Ranolazine
CV Therapeutics
Anti-anginal agent approved for patients not responsive to other therapies
The anti-anginal and anti-ischemic properties of ranolazine are not dependent on reductions in heart rate or blood pressure.
Ranolazine was approved on January 27, 2006, for the treatment of chronic angina. Because ranolazine prolongs the QT interval,
it should be reserved for patients who have not achieved an adequate response with other anti-anginal drugs.
Efficacy. The efficacy of ranolazine in the treatment of angina was evaluated in patients with chronic angina who remained symptomatic
despite treatment with the maximum dose of an anti-anginal agent. In the ERICA (Efficacy of Ranolazine in Chronic Angina)
trial, 565 patients were randomized to receive an initial dose of ranolazine 500 mg bid or placebo for 1 week, followed by
6 weeks of treatment with ranolazine 1,000 mg bid or placebo in addition to concomitant treatment with amlodipine 10 mg qd.
The mean number of angina attacks per week was 3.3 in the ranolazine group compared with 4.3 in the placebo group (P=.028). Likewise, the mean number of nitroglycerin doses per week was 2.7 in the ranolazine group compared with 3.6 in the
placebo group (P=.014). In the CARISA (Combination Assessment of Ranolazine In Stable Angina) study, 823 chronic angina patients were randomized
to receive 12 weeks of treatment with twice-daily ranolazine 750 mg, 1,000 mg, or placebo while continuing daily doses of
atenolol 50 mg, amlodipine 5 mg, or diltiazem 180 mg. Statistically significant (P<.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each ranolazine dose versus
placebo, at both trough (12 h after dosing) and peak (4 h after dosing) plasma levels. For the treadmill test, the mean difference
from placebo in exercise duration at peak plasma levels was 34 seconds for the 750-mg ranolazine dose compared with 26 seconds
for the 1,000-mg dose (P≤.05). Likewise, the mean difference from placebo in time to angina at peak plasma concentration was 38 seconds for both doses
(P≤.005). The mean number of angina attacks per week in this study was 2.5 and 2.1 for the 750- and 1,000-mg ranolazine groups,
respectively, compared with 3.3 for placebo (P=.006 and <.001, respectively). The mean number of nitroglycerin doses per week was 2.1 and 1.8 for the 750- and 1,000-mg
ranolazine groups, respectively, compared with 3.1 for placebo (P=.016 and <.001, respectively).
Safety. Ranolazine has been shown to prolong the QTc interval in a dose-related manner. While the clinical significance of the QTc
prolongation in the case of ranolazine is unknown, other drugs with this potential have been associated with torsades de pointes-type
arrhythmias and sudden death. Ranolazine is contraindicated in patients with existing QT prolongation, patients who are taking
QT-prolonging drugs, and patients who are taking potent or moderately potent CYP3A4 inhibitors. Ranolazine is also contraindicated
in patients with mild, moderate, or severe hepatic impairment. Ranolazine increases blood pressure by about 15 mmHg in patients
with severe renal impairment. Blood pressure monitoring should be conducted after initiation of ranolazine therapy in these
patients. Ranolazine may cause dizziness or lightheadedness, and patients should know how they react to the drug before they
operated an automobile or machinery or engage in activities that require mental alertness or coordination. Grapefruit juice
or grapefruit products should be avoided by patients taking ranolazine. The most frequently reported adverse events associated
with ranolazine include dizziness, headache, constipation, and nausea. Dosing. Ranolazine should be initiated at 500 mg bid and increased to 1,000 mg bid as needed, based on clinical symptoms. The maximum
recommended daily dose of ranolazine is 1,000 mg bid. Baseline and follow-up ECGs should be obtained to evaluate effects on
the QT interval. The concomitant administration of ranolazine and other commonly administered cardiovascular medications (amlodipine,
beta blockers, nitrates, antihypertensive agents) is well tolerated. Ranolazine may be taken with or without meals.
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