Pharmacology Update

Ranolazine Extended-Release Tablets (RanexaTM)

By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.

The FDA has approved a new drug with a unique mechanism of action for the treatment of chronic angina. Ranolazine reduces the frequency of chest pains by reducing the demand for oxygen but does not have significant effect on heart rate or blood pressure. Ranolazine is marketed by CV Therapeutics Inc., as RanexaTM.

Indications

Ranolazine is indicated for the treatment of chronic angina in patients who have not achieved adequate response with standard antianginal agents. It should be used in combination with amlodipine, beta-blockers, or nitrates.1

Dosage

The recommended initial dose is 500 mg twice daily. It may be increased to 1000 mg twice daily based on clinical need. It may be taken without regard to meals and should be swallowed whole (ie, not chewed, crushed, or broken).1

Ranolazine is supplied as 500 mg extended-release tablets.

Potential Advantages

Ranolazine is the first antianginal drug with minimal hemodynamic effects. The addition of ranolazine to patients with symptomatic severe chronic angina on standard doses of atenolol, amlodipine, or diltiazem provided additional antianginal relief.1,2

Potential Disadvantages

Ranolazine is less active in women than men.1 It produces a dose and plasma concentration-related increase in the QTc interval and reduction in T wave amplitude. The effect is greater in patients with hepatic dysfunction. Most frequent adverse events are dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Syncope has been reported in 0.7% of patients on the 2000 mg/day dose. In clinical studies, about 6% of patients discontinued treatment due to an adverse event compared to 3% treated with placebo. Potential inhibitors of CYP3A (eg, protease inhibitors, macrolide antibiotics, diltiazem, verapamil) should not be coadministered with ranolazine. Ranolazine and its metabolite are inhibitors of CYP3A and CYP2D6. Dosage adjustments may be needed in drugs metabolized by these isoenzymes. Ranolazine is also an inhibitor of P-gp and dose adjustments may be required with P-gp substrates (eg, digoxin). Concomitant use of agents that prolong QT interval is contraindicated. The absorption of ranolazine is highly variable due to extensive gut and liver metabolism.1

Comments

Ranolazine differs from currently available anti-angina agents. Its mechanism of action is believed to be partial inhibition of fatty acid oxidase resulting in facilitated carbohydrate oxidation. Since carbohydrate metabolism results in less oxygen requirement per ATP production the demand for oxygen is reduced.3 Ranolazine does not have a significant effect on heart rate or blood pressure although blood pressure reduction has been reported in patients with severe renal dysfunction.1 The approval of ranolazine was based on 2 clinical trials, ERICA (Efficacy of Ranolazine In Stable Angina) (n = 565) and CARISA (Combination Assessment of Ranolazine In Stable Angina) (n = 823). In both placebo-controlled studies ranolazine was added to patients on standard anti-angina medication, amlodipine in ERICA and atenolol, amlodipine, or diltiazem in CARISA. In ERICA, ranolazine (1000 mg twice daily) reduced the frequency of angina attacks (mean of 1/week) and nitroglycerine use (mean of 0.9 doses/week) compared to placebo at 6 weeks. In CARISA, similar reduction was seen (0.8 attacks per week for 750 mg twice daily and 1.2 for 1000 mg twice daily; 1 dose of nitroglycerine and 1.3 respectively).1,2 In CARISA, ranolazine was also shown to increase time to angina, time to 1 mm ST depression, and exercise duration both at peak and trough drug levels. The time-to-event difference from placebo ranged from 20-30 seconds at trough and 26-41 seconds at peak levels. Ranolazine has also been reported to be effective as monotherapy although this is not an approved indication.4 Ranolazine can increase QT interval but is otherwise well tolerated. No incidence of torsades de pointes was reported in CARISA. Ranolazine appears to be about ¼ as effective in women compared to men.1 The wholesale cost for ranolazine ranges from $5.50 to $11.00 per day.

Clinical Implications

It is estimated that 6.8 million Americans are annually diagnosed with angina.5 Many patients may continue to have symptoms after revascularization with PCI or CABG.6,7 Ranolazine is the first new antianginal agent to be approved in over a decade and its non-hemodynamic profile differs from current agents. It is indicated for use as add-on to standard therapy. The role may best suited for male patients with lower blood pressure or heart rates.

References

1. Ranexa Product Information. CV Therapeutics, Inc. January 2006.

2. Chaitman BR, et al. JAMA. 2004;291:309-316.

3. Wolff AA, et al. Heart Fail Rev. 2002;7:187-203.

4. Chaitman BR, et al. J Am Coll Cardiol. 2004;43:1375-1382.

5. http://www.fda.gov/bbs/topics/news/2006/NEW01306.html

6. Berger P. JAMA. 2004;291:365-366.

7. Holubkov R, et al. Am Heart J. 2002;144:826-833.