Ranolazine

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 antianginal indicated for the treatment of chronic angina.

2 DOSAGE AND ADMINISTRATION 500 mg twice daily and increase to 1000 mg twice daily, based on clinical symptoms

2.1Dosing 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.

2.2Dose Modification Dose

adjustments may be needed when ranolazine extended-release tablets are taken in combination with certain other drugs . 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 . 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 .

5 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. Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60 mL/min). If acute renal failure develops, discontinue ranolazine extended-release tablets.

5.1QT 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 . 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.

5.2Renal 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 . 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.

Ranolazine extended-release tablets are contraindicated in patients: Taking strong inhibitors of CYP3A Taking inducers of CYP3A With liver cirrhosis 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 )

8.1Pregnancy 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) . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, 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.

Most common adverse reactions (>4% and more common than with placebo) are dizziness, headache, constipation, nausea. To report SUSPECTED ADVERSE REACTIONS, contact Lifestar Pharma LLC at 1-888-995-4337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 . 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 .

6.2Postmarketing 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