Ranolazine 142387-99-3

Mechanism of action

Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia in rabbits. Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia in rats. The effects of ranolazine on the NaV 1. 7 and NaV 1. 8 sodium channels also make it potentially useful in the treatment of neuropathic pain. Ranolazine, a partial fatty acid oxidation inhibitor, shifts ATP production from fatty acid to more oxygen efficient carbohydrate oxidation. It was also discovered that inhibition of fatty acid oxidation (eg. with etomoxir or ranolazine) sensitizes human leukemia cells to apoptosis induction.

Indications for use

Ranolazine is indicated for the treatment of chronic angina. Ranolazine may be used in combination with beta-blockers, nitrates, calcium channel blockers, anti-platelet, therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. It has been shown to decrease angina episodes in individuals with coronary artery disease on maximal doses of amlodipine. In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine, or diltiazem. Unlike other antianginal medications such as nitrates and beta blockers, ranolazine does not significantly alter either the heart rate or blood pressure. For this reason, it is of particular use in individuals with angina that is nonresponsive to maximal tolerated doses of other anti-anginal medications. While it would seem from the mechanism of action that ranolazine may be of benefit in individuals with non-ST-elevation acute coronary syndromes and acute myocardial infarction (heart attack), the recently completed Merlin/TIMI-36 trial showed no benefit in this population.

Contraindications

Ranolazine is known to increase the QT interval on the electrocardiogram. While the mean increase in the corrected QT interval (QTc) is approximately 6 msec, about 5 percent of individuals may have QTc prolongations of 15 msec or longer. Extended QT intervals increase the risk of sudden cardiac death (SCD). The increase was 60% in adults, independently of other known risk factors, in an analysis of the Rotterdam Study. Because of this, caution should be used when ranolazine is used in combination with other medications that increase the QT interval. In addition, because the effect of ranolazine on the QT interval is increased in the setting of liver dysfunction, it is contraindicated in persons with mild to severe liver disease.

Drug interactions

While ranolazine is not significantly metabolized by cytochrome CYP2D6, it does inhibit this enzyme.

Digoxin

Simvastatin (Zocor)

Cyclosporine (Gengraf, Neoral, Restasis, Sandimmune)

various antidepressant medicines

Inhibitors of cytochrome CYP3A, including:

Diltiazem

Verapamil

Ketoconazole and other azole antifungals

Macrolide antibiotics

Ritonavir (Norvir)

Grapefruit products or grapefruit juice

QTc prolonging drugs, including:

Class Ia antiarrhythmic agents (eg, quinidine)

Class III antiarrhythmic agents (eg, dofetilide, sotalol)

Certain antipsychotics (eg, thioridazine, ziprasidone)

While caution should be used when administrating ranolazine in combination with any of the above medications, some combinations may be considered relatively safe. For instance, in the CARISA trial, ranolazine was used in individuals taking diltiazem without any adverse events attributable to the combination.

Trials

MERLIN TIMI 36 trial

This is the recent development in the field of ranolazine. This study was done in 6560 post ACS NSTEMI patients followed up for 1 year. Although ranolazine did not show significant benefit in study's primary endpoint of CV death, MI, or recurrent ischemia; it exhibited a potential benefit in arrhythmia. Among patients with ACS, ranolazine, an inhibitor of late INa, has anti-arrhythmic effects as assessed by Holter monitoring. In particular, patients treated with ranolazine had fewer episodes of VT > 8 beats, SVT, and ventricular pauses > 3 seconds. Ranolazine was associated with a 37% reduction in risk of VT lasting >= 8 beats. Reduction in VT >= 8 beats was significant and consistent in high - risk subgroups based on ejection fraction, corrected QT interval, TIMI risk score, history of heart failure, and the presence or absence of ischemia on ECG. Earlier there was a concern that ranolazine increases QT interval (approximately 2 to 6 ms) which has a theoretical risk of causing arrhythmia. Findings of MERLIN TIMI 36 should mitigate this concern. However, Studies specifically designed to evaluate the potential role of ranolazine as an anti-arrhythmic agent are warranted. Based on encouraging safety data shown in MERLIN TIMI 36 trial, CV therapeutics has applied to US FDA for first line angina indication. It has also applied to US FDA for 2 more indication such as HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits. Based on initial evaluation of data presented, US FDA has accepted the application and have set the action date as 27 July 2008.

Approval

Europe

On 24 April 2008 the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion,recommending to grant a marketing authorisation for the medicinal product Latixa, 375 mg, 500 mg and 750 mg prolonged-release tablets intended for treatment of patients with stable angina pectoris. The applicant for this medicinal product is CV Therapeutics Europe Limited. The approved indication is: “Latixa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists). ”

United States

U. S. Food and Drug Administration (FDA) has approved a new, first line indication for ranolazine for the treatment of chronic angina. The new labeling also provides information showing that ranolazine reduced arrhythmias including ventricular arrhythmias, new onset atrial fibrillation and a potentially dangerous slow heartbeat known as bradycardia in patients with coronary artery disease. In addition, the new labeling states that Ranexa reduces hemoglobin A1c (HbA1c) in patients with diabetes. According to the revised labeling, ranolazine is indicated for the treatment of chronic angina and may be used alone or in combination with traditional therapies for chronic angina, such as beta blockers, calcium channel blockers and nitrates, and common cardio-protective treatments for cardiovascular disease such as anti-platelet therapy, lipid-lowering therapy, ACE inhibitors and angiotensin receptor blockers. Ranolazine may now be used as part of a medical therapy regimen for chronic angina patients, regardless of whether or not they receive a stent or other medical intervention. Ranolazine does not reduce heart rate or blood pressure and, unlike long acting nitrates, ranolazine can be prescribed for patients taking oral erectile dysfunction treatments. These new labeling changes were supported by a supplemental new drug application submitted in September 2007 that included data from the 6,560 patient MERLIN-TIMI 36 trial, which showed no adverse trend in death or arrhythmia in a high risk acute coronary syndromes patient population. The revised labeling includes new language noting that there was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia and new atrial fibrillation) in patients treated with Ranexa versus placebo. This difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization or a reduction in arrhythmia symptoms. The revised labeling also includes new language noting that ranolazine produces small reductions in HbA1c. Though ranolazine should not be considered a treatment for diabetes, ranolazine may be a particularly useful medication for the reduction of chronic angina in this patient population, which is difficult to treat because some antianginal medications such as beta blockers increase HbA1c.