ranolazine

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) ] .

Most common adverse reactions (>4% and more common than with placebo) are dizziness, headache, constipation, nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 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%…

Ranolazine extended-release tablets is 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 )

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.

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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 ). 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 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) ].