Ranolazine

427.54

427.54

1308068-626-2

759100

DTXSID3045196

White to off-white solid

C01EB18|C - Cardiovascular system

2933990090

74.3

2.7

Solid

1.2±0.1 g/cm3

119-1200C

624.1°C at 760 mmHg

331.2±31.5 °C

1.586

H2O: Very slightly soluble

-20°C Freezer

4.56X10-16 mm Hg at 25 deg C (est)

2.2None

Henry's Law constant = 3.56X10-22 atm-cu m/mol at 25 °C (est)

2.2

205.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

MW: 500.46 White to crystalline powder from methanol/ether; mp 164-166 °C. Readily soluble in water. /Dihydrochloride/|Hydroxyl radical reaction rate constant = 2.47X10-10 cu cm/molec-sec at 25 °C (est)

UN 2811 6.1 / PGIII

P201, P202, P260, P261, P264, P270, P271, P280, P281, P301+P310, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P309+P311, P312, P314, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ranolazine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H301 (27.27%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 12 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The reported LD50 of oral ranolazine in the rat is 980 mg/kg.[MSDS] High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation.

In large preregistration clinical trials, ranolazine was not associated with serum aminotransferase and alkaline phosphatase elevations during treatment and no instances of symptomatic acute liver injury were reported. Since its approval and more wide spread use, ranolazine has been linked to a single instance of mildly symptomatic, rapidly reversible, anicteric liver injury (Case 1). Immunoallergic and autoimmune features were not present. Recovery was rapid once ranolazine was discontinued.

Do not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of ranolazine 3.2-fold|Ranolazine is a substrate and an inhibitor of the p-glycoprotein transport system; potential pharmacokinetic interactions with p-glycoprotein inhibitors (increased absorption of ranolazine). When ranolazine is co-administered with other substrates, dosage of such drugs may have to be reduced.|Potential pharmacodynamic interaction (possible additive effects on QT interval). Ranolazine should be avoided in patients receiving drugs that are known to prolong the QT interval (eg, class Ia (eg, quinidine) or III (eg, dofetilide, sotalol) antiarrhythmic agents, antipsychotic agents (eg, thioridazine, ziprasidone)).|Potential pharmacokinetic interaction (increased plasma ranolazine concentrations). Ranolazine should not be used with ketoconazole (a potent CYP3A inhibitor) or itraconazole.|For more Interactions (Complete) data for Ranolazine (17 total), please visit the HSDB record page.

In patients with varying degrees of renal impairment, ranolazine plasma levels increased up to 50%. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.|Ranolazine is contraindicated in patients with clinically significant hepatic impairment. Plasma concentrations of ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment.|Of the chronic angina patients treated with ranolazine in controlled studies, 496 (48%) were >/= 65 years of age, and 114 (11%) were >/= 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients >/= 65 years compared to younger patients, but patients >/= 75 years of age on ranolazine, compared to placebo, had a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy.|Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranexa had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of Ranexa is required in patients with heart failure.

Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for alpha-1 acid glycoprotein.

Ranolazine is indicated for the treatment of chronic angina. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors. Ranolazine has also been used off-label for the treatment of certain arrhythmias, including ventricular tachycardia, however, this use is not strongly supported by scientific evidence. Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control, which are not yet approved indications.|FDA Label|Ranexa 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 anti-anginal therapies (such as beta-blockers and / or calcium antagonists).|Treatment of supraventricular arrhythmias

Ranolazine is a unique, orally available antiangina agent. Chronic ranolazine therapy has not been associated with serum enzyme elevations, but has been linked to rare cases of mild, clinically apparent liver injury.

Antiangina Agents

Enzyme Inhibitors; Angina Pectoris/drug therapy|Ranolazine is indicated for the treatment of chronic angina. Ranolazine may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. /Included in US product label/

Ranolazine is contraindicated in patients: taking strong inhibitors of CYP3A; taking inducers of CYP3A; with clinically significant hepatic impairment.|Ranolazine has been shown to prolong the QT interval corrected for rate (QTc) in a dose-related manner. Although the clinical importance of QTc interval prolongation associated with ranolazine is not known, other drugs with this potential have been associated with torsades de pointes-type arrhythmias and sudden death. The mean effect on QTc interval with repeated dosing of ranolazine 1 g twice daily, at time of maximum plasma concentration (Tmax), is about 6 msec; however, in 5% of the population the prolongation of QTc interval is 15 msec. Age, weight, gender, race, heart rate, NYHA class I to IV CHF, and diabetes have no substantial effect on the relationship between ranolazine plasma concentrations and increases in QTc interval. The relationship between ranolazine concentrations and QTc remains linear over a concentration range up to fourfold greater than the concentrations produced by a ranolazine dosage of 1 g twice daily, and is not affected by changes in heart rate. The manufacturer states that ranolazine dosages exceeding 1 g twice daily should not be used.|The effects of ranolazine in patients with preexisting QT interval prolongation or receiving concomitant therapy with drugs that are known to prolong the QT interval have not been established. Because of possible additive effects on the QT interval, the manufacturer states that use of ranolazine should be avoided in patients with known QT interval prolongation (including congenital long QT syndrome and uncorrected hypokalemia), known history of ventricular tachycardia, and in patients receiving drugs that prolong the QTc interval (eg, class Ia (eg, quinidine) or III (eg, dofetilide, sotalol) antiarrhythmic agents, antipsychotic agents eg, thioridazine, ziprasidone).|Because the QTc-prolonging effect is increased approximately threefold in patients with hepatic dysfunction, ranolazine is contraindicated in patients with mild, moderate, or severe hepatic impairment.|For more Drug Warnings (Complete) data for Ranolazine (16 total), please visit the HSDB record page.

Tolerance to Ranolazine did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of Ranolazine.

Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise.

Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume. (See all compounds classified as Cardiovascular Agents.)|A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity. (See all compounds classified as Sodium Channel Blockers.)

The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%.|From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as unchanged drug.|The mean apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L.|The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%.|Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. ... Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-t increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.|After oral administration of ranolazine, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of (14)C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from ranolazine tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.|Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, ranolazine may be taken without regard to meals. Over the concentration range of 0.25 to 10 ug/mL, ranolazine is approximately 62% bound to human plasma proteins.|It is not known whether ranolazine is distributed into milk.|For more Absorption, Distribution and Excretion (Complete) data for Ranolazine (7 total), please visit the HSDB record page.

Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine. Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated.|Ranolazine is extensively metabolized in the intestine and liver by the cytochrome P-450 (CYP) isoenzyme system, mainly by CYP3A and, to a lesser extent, CYP2D6. In vitro studies indicate that ranolazine also is a p-glycoprotein substrate. At least 4 metabolites of ranolazine have been identified. The pharmacologic activity of these metabolites has not been fully established.|Ranolazine is metabolized rapidly and extensively in the liver and intestine ... The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine...

The apparent terminal half-life of ranolazine is 7 hours.|... Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). ...|... The four most abundant metabolites in plasma ... display apparent half-lives ranging from 6 to 22 hours.

Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others. The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed. Ranolazine inhibits sodium and potassium ion channel currents. It has been shown to exert weak activity on L-type calcium channels making it a weak direct vasodilator and exerts minimal direct effects on atrioventricular nodal conduction. Some additional mechanisms have been elucidated. Ranolazine exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation.|Ranolazine, a piperazine derivative, is an antianginal agent. Although the exact mechanism of antianginal activity of ranolazine has not been fully elucidated, results of early studies suggested that ranolazine shifted adenosine triphosphate (ATP) production away from fatty acid oxidation (ie, partial inhibition of fatty acid oxidation) in favor of more oxygen-efficient glucose oxidation, especially when free fatty acid concentrations were elevated (eg, during ischemia), leading to reduced oxygen demand and symptoms of ischemia without affecting cardiac work. However, these pharmacologic effects generally were observed at concentrations exceeding therapeutic plasma concentrations in clinical studies.|Recent data suggest that ranolazine may exert its antianginal and anti-ischemic effects through concentration-, voltage-, and frequency-dependent inhibition of the late (ie, sustained, persistent) sodium current and other cardiac ion channels and transporters. The late sodium current is created by inactivation of the sodium channel protein. However, angina (ie, ischemia, hypoxia) impairs sodium channel inactivation and increases the amount of sodium in cardiac cells, which facilitates calcium overload via the sodium-calcium exchange pump. Increased intracellular calcium may result in myocyte hyperexcitability and electrical instability, impaired diastolic relaxation, reduced coronary artery perfusion, impaired myocardial oxygen supply, increased oxygen demand, and ventricular dysfunction. Thus, ranolazine may decrease the magnitude of the late sodium current resulting in a net reduction in intracellular sodium concentrations, reversal of calcium overload, restoration of ventricular pump function, and prevention of ischemia-induced arrhythmias. Unlike other antianginal agents, the antianginal effects of ranolazine are not dependent upon reductions in heart rate or blood pressure.|The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.|/The authors/ investigated changes in Na(+) currents (I(Na)) in permanent (or chronic) atrial fibrillation (AF) and the effects of I(Na) inhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium. Electrical remodeling during AF is typically associated with alterations in Ca(2+) and K(+) currents. It remains unclear whether I(Na) is also altered. Right atrial appendages from patients with AF (n = 23) and in sinus rhythm (SR) (n = 79) were studied. Patch-clamp experiments in isolated atrial myocytes showed significantly reduced peak I(Na) density ( approximately 16%) in AF compared with SR, which was accompanied by a 26% lower expression of Nav1.5 (p < 0.05). In contrast, late I(Na) was significantly increased in myocytes from AF atria by approximately 26%. Ran (10 mumol/L) decreased late I(Na) by approximately 60% (p < 0.05) in myocytes from patients with AF but only by approximately 18% (p < 0.05) in myocytes from SR atria. Proarrhythmic activity was elicited in atrial trabeculae exposed to high [Ca(2+)](o) or isoprenaline, which was significantly reversed by Ran (by 83% and 100%, respectively). Increasing pacing rates from 0.5 to 3.0 Hz led to an increase in diastolic tension that could be significantly decreased by Ran in atria from SR and AF patients. Na(+) channels may contribute to arrhythmias and contractile remodeling in AF. Inhibition of I(Na) with Ran had antiarrhythmic effects and improved diastolic function.|For more Mechanism of Action (Complete) data for Ranolazine (11 total), please visit the HSDB record page.

In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope.|/CASE REPORTS/ A 77-year-old white man with chronic renal insufficiency was evaluated for moderate dyspnea on exertion (DOE). Cardiac and pulmonary workup revealed nonobstructive coronary artery disease and mild obstructive lung disease. The patient had been taking ranolazine 500 mg daily for possible angina for the past 2 months. Given the temporal association of his symptoms with drug initiation, ranolazine was discontinued during the hospitalization. One month after discontinuing ranolazine, the patient's DOE had completely resolved; the only intervention had been discontinuation of ranolazine. The patient's Naranjo algorithm score was 3, indicating a possible adverse drug reaction. ... Ranolazine may be associated with DOE in this elderly man.|/OTHER TOXICITY INFORMATION/ Ranolazine was shown to improve exercise parameters in patients with chronic angina. It works by switching myocardial energy metabolism from fatty acids to glucose, thus increasing the efficiency of ATP production under hypoxic conditions. Tumors are hypoxic and may also respond to ranolazine. ... These findings have implications for the use of ranolazine in patients with a history of malignant neoplasms or adenomatous polyps.

43285, RS

Oral: tablets, extended-release, film-coated: 500 mg, Ranexa (CV Therapeutics).

Human drugs -> Ranexa (previously Latixa) -> EMA Drug Category|Cardiac therapy -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients