Ranolazine

1 INDICATIONS AND USAGE Ranolazine extended-release tablet is indicated for the treatment of chronic angina. Ranolazine extended-release tablet 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 tablet is an antianginal indicated for the treatment of chronic angina. ( 1 )

2 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 tablet dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take ranolazine extended-release tablet with or without meals. Swallow ranolazine extended-release tablet whole; do not crush, break, or chew. The maximum recommended daily dose of ranolazine extended-release tablet is 1000 mg twice daily. If a dose of ranolazine extended-release tablet is missed, take the prescribed dose at the next scheduled time; do not double the next dose. 2.2 Dose Adjustments in Specific Populations Dose adjustments may be needed when ranolazine extended-release tablet is taken in combination with certain other drugs [see Drug Interactions (7.1) ] . Limit the maximum dose of ranolazine extended-release tablet to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of ranolazine extended-release tablet 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 tablet. Titrate ranolazine extended-release tablet based on clinical response [see Drug Interactions (7.1) ].

6 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 Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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, 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 in open-label, long-term studies; 1227 patients were exposed to ranolazine 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 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 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 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 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 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, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies (14.2) ]. Laboratory Abnormalities: Ranolazine 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, and is not accompanied by changes in BUN. In healthy volunteers, ranolazine 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 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. 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

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-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. 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 tablet 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 μg/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 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 (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 metoprolol. In extensive metabolizers of dextromethorphan, a substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan. OCT2 Substrates In subjects with type 2 diabetes mellitus, the exposure to metformin is increased by 40% and 80% following administration of ranolazine 500 mg twice daily and 1000 mg twice daily, respectively. If co-administered with ranolazine 1000 mg twice daily, do not exceed metformin doses of 1700 mg/day [see Drug Interactions (7.2) ].