Ranolazine

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

7 DRUG INTERACTIONS Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit ranolazine to 500 mg twice daily. ( 7.1 ) P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate ranolazine based on clinical response. ( 7.1 ) CYP3A substrates: Limit simvastatin to 20 mg when used with ranolazine. 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. ( 7.2 ) OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with ranolazine 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. ( 7.2 ) 7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use ranolazine 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 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 and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate ranolazine 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 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 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 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, and lower doses of these drugs may be required. Drugs Transported by OCT2 In subjects with type 2 diabetes mellitus, concomitant use of ranolazine 1000 mg twice daily and metformin results in increased plasma levels of metformin. When ranolazine 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 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 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 2-4% 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. 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 and any potential adverse effects on the breastfed infant from ranolazine 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 in controlled studies, 496 (48%) were ≥65 years of age, and 114 (11%) were ≥75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients ≥65 years compared to younger patients, but patients ≥75 years of age on ranolazine, 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 is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the C max 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 in subjects with severe renal impairment (CrCL <30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine 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 other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation [see Warnings and Precautions (5.2) ]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue ranolazine if acute renal failure develops. In a separate study, C max was increased between 40% and 50% in patients with mild, moderate, or severe renal impairment compared to patients with no renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis. 8.8 Use in Patients with Heart Failure Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranolazine had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of ranolazine is required in patients with heart failure. 8.9 Use in Patients with Diabetes Mellitus A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes. Ranolazine produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. Ranolazine should not be considered a treatment for diabetes.