Other cardiac preparations

Ranolazine

Approved 28 May 2019OralTablet, extended release

The FDA lists this product in 54 strengths and forms.

Indications

Ranolazine extended-release tablets are indicated for the treatment of chronic angina. Ranolazine extended-release tablets 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 tablets are an antianginal indicated for the treatment of chronic angina. (1)

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)

Warnings and precautions

QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval- prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. (5.1)
Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min). If acute renal failure develops, discontinue ranolazine. (5.2)

5.1QT Interval Prolongation

Ranolazine blocks I Kr 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.

5.2Renal Failure

Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking ranolazine. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue ranolazine 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.

At a glance

Brand name: Ranolazine
Drug class: Other cardiac preparations
Route: Oral
Dosage form: Tablet, extended release
Applicant: Sun Pharm
Status: Discontinued
FDA approval: 28 May 2019
Application: ANDA211707-002
RxCUI: 35829

Indications

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)

Warnings and precautions

QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval- prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. (5.1)
Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min). If acute renal failure develops, discontinue ranolazine. (5.2)

5.1QT Interval Prolongation

5.2Renal Failure

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)

7.1Effects 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)] .

7.2Effects 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)].

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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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, 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% 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)] .

6.2Postmarketing 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

Ranolazine

Indications

Contraindications

Warnings and precautions

5.1QT Interval Prolongation

5.2Renal Failure

At a glance

Two medicines in one question?

Ranolazine

Indications

Contraindications

Warnings and precautions

5.1QT Interval Prolongation

5.2Renal Failure

At a glance

Two medicines in one question?

Interactions

7.1Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do

7.2Effects of Ranolazine on Other Drugs Drugs Metabolized by CYP3A Limit

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trial Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information