Ranolazine

Ranolazine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

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)

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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

• 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 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): C n animal studies, ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate [see Nonclinical Toxicology (13.3)]. There are no adequate well-controlled studies in pregnant women. RANEXA should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus.
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

It is not known whether ranolazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ranolazine in nursing infants, decide whether to discontinue nursing or to discontinue RANEXA, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatic Use

Of the chronic angina patients treated with RANEXA 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 RANEXA, 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.

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

A pharmacokinetic study of RANEXA in subjects with severe renal impairment (CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving RANEXA 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 RANEXA if acute renal failure develops. In a separate study, Cmax 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.

Hepatic Impairment

RANEXA is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax 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)].

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.

Use in Patients with Heart Failure

Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. RANEXA 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 RANEXA is required in patients with heart failure.

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. RANEXA produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. RANEXA should not be considered a treatment for diabetes.

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.