Ranolazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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Overview
Ranolazine is an Anti-anginal that is FDA approved for the {{{indicationType}}} of treatment of chronic angina.. Common adverse reactions include constipation, nausea , dizziness , headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
<h4>Condition 1</h4>
Chronic Angina
- Dosing Information
- initial dosage: 500 mg PO bid increase
- maximum dosage: 1000 mg PO bid (based on clinical symptoms)
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ranolazine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
RANEXA 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)]
Warnings
QT Interval Prolongation
Ranolazine blocks IKr 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 [see Clinical Studies (14.2)]. 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.
Renal Failure
Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking RANEXA. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue RANEXA and treat appropriately [see Use in Specific Populations (8.7)]. 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.
Adverse Reactions
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 2,018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with RANEXA, 1,026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration. In addition, upon study completion, 1,251 patients received treatment with RANEXA in open-label, long-term studies; 1,227 patients were exposed to RANEXA 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 RANEXA 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 RANEXA 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 RANEXA 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 RANEXA 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 RANEXA 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 RANEXA, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies (14.2)].
Laboratory Abnormalities
RANEXA produces small reductions in hemoglobin A1c. RANEXA is not a treatment for diabetes. RANEXA 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 RANEXA, and is not accompanied by changes in BUN. In healthy volunteers, RANEXA 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 RANEXA in patients with severe renal impairment [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of RANEXA. 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 Tremor, paresthesia, abnormal coordination, 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. Psychiatric Disorders – hallucination Renal and Urinary Disorders – dysuria, urinary retention Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash
Drug Interactions
Effects of Other Drugs on Ranolazine
- Strong CYP3A Inhibitors
- Do not use RANEXA 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 RANEXA 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 RANEXA and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate RANEXA 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 RANEXA with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort [see Contraindications (4), Clinical Pharmacology (12.3)].
Effects of Ranolazine on Other Drugs
- Drugs Metabolized by CYP3A
- Limit the dose of simvastatin in patients on any dose of RANEXA 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 RANEXA may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].
- Drugs Transported by P-gp
- Drugs Metabolized by CYP2D6
- The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with RANEXA, and lower doses of these drugs may be required.
- Drugs Transported by OCT2
- In subjects with type 2 diabetes mellitus, concomitant use of RANEXA 1000 mg twice daily and metformin results in increased plasma levels of metformin. When RANEXA 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 RANEXA 500 mg twice daily [see Clinical Pharmacology (12.3)].
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Ranolazine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ranolazine in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ranolazine during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Ranolazine in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Ranolazine in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Ranolazine in geriatric settings.
Gender
There is no FDA guidance on the use of Ranolazine with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ranolazine with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Ranolazine in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Ranolazine in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ranolazine in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ranolazine in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Ranolazine Administration in the drug label.
Monitoring
There is limited information regarding Ranolazine Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Ranolazine and IV administrations.
Overdosage
There is limited information regarding Ranolazine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Ranolazine Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Ranolazine Mechanism of Action in the drug label.
Structure
There is limited information regarding Ranolazine Structure in the drug label.
Pharmacodynamics
There is limited information regarding Ranolazine Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Ranolazine Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Ranolazine Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Ranolazine Clinical Studies in the drug label.
How Supplied
There is limited information regarding Ranolazine How Supplied in the drug label.
Storage
There is limited information regarding Ranolazine Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Ranolazine Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Ranolazine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Ranolazine Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ranolazine Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.