Ranolazine
FDA Drug Information • Also known as: Aspruzyo Sprinkle, Ranolazine
- Brand Names
- Aspruzyo Sprinkle, Ranolazine
- Drug Class
- Anti-anginal [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED, EXTENDED RELEASE
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Ranolazine extended-release tablets are available as a film-coated, non-scored, extended-release tablet 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 an empirical 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 a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol. Ranolazine extended-release tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: ferrosoferric oxide, hypromellose, iron oxide yellow, magnesium stearate, methacrylic acid copolymer type C (contains polysorbate 80 and sodium lauryl sulfate), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide and talc. Additional inactive ingredient for the 500 mg tablets include iron oxide red. Structure
What Is Ranolazine Used For?
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 )
Dosage and Administration
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) ].
Side Effects (Adverse Reactions)
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,...
Drug Interactions
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...
Contraindications
4 CONTRAINDICATIONS Ranolazine 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 )
Pregnancy and Breastfeeding
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.
Overdosage
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. In cases of extreme overdose of ranolazine 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.
How Supplied
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].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.