Ranolazine

1 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)

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) ].

3 DOSAGE FORMS AND STRENGTHS Ranolazine extended-release tablets are supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths: • 500 mg tablets are light orange colored, debossed with “ RL49 ” on one side and plain on the other side. • 1000 mg tablets are pale yellow colored, debossed with “ RL50 ” on one side and plain on the other side. Extended-release tablets: 500 mg, 1000 mg (3)

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

6 ADVERSE REACTIONS Most common adverse reactions (greater than 4% and more common than with placebo) are dizziness, headache, constipation, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA, Inc., at 1-855-664-7744 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 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 (greater than 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 (less than 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 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 ranolaz …

7 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 available on high doses, when used with ranolazine extended-release tablets. ( 7.2 ) 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 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on ranolazine extended-release tablets use in pregnant women to inform any drug-associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures 4 times the maximum recommended human dose (MRHD) (see Data). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Embryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine during organogenesis. In rats, decreased fetal weight and reduced ossification were observed at doses (corresponding to 4-fold the AUC for the MRHD) that caused maternal weight loss. No adverse fetal effects were observed in either species exposed (AUC) to ranolazine at exposures (AUC) equal to the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk [see Use in Specific Populations ( 8.1 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ranolazine extended-release tablets and any potential adverse effects on the breastfed infant from ranolazine extended-release tablets or from the underlying maternal condition. Adult female rats were administered ranolazine orally from gestation day 6 through postnatal day 20. No adverse effects on pup development, behavior, or reproduction parameters were observed at a maternal dosage level of 60 mg/kg/day (equal to the MHRD based on AUC). At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via the maternal milk. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Of the chronic angina patients treated with ranolazine extended-release tablets in controlled studies, 496 (48%) were greater than or equal to 65 years of age, and 114 (11%) were greater than or equal to 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients greater than or equal to 65 years compared to younger patients, but patients greater than or equal to 75 years of age on ranolazine extended-release tablets, 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. 8.6 Use in Patients with Hepatic Impairment Ranolazine extended-release tablets are contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [see Clinical Pharmacology ( 12.2 )] . 8.7 Use in Patients with Renal Impairment A pharmacokinetic study of ranolazine extended-release tablets in subjects with severe renal impairment (CrCL less than 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine extended-release tablets 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the oth …

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.

11 DESCRIPTION Ranolazine tablets are available as film-coated, non-scored, extended-release tablets for oral administration. Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N ‐(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has a molecular formula of C 24 H 33 N 3 O 4 , a molecular weight of 427.54 g/mole, and the following structural formula: Ranolazine is an off-white to white powder. Ranolazine is soluble in dichloromethane and methanol. Ranolazine extended-release tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium hydroxide, sodium lauryl sulfate, titanium dioxide and triacetin. Additional inactive ingredients for the 500 mg tablet include ferric oxide yellow, ferric oxide red; additional inactive ingredients for the 1000 mg tablet include ferric oxide yellow. spl-ranolazine-ER-tablets-structure

10 OVERDOSAGE Hypotension, QT prolongation, bradycardia, myoclonic activity, severe tremor, unsteady gait/incoordination, dizziness, nausea, vomiting, dysphasia, and hallucinations have been seen in cases of oral overdose of ranolazine extended-release tablets. In cases of extreme overdose of ranolazine extended-release tablets fatal outcomes have been reported. In clinical studies, high intravenous exposure resulted in diplopia, paresthesia, confusion, and syncope. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ranolazine extended-release tablets, 500 mg are light orange colored, oval shaped, beveled edge, biconvex, film coated tablets debossed with "588" on one side and plain on other side and are supplied as follows: NDC 72578-064-14 in bottles of 60 tablets with child-resistant closure NDC 72578-064-01 in bottles of 100 tablets with child-resistant closure NDC 72578-064-05 in bottles of 500 tablets NDC 72578-064-77 in unit-dose blister cartons of 100 Tablets (10 x 10 Unit-dose) Ranolazine extended-release tablets, 1000 mg are pale yellow colored, oval shaped, beveled edge, biconvex, film coated tablets debossed with "589" on one side and plain on other side and are supplied as follows: NDC 72578-065-14 in bottles of 60 tablets with child-resistant closure NDC 72578-065-01 in bottles of 100 tablets with child-resistant closure NDC 72578-065-05 in bottles of 500 tablets NDC 72578-065-77 in unit-dose blister cartons of 100 Tablets (10 x 10 Unit-dose) Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].