Ranolazine

INDICATIONS AND USAGE Ranolazine extended-release tablets are indicated for the treatment of chronic angina. Ranolazine extended-release tablets may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. Ranolazine extended-release tablets are an antianginal indicated for the treatment of chronic angina. ( 1 )

DOSAGE AND ADMINISTRATION 500 mg twice daily and increase to 1000 mg twice daily, based on clinical symptoms ( 2.1 ) 2.1 Dosing Information Initiate Ranolazine Extended-Release Tablets dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranolazine Extended-Release Tablets with or without meals. Swallow Ranolazine Extended-Release Tablets whole; do not crush, break, or chew. The maximum recommended daily dose of Ranolazine Extended-Release Tablets is 1000 mg twice daily. If a dose of Ranolazine Extended-Release Tablets is missed, take the prescribed dose at the next scheduled time; do not double the next dose. 2.2 Dose Modification Dose adjustments may be needed when Ranolazine Extended-Release Tablets is taken in combination with certain other drugs [see Drug Interactions (7.1) ]. Limit the maximum dose of Ranolazine Extended-Release Tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of Ranolazine Extended-Release Tablets with strong CYP3A inhibitors is contraindicated [see Contraindications (4) , Drug Interactions (7.1) ]. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranolazine Extended-Release Tablets. Titrate Ranolazine Extended-Release Tablets based on clinical response [see Drug Interactions (7.1) ]. 2.1 Dosing Information Initiate Ranolazine Extended-Release Tablets dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranolazine Extended-Release Tablets with or without meals. Swallow Ranolazine Extended-Release Tablets whole; do not crush, break, or chew. The maximum recommended daily dose of Ranolazine Extended-Release Tablets is 1000 mg twice daily. If a dose of Ranolazine Extended-Release Tablets is missed, take the prescribed dose at the next scheduled time; do not double the next dose. 2.2 Dose Modification Dose adjustments may be needed when Ranolazine Extended-Release Tablets is taken in combination with certain other drugs [see Drug Interactions (7.1) ]. Limit the maximum dose of Ranolazine Extended-Release Tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of Ranolazine Extended-Release Tablets with strong CYP3A inhibitors is contraindicated [see Contraindications (4) , Drug Interactions (7.1) ]. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranolazine Extended-Release Tablets. Titrate Ranolazine Extended-Release Tablets based on clinical response [see Drug Interactions (7.1) ].

WARNINGS AND PRECAUTIONS • QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval-prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. ( 5.1 ) • Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60mL/min). If acute renal failure develops, discontinue Ranolazine Extended-Release Tablets. ( 5.2 ) 5.1 QT Interval Prolongation Ranolazine blocks I Kr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death [see Clinical Studies (14.2) ]. However, there is little experience with high doses (>1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. 5.2 Renal Failure Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] <30 mL/min) while taking Ranolazine Extended-Release Tablets. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue Ranolazine Extended-Release Tablets and treat appropriately [see Use in Specific Populations (8.7) ]. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL <60 mL/min) for increases in serum creatinine accompanied by an increase in BUN. 5.1 QT Interval Prolongation Ranolazine blocks I Kr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death [see Clinical Studies (14.2) ]. However, there is little experience with high doses (>1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. 5.2 Renal Failure Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] <30 mL/min) while taking Ranolazine Extended-Release Tablets. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue Ranolazine Extended-Release Tablets and treat appropriately [see Use in Specific Populations (8.7) ]. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL <60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.

CONTRAINDICATIONS Ranolazine extended-release tablets are contraindicated in patients: 1. Taking strong inhibitors of CYP3A [see Drug Interactions (7.1) ] 2. Taking inducers of CYP3A [see Drug Interactions (7.1) ] 3. With liver cirrhosis [see Use in Specific Populations (8.6) ] 4. Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) ( 4 , 7.1 ) 5. CYP3A inducers (e.g., rifampin, phenobarbital, St.John's wort) ( 4 , 7.1 ) 6. Liver cirrhosis ( 4 , 8.6 )

DRUG INTERACTIONS • Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit Ranolazine Extended-Release Tablets to 500 mg twice daily. ( 7.1 ) • P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate Ranolazine Extended-Release Tablets based on clinical response. ( 7.1 ) • CYP3A substrates: Limit simvastatin to 20 mg when used with Ranolazine Extended-Release Tablets. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with Ranolazine Extended-Release Tablets. ( 7.2 ) • OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with Ranolazine Extended-Release Tablets 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses. ( 7.2 ) • Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with Ranolazine Extended-Release Tablets. ( 7.2 ) See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient Labeling 7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use Ranolazine Extended-Release Tablets with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications (4) , Clinical Pharmacology (12.3) ]. Moderate CYP3A Inhibitors Limit the dose of Ranolazine Extended-Release Tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]. P-gp Inhibitors Concomitant use of Ranolazine Extended-Release Tablets and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate Ranolazine Extended-Release Tablets based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2) ]. CYP3A Inducers Do not use Ranolazine Extended-Release Tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort [see Contraindications (4) , Clinical Pharmacology (12.3) ]. 7.2 Effects of Ranolazine on Other Drugs Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of Ranolazine Extended-Release Tablets to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as Ranolazine Extended-Release Tablets may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3) ]. Drugs Transported by P-gp Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3) ]. Drugs Metabolized by CYP2D6 The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranolazine Extended-Release Tablets, and lower doses of these drugs may be required. Drugs Transported by OCT2 In subjects with type 2 diabetes mellitus, concomitant use of Ranolazine Extended-Release Tablets 1000 mg twice daily and metformin results in increased plasma levels of metformin. When Ranolazine Extended-Release Tablets 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranolazine Extended-Release Tablets 500 mg twice daily [see Clinical Pharmacology (12.3) ]. 7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use Ranolazine Extended-Release Tablets with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications (4) , Clinical Pharmacology (12.3) ]. Moderate CYP3A Inhibitors Limit the dose of Ranolazine Extended-Release Tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]. P-gp Inhibitors Concomitant use of Ranolazine Extended-Release Tablets and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate Ranolazine Extended-Release Tablets based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2) ]. CYP3A Inducers Do not use Ranolazine Extended-Release Tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort [see Contraindications (4) , Clinical Pharmacology (12.3) ]. 7.2 Effects of Ranolazine on Other Drugs Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of Ranolazine Extended-Release Tablets to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as Ranolazine Extended-Release Tablets may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3) ]. Drugs Transported by P-gp Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3) ]. Drugs Metabolized by CYP2D6 The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranolazine Extended-Release Tablets, and lower doses of these drugs may be required. Drugs Transported by OCT2 In subjects with type 2 diabetes mellitus, concomitant use of Ranolazine Extended-Release Tablets 1000 mg twice daily and metformin results in increased plasma levels of metformin. When Ranolazine Extended-Release Tablets 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranolazine Extended-Release Tablets 500 mg twice daily [see Clinical Pharmacology (12.3) ].

ADVERSE REACTIONS Most common adverse reactions (>4% and more common than with placebo) are dizziness, headache, constipation, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact i3 Pharmaceuticals, LLC at 1-844-874-7353 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with Ranolazine Extended-Release Tablets, 1026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks’ duration. In addition, upon study completion, 1251 patients received treatment with Ranolazine Extended-Release Tablets in open-label, long-term studies; 1227 patients were exposed to Ranolazine Extended-Release Tablets for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years. At recommended doses, about 6% of patients discontinued treatment with Ranolazine Extended-Release Tablets because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on Ranolazine Extended-Release Tablets than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported treatment- emergent adverse reactions (>4% and more common on Ranolazine Extended-Release Tablets than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with Ranolazine Extended-Release Tablets and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders – bradycardia, palpitations Ear and Labyrinth Disorders – tinnitus, vertigo Eye Disorders – blurred vision Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema Metabolism and Nutrition Disorders – anorexia Nervous System Disorders – syncope (vasovagal) Psychiatric Disorders – confusional state Renal and Urinary Disorders – hematuria Respiratory, Thoracic, and Mediastinal Disorders – dyspnea Skin and Subcutaneous Tissue Disorders – hyperhidrosis Vascular Disorders – hypotension, orthostatic hypotension Other (<0.5%) but potentially medically important adverse reactions observed more frequently with Ranolazine Extended-Release Tablets than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia. A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for Ranolazine Extended-Release Tablets, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies (14.2)]. Laboratory Abnormalities: Ranolazine Extended-Release Tablets produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine’s tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of Ranolazine Extended-Release Tablets, and is not accompanied by changes in BUN. In healthy volunteers, Ranolazine Extended-Release Tablets 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of Ranolazine Extended-Release Tablets in patients with severe renal impairment [see Warnings and Precautions (5.2) , Use in Specific Populations (8.7) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Ranolazine Extended-Release Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Nervous System Disorders – Abnormal coordination, myoclonus, paresthesia, tremor, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking ranolazine. The onset of events was often associated with an increase in ranolazine dose or exposure. Many patients reported symptom resolution following drug discontinuation or dose decrease. Metabolism and Nutrition Disorders – Cases of hypoglycemia have been reported in diabetic patients on antidiabetic medication. Psychiatric Disorders – hallucination Renal and Urinary Disorders – dysuria, urinary retention Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with Ranolazine Extended-Release Tablets, 1026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks’ duration. In addition, upon study completion, 1251 patients received treatment with Ranolazine Extended-Release Tablets in open-label, long-term studies; 1227 patients were exposed to Ranolazine Extended-Release Tablets for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years. At recommended doses, about 6% of patients discontinued treatment with Ranolazine Extended-Release Tablets because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on Ranolazine Extended-Release Tablets than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported treatment- emergent adverse reactions (>4% and more common on Ranolazine Extended-Release Tablets than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with Ranolazine Extended-Release Tablets and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders – bradycardia, palpitations Ear and Labyrinth Disorders – tinnitus, vertigo Eye Disorders – blurred vision Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema Metabolism and Nutrition Disorders – anorexia Nervous System Disorders – syncope (vasovagal

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (I Na ). However, the relationship of this inhibition to angina symptoms is uncertain. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of I Kr , which prolongs the ventricular action potential. 12.2 Pharmacodynamics Hemodynamic Effects Patients with chronic angina treated with ranolazine in controlled clinical studies had minimal changes in mean heart rate (<2 bpm) and systolic blood pressure (<3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients. Electrocardiographic Effects Dose and plasma concentration-related increases in the QTc interval [see WARNINGS AND PRECAUTIONS ( 5.1 )] , reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with ranolazine. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At T max following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see CONTRAINDICATIONS ( 4 )] . Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine. No proarrhythmic effects were observed on 7-day Holter recordings in 3162 acute coronary syndrome patients treated with ranolazine. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with ranolazine (80%) versus placebo (87%), including ventricular tachycardia ≥3 beats (52% versus 61%). However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms. 12.3 Pharmacokinetics 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 C max 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. The apparent terminal half-life of ranolazine is 7 hours. 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, C max and AUC 0-τ 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. Absorption and Distribution 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 extended-release 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 C max and AUC of ranolazine. Therefore, ranolazine may be taken without regard to meals. Over the concentration range of 0.25 to 10 mcg/mL, ranolazine is approximately 62% bound to human plasma proteins. Metabolism and Excretion Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. 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, and display apparent half-lives ranging from 6 to 22 hours. Drug Interactions Effect of Other Drugs on Ranolazine: In vitro data indicate that ranolazine is a substrate of CYP3A and, to a lesser degree, of CYP2D6. Ranolazine is also a substrate of P-glycoprotein. Strong CYP3A Inhibitors Plasma levels of ranolazine with ranolazine 1000 mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see CONTRAINDICATIONS ( 4 )] . Moderate CYP3A Inhibitors Plasma levels of ranolazine with ranolazine 1000 mg twice daily are increased by 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with ranolazine 750 mg twice daily are increased by 100% by verapamil 120 mg three times daily [see DRUG INTERACTIONS ( 7.1 )] . Weak CYP3A Inhibitors The weak CYP3A inhibitors simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers. CYP3A Inducers Rifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see CONTRAINDICATIONS ( 4 )] . CYP2D6 Inhibitors Paroxetine 20 mg once daily increased ranolazine concentrations by 20% in healthy volunteers receiving ranolazine 1000 mg twice daily. No dose adjustment of ranolazine is required in patients treated with CYP2D6 inhibitors. Digoxin Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily. Effect of Ranolazine on Other Drugs: In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2. CYP3A Substrates The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are increased by 100% in healthy volunteers receiving 80 mg once daily and ranolazine extended-release tablets 1000 mg twice daily [see DRUG INTERACTIONS ( 7.2 )] . Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with ranolazine extended-release tablets (1000 mg twice daily) in healthy volunteers. However, in one subject the exposure to atorvastatin and metabolites was increased by ~400% in the presence of ranolazine. Diltiazem The pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and ranolazine 1000 mg twice daily. P-gp Substrates Ranolazine increases digoxin concentrations by 50% in healthy volunteers receiving ranolazine 1000 mg twice daily and digoxin 0.125 mg once daily [see DRUG INTERACTIONS ( 7.2 )]. CYP2D6 Substrates Ranolazine 750 mg twice daily increases the plasma concentrations of a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metopr