Ranexa (ranolazine) is an orally-available, extended release anti-ischemic/anti-anginal drug, designed to act without reducing heart rate or blood pressure.

Ranexa is specifically indicated for the treatment of chronic angina in patients who have failed to respond to prior angina therapy. It is contraindicated in patients with pre-existing QT interval prolongation (see Side Effects section, below).

Ranexa is supplied as a film-coated extended release tablet. Recommended initial dosing is 500 mg twice daily; this may be escalated to a maximum dose of 1000 mg twice daily, based on disease response.

FDA Approval
Approval of Ranexa was based on a pair of clinical trials, dubbed ERICA (Efficacy of Ranolazine In Chronic Angina) and CARISA (Combination Assessment of Ranolazine In Stable Angina).

ERICA Study
In this placebo controlled study, 565 patients were randomized to receive a 1 week loading regimen of 500 mg Ranexa or placebo twice daily, followed by a 6 week regimen of 1000 mg Ranexa or placebo twice daily, in combination with 10 mg amlodipine once daily. Trial data showed that Ranexa significantly decreased frequency of angina attacks (mean 3.3 attacks per week, vs. 4.3 for placebo; p=0.028) and need for intervention treatment with nitroglycerin (mean 2.7 doses per week, vs. 3.6 for placebo; p=0.014). The drug was seen to have higher efficacy in male patients.

CARISA Study
This placebo controlled study enrolled 823 patients, who received one of two twice daily doses of Ranexa (750 mg or 1000 mg) or placebo, in combination with continued background therapy (50 mg atenolol, 5 mg amlodipine, or 180 mg diltiazem CD). Trial data yielded a significant increase in modified Bruce treadmill exercise tolerance (p<0.05) and time to angina onset (p<0.05) at both peak (4 hours post dose) and trough (12 hours post dose) drug plasma concentrations. Both doses significantly reduced angina frequency (750 mg: 2.5 attacks/week; 1000 mg: 2.1 attacks/week; vs. 3.3 attacks/week for placebo; p=0.006 and p<0.001, respectively) and nitroglycerin intervention (750 mg: 2.1 doses/week; 1000 mg: 1.8 doses/week; vs. 3.1 doses/week for placebo; p=0.016 and p<0.001). There was no significant difference in efficacy between the two doses of Ranexa.

Ongoing Study Commitments

• The impact of renal impairment on exposure to ranolazine should be better defined. One way of achieving this would be to re-do the population pharmacokinetics of ranolazine using the entire database available including patients with renal impairment. The report of the re-analysis should be submitted to the Agency by July 27, 2006.
  Protocol Submission: Not Applicable
  Study Start: Not Applicable
  Final Report Submission: by 07/06
• Alternatively, a new pharmacokinetic study should be performed in patients with different degrees of renal impairment. The report of this study should be submitted to the Agency by January 2008.
  Protocol Submission: Not Applicable
  Study Start: Not Applicable
  Final Report Submission: by 01/08

Adverse events associated with the use of Ranexa may include, but are not limited to, the following:

• Constipation
• Dizziness
• Nausea
• Headache
• Palpitations
• Tinnitus
• Abdomnial Pain
• Peripheral Edema
• Dyspnea

In addition, Ranexa was shown to dose-dependently prolong cardiac QTc interval; this prolongation was independent of age, weight, gender, race, heart rate, CHF NYHA Class I to IV, and diabetic status. Other drugs associated with significant QTc prolongation have been associated with torsades de pointes-type arrhythmias and sudden death. Further, the drug's QTc-prolonging effects are increased in patients with hepatic dysfunction, and in patients on medication which inhibits the metabolic enzyme CYP3A. Ranolazine is contra-indicated for subjects with existing QTc prolongations, in patients with all-grade liver disease and in patients on drugs which inhibit CYP3A (including azole antibiotics, macrolide antibiotics, HIV protease inhibitor, and others). Subjects are advised to monitor symptoms of QTc prolongation closely, in collaboration with their physicians.

Ranexa's mechanism of action has not been fully characterized. The drug has been shown to exert its anti-anginal and anti-ischemic effects without reducing heart rate or blood pressue. The drug does not increase the rate-pressure product at maximal exercise levels. It is suspected that the drug exerts some of its effects by eliciting changes in cardiac metabolism.

Timmis AD, Chaitman BR, Crager M Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. European Heart Journal 2006 Jan;27(1):42-8. Epub 2005 Sep 21

Abdallah H, Jerling M Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets. Journal of Clinical Pharmacology 2005 Jul;45(7):802-9

Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. Journal of Clinical Pharmacology 2005 Apr;45(4):422-33

Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Cordeiro JM, Thomas G Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 2004 Aug 24;110(8):904-10. Epub 2004 Aug 9

Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson JJ, Hebert DA, Wolff AA; MARISA Investigators Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. Journal of the American College of Cardiology 2004 Apr 21;43(8):1375-82

For additional information regarding Ranexa or Chronic Angina, please visit the Ranexa web page.