brand ranexa er 500 mg tablet

Uses

Angina

Ranolazine is used in the management of chronic stable angina pectoris. Ranolazine may be used in combination with β-adrenergic blocking agents, calcium-channel blocking agents, nitrates, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blocking agents, antiplatelet therapy, and lipid-lowering therapy. The effect of ranolazine on exercise tolerance or the frequency of anginal attacks appears to be smaller in women than in men.

The current indication for ranolazine is based principally on the results of 2 randomized, double-blind, placebo-controlled trials in patients with chronic stable angina pectoris who remained symptomatic despite treatment with another antianginal agent. In the Efficacy of Ranolazine in Chronic Angina (ERICA) trial, patients who remained symptomatic despite treatment with the maximum recommended adult dosage of amlodipine were randomized to receive ranolazine (500 mg twice daily for 1 week, followed by 1 g twice daily for 6 weeks) or placebo, in combination with amlodipine 10 mg daily and sublingual nitrates as needed; 45% of patients also received long-acting nitrates. During the 6-week comparison period (i.e., following titration to ranolazine 1 g twice daily), the mean frequencies of anginal attacks (3.3 versus 4.3 attacks per week) and of nitroglycerin use (2.7 versus 3.6 doses per week) were lower in patients receiving ranolazine than in those receiving placebo. The magnitude of the treatment effect was smaller in women than in men.

In the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, patients with chronic stable angina pectoris and coronary artery disease who were symptomatic despite treatment with atenolol, amlodipine, or diltiazem were randomized to receive ranolazine 750 mg or 1 g twice daily or placebo for 12 weeks, in combination with atenolol 50 mg, amlodipine 5 mg, or extended-release diltiazem hydrochloride 180 mg daily and with sublingual nitrates as needed. (The manufacturer states that ranolazine should not be administered concomitantly with diltiazem.) Exercise duration, as measured by exercise treadmill testing, was increased in patients receiving ranolazine compared with those receiving placebo, and the increase was associated with minimal changes in blood pressure and heart rate. At the time of trough plasma ranolazine concentrations (i.e., 12 hours after dosing), treadmill exercise time for patients receiving ranolazine exceeded that for patients receiving placebo by an average of 24 seconds. The effects on exercise duration of the 2 ranolazine dosages (750 mg or 1 g twice daily) were similar. Improvements in exercise tolerance were smaller in women than in men.

In clinical trials, rebound increases in angina, as measured by exercise duration, were not reported following abrupt discontinuance of ranolazine.

In the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial, patients presenting within 48 hours of ischemic symptoms were randomized to receive either ranolazine (initiated IV and followed by oral ranolazine extended-release 1000-mg tablets twice daily) or matching placebo for a median of 348 days in addition to standard treatment. Addition of ranolazine to standard treatment for acute coronary syndromes has not been shown to reduce major cardiovascular events However, the cumulative incidence of recurrent ischemia was significantly lower in patients allocated to ranolazine compared with those allocated to placebo. No difference between the two groups in the occurrence of cardiovascular death, myocardial infarction, or severe recurrent ischemia was observed. Findings of this study together with observed favorable overall profile of safety, provided additional evidence to guide the use of ranolazine as antianginal therapy in patients with chronic angina.

Dosage and Administration

Administration

Ranolazine is administered orally without regard to meals. Ranolazine tablets should be swallowed whole and not broken, chewed, or crushed. If a dose of ranolazine is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.

Dosage

The recommended initial adult dosage of ranolazine for adjunctive therapy in the management of chronic stable angina pectoris is 500 mg twice daily; dosage may be increased based on clinical response up to the maximum recommended dosage of 1 g twice daily. Dosages exceeding 1 g twice daily are poorly tolerated and should not be used.

Ranolazine is contraindicated in patients receiving inducers or strong inhibitors of cytochrome P-450 isoenzyme 3A (CYP3A). Ranolazine dosage should not exceed 500 mg twice daily in patients receiving moderate CYP3A inhibitors.(See Drug Interactions.)

Special Populations

Ranolazine is contraindicated in patients with hepatic cirrhosis.(See Cautions: Contraindications.)

The manufacturer makes no specific dosage recommendations for patients with renal impairment. Presence of renal impairment should be considered when selecting an appropriate ranolazine dosage. Blood pressure increases of up to 15 mm Hg have occurred in patients with severe renal impairment receiving ranolazine 500 mg twice daily; blood pressure should be monitored periodically after initiation of ranolazine in patients with severe renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer states that dosage adjustment of ranolazine is not required in patients with New York Heart Association (NYHA) class I to IV congestive heart failure (CHF).

The manufacturer states that dosage adjustment of ranolazine is not required in patients with diabetes mellitus.

Cautions

Contraindications

Hepatic cirrhosis.

Concomitant use with inducers or potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A.(See Drug Interactions.)

Known hypersensitivity to ranolazine or any ingredient in the formulation.

Warnings/Precautions

Prolongation of QT Interval

Ranolazine has been shown to prolong the QT interval corrected for rate (QT_c) in a dose-related manner. Although the clinical importance of QT_c 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. Increased risk of proarrhythmia or sudden death has not been observed in clinical experience with ranolazine in patients with acute coronary syndromes. However, experience is limited with high ranolazine dosages (greater than 1 g twice daily) or exposure, use with other QT_c interval-prolonging drugs or potassium channel variants resulting in a long QT_c interval, or in patients with a family history of long QT_c syndrome or with known acquired or congenital QT_c interval prolongation. The mean effect on QT_c interval with repeated dosing of ranolazine 1 g twice daily, at time of maximum plasma concentration (T_max), is about 6 msec; however, in 5% of the population the prolongation of QT_c interval is at least 15 msec. Age, weight, gender, race, heart rate, NYHA class I to IV heart failure, diabetes, and renal impairment have no substantial effect on the relationship between plasma ranolazine concentrations and increases in QT_c interval. The relationship between ranolazine concentrations and QT_c remains linear over a concentration range up to concentrations several times higher than those 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.

No proarrhythmic effects were observed in 7-day Holter monitor recordings in patients with acute coronary syndrome receiving ranolazine. Patients receiving ranolazine had a lower incidence of arrhythmias (ventricular tachycardia lasting 8 or more beats, bradycardia, supraventricular tachycardia, new atrial fibrillation) compared with patients receiving placebo; however, no reduction in mortality, hospitalization secondary to arrhythmia, or arrhythmia symptoms was observed.

Ranolazine is metabolized principally by the cytochrome P-450 (CYP) isoenzyme 3A; thus, use of ranolazine with potent inhibitors of CYP3A should be avoided because concomitant administration may increase plasma ranolazine concentrations and QT_c interval prolongation. Ranolazine dosage should not exceed 500 mg twice daily in patients receiving moderately potent CYP3A inhibitors.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Because the QT_c-prolonging effect is increased approximately threefold in patients with hepatic dysfunction, ranolazine is contraindicated in patients with hepatic cirrhosis.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Specific Populations

Pregnancy

Category C.

Lactation

It is not known whether ranolazine is distributed into milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions to ranolazine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.

Geriatric Use

A substantial number of patients studied in controlled clinical trials of ranolazine for management of chronic angina were geriatric (i.e., 48% were 65 years of age or older and 11% were 75 years of age or older). No overall differences in efficacy were observed between older and younger patients. In addition, no differences in safety were reported between patients 65 years of age or older and younger patients. However, in patients 75 years of age or older, higher and greater severity of adverse effects and drug discontinuance associated with ranolazine (compared with placebo) was observed. In general, dosage of ranolazine should be selected cautiously in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Hepatic Impairment

In patients with cirrhosis and mild or moderate (Child-Pugh class A or B, respectively) hepatic impairment receiving ranolazine, plasma ranolazine concentrations were 30 or 80% higher, respectively, than in healthy individuals. These patients, had greater increases in QT_c interval than healthy individuals having the same plasma concentrations of the drug.(See Prolongation of QT Interval under Warnings/Precautions: Warnings, in Cautions.)

Renal Impairment

In a study in patients with mild, moderate, or severe renal impairment, plasma ranolazine concentrations increased by 40-50%; the increase in ranolazine exposure appeared similar in patients with renal failure independent of the degree of impairment. Blood pressure increases of up to 15 mm Hg have occurred in patients with severe renal impairment receiving ranolazine 500 mg twice daily; blood pressure should be monitored periodically after initiation of ranolazine in patients with severe renal impairment. Safety and efficacy of ranolazine in patients undergoing dialysis have not been established.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in 4% or more of patients receiving ranolazine and more frequently than placebo include constipation, dizziness, nausea, and headache.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Ranolazine is metabolized by the cytochrome P-450 (CYP) isoenzyme system, mainly by CYP3A and, to a lesser extent, CYP2D6. Ranolazine is a weak inhibitor of CYP isoenzyme 3A and a moderate inhibitor of CYP isoenzyme 2D6. Pharmacokinetic interactions are likely with drugs that are inhibitors (potent or moderately potent) or substrates of CYP3A with possible alteration in metabolism and concentrations of ranolazine and/or the other drug; pharmacokinetic interactions also are possible with CYP2D6 substrates.

The manufacturer states that ranolazine should not be used concomitantly with strong inhibitors of CYP3A (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir) or with inducers of CYP3A (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort). The manufacturer also states that ranolazine dosage should not exceed 500 mg twice daily in patients receiving moderate CYP3A inhibitors (e.g., diltiazem, erythromycin, fluconazole, grapefruit juice or grapefruit-containing products, verapamil) concomitantly with ranolazine.

Concentrations of drugs metabolized by CYP3A may be increased in patients receiving ranolazine. Dosage adjustment of sensitive CYP3A substrates (e.g., lovastatin) or CYP3A substrates with a narrow therapeutic index (e.g., cyclosporine, sirolimus, tacrolimus) may be required. Simvastatin dosage should not exceed 20 mg daily in patients receiving concomitant ranolazine therapy.

Ranolazine does not appear to inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, or 2E1; it is unlikely that ranolazine may alter pharmacokinetics of drugs metabolized by these isoenzymes.

Drugs that Inhibit the p-Glycoprotein Transport System

Ranolazine is a substrate and a moderate 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. The manufacturer states that dosage of ranolazine should be titrated down as needed based on clinical response in patients receiving p-glycoprotein inhibitors (e.g., cyclosporine) concomitantly with ranolazine.

Drugs Known to Prolong the QT Interval

Potential pharmacodynamic interaction (possible additive effects on QT interval). Experience with concomitant use of ranolazine with drugs that are known to prolong the QT interval (e.g., class Ia [e.g., quinidine] or III [e.g., dofetilide, sotalol] antiarrhythmic agents, antipsychotic agents [e.g., thioridazine, ziprasidone]) is limited.(See Prolongation of QT Interval under Warnings/Precautions: Warnings, in Cautions.)

Antituberculosis Agents

Pharmacokinetic interaction (decreased plasma ranolazine concentrations). Ranolazine should not be used with rifabutin, rifampin, or rifapentine (CYP3A inducers).

Azole Antifungal Agents

Pharmacokinetic interaction (increased plasma ranolazine concentrations). Ranolazine should not be used with ketoconazole (a potent CYP3A inhibitor) or itraconazole.(See Cautions: Contraindications.) Ranolazine dosage should not exceed 500 mg twice daily in patients receiving fluconazole (a moderate CYP3A inhibitor).

Calcium-channel Blocking agents

Pharmacokinetic interaction (increases in plasma ranolazine concentrations) with diltiazem (a moderately potent CYP3A inhibitor). However, ranolazine does not appear to affect the pharmacokinetics of diltiazem. The manufacturer states that ranolazine dosage should not exceed 500 mg twice daily in patients receiving diltiazem concomitantly with ranolazine.

Pharmacokinetic interaction (increased plasma ranolazine concentrations) with verapamil. The manufacturer states that ranolazine dosage should not exceed 500 mg twice daily in patients receiving verapamil concomitantly with ranolazine.

Carbamazepine

Potential pharmacokinetic interaction (decreased plasma ranolazine concentrations). Ranolazine should not be used with carbamazepine (a CYP3A inducer).

Cimetidine

Pharmacokinetic interaction unlikely. Cimetidine does not appear to increase the plasma concentrations of ranolazine; the manufacturer states that dosage adjustment of ranolazine is not required with concomitant use of cimetidine.

Cyclosporine

Potential pharmacokinetic interaction (increased ranolazine concentrations). Dosage of ranolazine should be titrated down as needed based on clinical response when used concomitantly with P-gp inhibitors such as cyclosporine.

Potential pharmacokinetic interaction (increased cyclosporine concentrations). Adjustment of cyclosporine dosage may be required.

Dextromethorphan

Formation of dextrorphan, the main metabolite of dextromethorphan, is partially inhibited by ranolazine in extensive metabolizers of dextromethorphan.

Digoxin

Pharmacokinetic interaction (increased plasma concentrations of digoxin). However, digoxin does not appear to alter the plasma concentrations of ranolazine. The manufacturer states that dosage adjustment of digoxin may be necessary with concomitant use of ranolazine.

HIV Protease Inhibitors

Potential pharmacokinetic interaction (increased plasma ranolazine concentrations) with HIV protease inhibitors. The manufacturer states that these drugs should not be administered concomitantly with ranolazine.

Macrolide Antibiotics

Potential pharmacokinetic interaction (increased plasma ranolazine concentrations) with macrolide antibiotics (e.g., erythromycin, clarithromycin); the manufacturer states that clarithromycin should not be used concomitantly with ranolazine. Ranolazine dosage should not exceed 500 mg twice daily in patients receiving erythromycin concomitantly with ranolazine.

Metoprolol

Pharmacokinetic interaction (increased exposure to drugs mainly metabolized by CYP2D6) with metoprolol. The manufacturer states that adjustment of metoprolol dosage is not required.

Paroxetine

Pharmacokinetic interaction (increased plasma ranolazine concentrations). However, the manufacturer states that dosage adjustment of ranolazine is not required with concomitant use of paroxetine or other inhibitors of CYP2D6.

Psychotherapeutic Agents

Potential pharmacokinetic interaction (increased exposure to drugs mainly metabolized by CYP2D6) with some psychotherapeutic agents (e.g., antipsychotics, tricyclic antidepressants). The manufacturer states that dosage reduction of drugs metabolized by CYP2D6 may be required with concomitant use of ranolazine.

Simvastatin

Simvastatin does not appear to increase the plasma concentrations of ranolazine. Pharmacokinetic interaction (increased plasma concentrations of simvastatin and its active metabolite). Simvastatin dosage should not exceed 20 mg daily in patients receiving concomitant ranolazine therapy.

St. John's Wort

Potential pharmacokinetic interaction (decreased plasma ranolazine concentrations). Ranolazine should not be used with St. John's wort (a CYP3A inducer).

Warfarin

Pharmacokinetic interaction unlikely.

Grapefruit

Potential pharmacokinetic interaction (increased plasma ranolazine concentrations) with grapefruit juice; the manufacturer states that ranolazine dosage should not exceed 500 mg twice daily when grapefruit juice or grapefruit-containing foods are administered concomitantly with the drug.