Indication

  • Ranexa is indicated for the treatment of chronic angina.
  • Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.
SEE LESS

In the Phase 3 CARISA trial

Ranexa®: Superior clinical effects in treating chronic angina

Ranexa 1000 mg BID,* when added to a beta-blocker or a calcium channel blocker, was superior to those treatments plus placebo at:

  • Increasing exercise duration
  • Increasing the time to onset of ischemia during exercise testing at peak plasma concentrations
  • Decreasing angina frequency
  • Decreasing nitroglycerin use
*Limit the dose of Ranexa to 500 mg BID when coadministered with diltiazem, verapamil, or other moderate CYP3A inhibitors.

Well-studied safety profile

The most common adverse reactions (> 4% and more common than with placebo) during treatment with Ranexa were dizziness, headache, constipation, and nausea.

See below for CARISA trial design and baseline characteristics.

CARISA TRIAL DESIGN1

  • CARISA (Combination Assessment of Ranolazine In Stable Angina) was a double-blind, randomized, placebo-controlled clinical trial of 823 patients with chronic angina who received Ranexa 750 mg BID (n = 272), Ranexa 1000 mg BID (n = 261), or placebo (n = 258) for 12 weeks (note: 750 mg is not an approved dose)
  • At the physician's discretion, patients received either atenolol 50 mg, amlodipine 5 mg, or diltiazem 180 mg once daily as required background antianginal therapy. Sublingual nitrates were used as needed
  • Primary endpoint was exercise duration at trough drug levels at 12 weeks (modified Bruce treadmill test). Secondary endpoints included exercise duration at peak drug levels, time to angina and 1-mm ST-segment depression at peak and trough levels (modified Bruce treadmill test) and weekly angina attacks and weekly nitroglycerin use as reported in patient diaries

CARISA BASELINE CHARACTERISTICS

  Ranexa CARISA baseline characteristics

Treatment comparison P values for continuous variables are from an analysis of variance with effects fitted for treatment and background therapy. Treatment comparison P values for categorical variables are based on a Cochran-Mantel-Haenszel test stratified by background therapy.
Without pathologic Q waves.

Note: 750 mg is not an approved dose.

Contraindications

  • Ranexa is contraindicated in patients:
    • Taking strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
    • Taking inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St John’s wort)
    • With liver cirrhosis

Important Safety Information

Contraindications

  • Ranexa is contraindicated in patients:
    • Taking strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
    • Taking inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St John’s wort)
    • With liver cirrhosis

Warnings and Precautions

  • Ranexa blocks lKr and prolongs the QTc interval in a dose-related manner.
  • Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, with other QT-prolonging drugs, with potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.
  • Acute renal failure has been observed in patients with severe renal impairment while on Ranexa. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment. Discontinue Ranexa if acute renal failure develops.

Adverse Reactions

  • The most common adverse reactions (> 4% and more common than with placebo) during treatment with Ranexa were dizziness, headache, constipation, and nausea.

Dosage and Administration

  • Begin treatment with 500 mg twice daily and increase to the maximum recommended dose of 1000 mg twice daily, based on clinical symptoms. Ranexa should be swallowed whole; do not crush, break or chew.
  • Limit the dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products). See Drug Interactions for additional dosing considerations.

Drug Interactions

  • Inducers and strong inhibitors of CYP3A: Do not use Ranexa (see Contraindications).
  • Moderate CYP3A inhibitors: Limit Ranexa to 500 mg twice daily (see Dosage and Administration).
  • P-gp inhibitors (e.g., cyclosporine): Ranexa exposure increased; titrate Ranexa based on clinical response.
  • CYP3A substrates: Limit simvastatin to 20 mg once daily when used with Ranexa. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with Ranexa.
  • Drugs transported by P-gp (e.g., digoxin) or metabolized by CYP2D6 (e.g., tricyclic antidepressants and antipsychotics): Doses of these drugs may need to be reduced.
  • Drugs transported by OCT2: Limit metformin to 1700 mg per day when used with Ranexa 1000 mg twice daily. Monitor blood glucose and risks associated with high metformin exposure.

Please see full Prescribing Information for Ranexa.

Reference:

  1. 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. JAMA. 2004;291(3):309-316.
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