Ranolazine
Encyclopedia
Ranolazine, sold under the trade name
Ranexa by Gilead Sciences
(who acquired the developer, CV Therapeutics in 2009), is an antianginal
medication. In India it is sold under the name "Ranozex". On January 31, 2006, ranolazine was approved for use in the United States
by the FDA
for the treatment of chronic angina pectoris.
.
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.
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 blocker
s, 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.
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.
system.
, it does inhibit this enzyme. Because of this, the doses of medications metabolized by cytochrome CYP2D6 may need to be reduced to prevent toxicity.
Drugs that may interact with ranolazine include:
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.
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.
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.
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
Ranexa by Gilead Sciences
Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics. For many years since the company was founded, the company concentrated primarily on antiviral drugs to treat patients infected with HIV, hepatitis B or influenza. In 2006, Gilead acquired two...
(who acquired the developer, CV Therapeutics in 2009), is an antianginal
Antianginal
An antianginal is any drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.-Nitrates:Nitrates cause vasodilation of the venous capacitance vessels by stimulating the endothelium-derived relaxing factor...
medication. In India it is sold under the name "Ranozex". On January 31, 2006, ranolazine was approved for use in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for the treatment of chronic angina pectoris.
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 painNeuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
.
Ranolazine, a partial fatty acid oxidation inhibitor, shifts ATP production from fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
to more oxygen efficient carbohydrate oxidation.
It was also discovered that inhibition of fatty acid oxidation (eg. with etomoxir or ranolazine) sensitizes human leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
cells to apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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
Amlodipine
Amlodipine is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina...
. In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine
Amlodipine
Amlodipine is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina...
, or diltiazem
Diltiazem
Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
.
Unlike other antianginal medications such as nitrates and beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
s, 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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(heart attack), the recently completed Merlin/TIMI-36 trial showed no benefit in this population.
Contraindications
Ranolazine is known to increase the QT intervalQT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
on the electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
. While the mean
Mean
In statistics, mean has two related meanings:* the arithmetic mean .* the expected value of a random variable, which is also called the population mean....
increase in the corrected QT interval (QTc) is approximately 6 msec
Millisecond
A millisecond is a thousandth of a second.10 milliseconds are called a centisecond....
, about 5 percent of individuals may have QTc prolongations of 15 msec or longer.
Extended QT intervals increase the risk of sudden cardiac death
Sudden Cardiac Death
Sudden cardiac death is natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms. Other forms of sudden death may be noncardiac in origin...
(SCD). The increase was 60% in adults, independently of other known risk factors, in an analysis of the Rotterdam Study
Rotterdam Study
The Rotterdam Study is a prospective, population-based cohort study. The aim of the Rotterdam Study is to investigate factors that determine the occurrence of cardiovascular, neurological, ophthalmological, endocrinological, and psychiatric diseases in elderly people.The study was established in...
.
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.
Metabolism
Ranolazine is metabolized in the liver, particularly by one of the cytochrome CYP3A enzymes, a member of the cytochrome P450Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
system.
Drug interactions
While ranolazine is not significantly metabolized by cytochrome CYP2D6CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
, it does inhibit this enzyme. Because of this, the doses of medications metabolized by cytochrome CYP2D6 may need to be reduced to prevent toxicity.
Drugs that may interact with ranolazine include:
- DigoxinDigoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
- SimvastatinSimvastatinSimvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
(Zocor) - Cyclosporine (Gengraf, Neoral, Restasis, Sandimmune)
- various antidepressant medicines
- Inhibitors of cytochrome CYP3A, including:
- DiltiazemDiltiazemDiltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
- VerapamilVerapamilVerapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
- KetoconazoleKetoconazoleKetoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
and other azole antifungals - Macrolide antibioticsMacrolideThe macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
- RitonavirRitonavirRitonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
(Norvir) - Grapefruit products or grapefruit juiceGrapefruit juiceGrapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
- Diltiazem
- QTc prolonging drugs, including:
- Class Ia antiarrhythmic agentAntiarrhythmic agentAntiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
s (eg, quinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
) - Class III antiarrhythmic agents (eg, dofetilideDofetilideDofetilide is a class III antiarrhythmic agent.It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide....
, sotalolSotalolSotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels...
) - Certain antipsychotics (eg, thioridazineThioridazineThioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
, ziprasidoneZiprasidoneZiprasidone was the fifth atypical antipsychotic to gain FDA approval . In the United States, Ziprasidone is Food and Drug Administration approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients...
)
- Class Ia antiarrhythmic agent
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.
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.
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.