 & to a lesser extent cyt P450 2D6 Monitor: ECG, baseline and follow-up Adverse effects: 1) increased QT interval 2) dizziness (6%), headache (6%), constipation (4%), nausea (4%) 3) others < 2% - palpitations, tinitus, vertigo, abdominal pain, xerostomia, vomiting, peripheral edema, dyspnea Drug interactions: 1) drugs that inhibit cyt P450 3A4 increase ranolazine levels (diltiazem, verapamil, HIV protease inhibitors, macrolides) 2) drugs that inhibit cyt P450 2D6 do not increase ranolazine levels significantly 3) ranolazine inhibits cyt P450 3A4 & cyt P450 2D6, thus may increase levels of drugs metabolized by these enzymes (simvastatin levels doubled) 4) ranolazine inhibits P-glycoprotein and may increase levels of drugs eliminated in part by P-glycoprotein (digoxin levels increased 1.5 fold) 5) avoid other drugs that prolong QT interval (amiodarone, erythromycin, quinidine, sotalol, etc) Mechanism of action: 1) inhibits late myocyte Na+ current 2) no significant effect on heart rate or blood pressure 3) facilitates myocardium functioning during ischemia a) reduces intracellular Na+ & Ca+2 during myocardial ischemia b) partially inhibits fatty acid oxidation, thus increases glucose oxidation c) may decrease myocardial oxygen demand 4) inhibits P-glycoprotein

General

metabolic agent (metabolic modifier)

References

  1. Prescriber's Letter 13(3): 2006 New Drug: Ranexa (ranolazine) Detail-Document#: 220302 (subscription needed) http://www.prescribersletter.com
  2. Morrow DA et al, Effects of ranolazine on recurrent cardiovascular events in patients with non ST_segment elevation acute coronary syndromes: The MERLIN-TIMI 36 randomized trial, JAMA 2007, 297:1775 PMID: 17456819
  3. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  4. Weisz G et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015 Oct 13; PMID: 26474810 - Alexander KP et al. Effects of ranolazine on angina and quality of life after percutaneous coronary intervention with incomplete revascularization: Results from the ranolazine for incomplete vessel revascularization (RIVER-PCI) trial. Circulation 2015 Nov 10; PMID: 26555329 - Head SJ, Kappetein AP. Coronary artery disease: A dam in the river for ranolazine. Lancet 2015 Oct 13; PMID: 26474812
  5. Guerra F, Romandini A, Barbarossa A et al Ranolazine for rhythm control in atrial fibrillation: A systematic review and meta-analysis. Int J Cardiol. 2017 Jan 15;227:284-291.Review. PMID: 27839812
  6. Trivedi C, Upadhyay A, Solanki K. Efficacy of ranolazine in preventing atrial fibrillation following cardiac surgery: Results from a meta-analysis. J Arrhythm. 2017 Jun;33(3):161-166. Review. PMID: 28607609 Free PMC Article
  7. Gong M, Zhang Z, Fragakis N, Korantzopoulos P et al Role of ranolazine in the prevention and treatment of atrial fibrillation: A meta-analysis of randomized clinical trials. Heart Rhythm. 2017 Jan;14(1):3-11. Epub 2016 Oct 13. PMID: 27746384