Label: RANEXA- ranolazine tablet, film coated, extended release

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated September 17, 2014

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use
    Ranexa safely and effectively. See full prescribing information for
    Ranexa.
     
    Ranexa ® (ranolazine) extended-release tablets
    Initial U.S. Approval: 2006

    INDICATIONS AND USAGE

    Ranexa is indicated for the treatment of chronic angina. (1)

    DOSAGE AND ADMINISTRATION

    500 mg twice daily and increase to 1000 mg twice daily, based on clinical symptoms ( 2.1)

    DOSAGE FORMS AND STRENGTHS

    Extended-release tablets: 500 mg, 1000 mg (3)

    CONTRAINDICATIONS

    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)

    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 Gilead Sciences, Inc., at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit Ranexa to 500 mg twice daily. ( 7.1)
    P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate Ranexa based on clinical response. ( 7.1)
    CYP3A substrates: Limit simvastatin to 20 mg when used with Ranexa. 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 Ranexa. ( 7.2)
    Drugs transported by P-gp or metabolized by CYP2D6 (e.g., digoxin, tricyclic antidepressants): May need reduced doses of these drugs when used with Ranexa. ( 7.2)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 9/2014

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    Ranexa is indicated for the treatment of chronic angina.

    Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Dosing Information

    Initiate Ranexa dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranexa with or without meals. Swallow Ranexa tablets whole; do not crush, break, or chew.

    The maximum recommended daily dose of Ranexa is 1000 mg twice daily.

    If a dose of Ranexa 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 Ranexa is taken in combination with certain other drugs [see Drug Interactions (7.1)]. Limit the maximum dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of Ranexa 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 Ranexa. Titrate Ranexa based on clinical response [see Drug Interactions (7.1)].

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  • 3 DOSAGE FORMS AND STRENGTHS

    Ranexa is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths:

    500 mg tablets are light orange, with GSI500 on one side
    1000 mg tablets are pale yellow, with GSI1000 on one side
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  • 4 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)]
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  • 5 WARNINGS AND PRECAUTIONS

    5.1 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.

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  • 6 ADVERSE REACTIONS

    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 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 Trials (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. 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. The elevated creatinine levels are likely due to a blockage of creatinine's tubular secretion by ranolazine or one of its metabolites.

    6.2 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, hypoesthesia

    Psychiatric Disorders – hallucination

    Skin and Subcutaneous Tissue Disorders – angioedema, rash, pruritus

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  • 7 DRUG INTERACTIONS

    7.1 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, rifapentin, 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 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.

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C

    In 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 Reproductive Toxicology Studies (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.

    8.3 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.

    8.4 Pediatric Use

    Safety and effectiveness have not been established in pediatric patients.

    8.5 Geriatric 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.

    8.6 Use in Patients with 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)].

    8.7 Use in Patients with Renal Impairment

    Compared to patients with no renal impairment, Cmax was increased between 40% and 50% in patients with mild, moderate or severe 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.

    8.8 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.

    8.9 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.

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  • 10 OVERDOSAGE

    High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces 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.

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  • 11 DESCRIPTION

    Ranexa (ranolazine) is 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 C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula:

    Chemical Structure

    Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water.

    Ranexa tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain.

    The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.

    12.2 Pharmacodynamics

    Hemodynamic Effects

    Patients with chronic angina treated with Ranexa in controlled clinical studies had minimal changes in mean heart rate (< 2 bpm) and systolic blood pressure (< 3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients.

    Electrocardiographic Effects

    Dose and plasma concentration-related increases in the QTc interval [see Warnings and Precautions (5.1)], reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with Ranexa. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see Contraindications (4)].

    Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine.

    No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 acute coronary syndrome patients treated with Ranexa. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia ≥ 3 beats (52% versus 61%). However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms.

    12.3 Pharmacokinetics

    Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with Ranexa. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.

    Absorption and Distribution

    After oral administration of Ranexa, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from Ranexa tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.

    Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, Ranexa may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL, ranolazine is approximately 62% bound to human plasma proteins.

    Metabolism and Excretion

    Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display apparent half-lives ranging from 6 to 22 hours.

    Drug Interactions

    Effect of other drugs on ranolazine

    In vitro data indicate that ranolazine is a substrate of CYP3A and, to a lesser degree, of CYP2D6. Ranolazine is also a substrate of P-glycoprotein.

    Strong CYP3A Inhibitors

    Plasma levels of ranolazine with Ranexa 1000 mg twice daily are 3.2-fold higher if coadministered with ketoconazole 200 mg twice daily [see Contraindications (4)].

    Moderate CYP3A Inhibitors

    Plasma levels of ranolazine with Ranexa 1000 mg twice daily are increased about 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with Ranexa 750 mg twice daily are increased about 100% by verapamil 120 mg three times daily [see Drug Interactions 7.1].

    Weak CYP3A Inhibitors

    The weak CYP3A inhibitors simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers.

    CYP3A Inducers

    Rifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see Contraindications (4)].

    CYP2D6 Inhibitors

    Paroxetine 20 mg once daily increased ranolazine concentrations 20% in healthy volunteers receiving Ranexa 1000 mg twice daily. No dose adjustment of Ranexa is required in patients treated with CYP2D6 inhibitors.

    Digoxin

    Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily.

    Effect of ranolazine on other drugs

    In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2.

    CYP3A Substrates

    The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each doubled in healthy subjects receiving 80 mg once daily and Ranexa 1000 mg twice daily [see Drug Interactions (7.2)].

    Diltiazem

    The pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and Ranexa 1000 mg twice daily.

    P-gp Substrates

    Ranolazine increases digoxin concentrations 50% in healthy volunteers receiving Ranexa 1000 mg twice daily and digoxin 0.125 mg once daily [see Drug Interactions (7.2)].

    CYP2D6 Substrates

    Ranexa 750 mg twice daily increases the plasma concentrations of a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, a substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays.

    There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m2/day) and 50 mg/kg/day for 24 months in mice (150 mg/m2/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a surface area basis. A published study reported that ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily [see References (15)]. The clinical significance of this finding is unclear.

    13.3 Reproductive Toxicology Studies

    Animal reproduction studies with ranolazine were conducted in rats and rabbits.

    There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). Reduced ossification of sternebrae was observed in fetuses of pregnant rabbits dosed at 150 mg/kg/day (1.5 times the MRHD on a surface area basis). These doses in rats and rabbits were associated with an increased maternal mortality rate.

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  • 14 CLINICAL STUDIES

    14.1 Chronic Stable Angina

    CARISA (Combination Assessment of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily Ranexa 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed.

    In this trial, statistically significant (p < 0.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each Ranexa dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. The changes versus placebo in exercise parameters are presented in Table 1. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose.

    Table 1 Exercise Treadmill Results (CARISA)
    Mean Difference from Placebo (sec)
    Study CARISA (N = 791)
    Ranexa Twice-daily Dose 750 mg 1000 mg
    *
    p-value ≤ 0.05
    p-value ≤ 0.005

    Exercise Duration

      Trough

    24*

    24*

      Peak

    34

    26*

    Time to Angina

      Trough

    30*

    26*

      Peak

    38

    38

    Time to 1 mm ST-Segment Depression

      Trough

    20

    21

      Peak

    41

    35

    The effects of Ranexa on angina frequency and nitroglycerin use are shown in Table 2.

    Table 2 Angina Frequency and Nitroglycerin Use (CARISA)
    Placebo Ranexa
    750 mg*
    Ranexa
    1000 mg*
    *
    Twice daily

    Angina Frequency
    (attacks/week)

    N

    258

    272

    261

    Mean

    3.3

    2.5

    2.1

    p-value vs placebo

    0.006

    < 0.001

    Nitroglycerin Use
    (doses/week)

    N

    252

    262

    244

    Mean

    3.1

    2.1

    1.8

    p-value vs placebo

    0.016

    < 0.001

    Tolerance to Ranexa did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of Ranexa.

    Ranexa has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In addition, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Table 3. Statistically significant decreases in angina attack frequency (p = 0.028) and nitroglycerin use (p = 0.014) were observed with Ranexa compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.

    Table 3 Angina Frequency and Nitroglycerin Use (ERICA)
    Placebo Ranexa*
    *
    1000 mg twice daily

    Angina Frequency
    (attacks/week)

    N

    281

    277

    Mean

    4.3

    3.3

    Median

    2.4

    2.2

    Nitroglycerin Use
    (doses/week)

    N

    281

    277

    Mean

    3.6

    2.7

    Median

    1.7

    1.3

    Gender

    Effects on angina frequency and exercise tolerance were considerably smaller in women than in men. In CARISA, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level. In ERICA, where the primary endpoint was angina attack frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males.

    Race

    There were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup.

    14.2 Lack of Benefit in Acute Coronary Syndrome

    In a large (n = 6,560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine [see Clinical Pharmacology (12.2)], and there was no difference between Ranexa and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).

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  • 15 REFERENCES

    M.A. Suckow et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC (min/+) mice. Cancer Letters 209(2004):165−9.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Ranexa is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths:

    500 mg tablets are light orange, with GSI500 on one side
    1000 mg tablets are pale yellow, with GSI1000 on one side

    Ranexa (ranolazine) extended-release tablets are available in:

    Strength NDC

    Unit-of-Use Bottle (60 Tablets)

    500 mg

    61958-1003-1

    Unit-of-Use Bottle (60 Tablets)

    1000 mg

    61958-1004-1

    Store Ranexa tablets at 25 °C (77 °F) with excursions permitted to 15 ° to 30 °C (59 ° to 86 °F).

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  • 17 PATIENT COUNSELING INFORMATION

    To ensure safe and effective use of Ranexa, the following information and instructions should be communicated to the patient when appropriate.

    Patients should be advised:

    that Ranexa will not abate an acute angina episode
    to inform their physician of any other medications when taken concurrently with Ranexa, including over-the-counter medications
    that Ranexa may produce changes in the electrocardiogram (QTc interval prolongation)
    to inform their physician of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone)
    that Ranexa should not be used in patients who are receiving drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir)
    that initiation of treatment with Ranexa should be avoided during administration of inducers of CYP3A (e.g., rifampin, rifabutin, rifapentin, barbiturates, carbamazepine, phenytoin, St. John's wort)
    to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin)
    to inform their physician if they are receiving P-gp inhibitors (e.g., cyclosporine)
    that grapefruit juice or grapefruit products should be limited when taking Ranexa
    that Ranexa should not be used in patients with liver cirrhosis
    that doses of Ranexa higher than 1000 mg twice daily should not be used
    that if a dose is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled
    that Ranexa may be taken with or without meals
    that Ranexa tablets should be swallowed whole and not crushed, broken, or chewed
    to contact their physician if they experience fainting spells while taking Ranexa
    that Ranexa may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile, or machinery, or engage in activities requiring mental alertness or coordination
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  • SPL UNCLASSIFIED SECTION

    Manufactured for:
    Gilead Sciences, Inc.
    Foster City, CA 94404

    Ranexa is a registered trademark of Gilead Sciences, Inc.
    © 2011 Gilead Sciences, Inc.

    21-526-GS-011

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  • PATIENT PACKAGE INSERT

    PATIENT INFORMATION
    Ranexa® (rah NEX ah)
    (ranolazine)
    extended-release tablets
    Dosing Strengths:
    500 mg tablets
    1000 mg tablets

    Read this Patient Information before you start taking Ranexa and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

    What is Ranexa?

    Ranexa is a prescription medicine used to treat angina that keeps coming back (chronic angina).

    Ranexa may be used with other medicines that are used for heart problems and blood pressure control.

    It is not known if Ranexa is safe and effective in children.

    Who should not take Ranexa?

    Do not take Ranexa if:

    you take any of the following medicines:
    1.
    for fungus infection: ketoconazole (Nizoral ®), itraconazole (Sporanox ®, Onmel)
    2.
    for infection: clarithromycin (Biaxin ®)
    3.
    for depression: nefazodone
    4.
    for HIV: nelfinavir (Viracept ®), ritonavir (Norvir ®), lopinavir and ritonavir (Kaletra ®) indinavir (Crixivan ®), saquinavir (Invirase ®)
    5.
    for tuberculosis (TB): rifampin (Rifadin ®), rifabutin (Mycobutin ®), rifapentin (Priftin ®)
    6.
    for seizures: phenobarbital, phenytoin (Phenytek ®, Dilantin ® Dilantin-125 ®), carbamazepine (Tegretol ®)
    7.
    St. John's wort (Hypericum perforatum)
    you have scarring (cirrhosis) of your liver

    What should I tell my doctor before taking Ranexa?

    Before you take Ranexa, tell your doctor if you:

    have or have a family history of a heart problem, called 'QT prolongation' or 'long QT syndrome'.
    have liver problems.
    are pregnant or plan to become pregnant . It is not known if Ranexa will harm your unborn baby.
    are breast-feeding or plan to breast-feed. It is not known if Ranexa passes into your breast milk. You and your doctor should decide if you will take Ranexa or breast-feed. You should not do both.

    Tell your doctor about all the medicines you take, including all prescription and non-prescription medicines, vitamins and herbal supplements. Ranexa may affect the way other medicines work and other medicines may affect how Ranexa works.

    Tell your doctor if you take medicines:

    for your heart
    for cholesterol
    for infection
    for fungus
    for transplant
    for nausea and vomiting because of cancer treatments
    for mental problems

    Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.

    How should I take Ranexa?

    Take Ranexa exactly as your doctor tells you.
    Your doctor will tell you how much Ranexa to take and when to take it.
     
    Do not change your dose unless your doctor tells you to.
    Tell your doctor if you still have symptoms of angina after starting Ranexa.
    Take Ranexa by mouth, with or without food.
    Swallow the Ranexa tablets whole. Do not crush, break, or chew Ranexa tablets before swallowing.
    If you miss a dose of Ranexa, wait to take the next dose of Ranexa at your regular time. Do not make up for the missed dose. Do not take more than 1 dose at a time.
    If you take too much Ranexa, call your doctor, or go to the nearest emergency room right away.

    What should I avoid while taking Ranexa?

    Grapefruit and grapefruit juice. Limit products that have grapefruit in them. They can cause your blood levels of Ranexa to increase.
    Ranexa can cause dizziness, lightheadness, or fainting. If you have these symptoms, do not drive a car, use machinery, or do anything that needs you to be alert.

    What are the possible side effects of Ranexa?

    Ranexa may cause serious side effects, including:

    1.
    changes in the electrical activity of your heart called QT prolongation. Your doctor may check the electrical activity of your heart with an ECG. Tell your doctor right away if you feel faint, lightheaded, or feel your heart beating irregularly or fast while taking Ranexa. These may be symptoms related to QT prolongation.

    The most common side effects of Ranexa include:

    1.
    dizziness
    2.
    headache
    3.
    constipation
    4.
    nausea

    Tell your doctor if you have any side effect that bothers you or does not go away.

    These are not all the possible side effects of Ranexa. For more information, ask your doctor or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Ranexa?

    Store Ranexa tablets at room temperature between 59° to 86°F (15° to 30°C )

    Keep Ranexa and all medicines out of the reach of children.

    General information about Ranexa

    Medicines are sometimes prescribed for purposes other than those listed in Patient Information. Do not use Ranexa for a condition for which it was not prescribed. Do not give Ranexa to other people, even if they have the same condition you have. It may harm them.

    The Patient Information summarizes the most important information about Ranexa. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Ranexa that is written for health professionals.

    For more information, go to www.ranexa.com or call Gilead Sciences, Inc. at 1-800-445-3235.

    What is chronic angina?

    Chronic angina means pain or discomfort in the chest, jaw, shoulder, back, or arm that keeps coming back. There are other possible signs and symptoms of angina including shortness of breath. Angina usually comes on when you are active or under stress. Chronic angina is a symptom of a heart problem called coronary heart disease (CHD), also known as coronary artery disease (CAD). When you have CHD, the blood vessels in your heart become stiff and narrow. Oxygen-rich blood cannot reach your heart muscle easily. Angina comes on when too little oxygen reaches your heart muscle.

    What are the ingredients in Ranexa?

    Active ingredient: ranolazine

    Inactive ingredients:
    500 mg tablet: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red.
    1000 mg tablet: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, lactose monohydrate, triacetin, and Iron Oxide Yellow.

    This Patient Information has been approved by the U.S. Food and Drug Administration.

    Manufactured for:
    Gilead Sciences, Inc.
    Foster City, CA 94404

    Issued December 2011
    Ranexa is a registered trademark of Gilead Sciences, Inc.
    © 2011 Gilead Sciences, Inc.

    All other trademarks are the property of their respective owners.

    D-21-526-GS-011

    Cardinal Health

    Zanesville, OH 43701

    IU46029181012

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  • Principal Display Panel - Pouch

    Ranexa®

    (ranolazine extended-release tablet)

    500 mg

    pouch
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  • Principal Display Panel - Carton

    Ranexa®

    (ranolazine extended-release tablets)

    500 mg

    60 Tablets

    carton label
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  • PRINCIPAL DISPLAY PANEL

    Ranex 500 mg

    Ranolazine Extended-Release Tablets

    10 Tablets

    bag label
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  • INGREDIENTS AND APPEARANCE
    RANEXA 
    ranolazine tablet, film coated, extended release
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-4428(NDC:61958-1003)
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    ranolazine (UNII: A6IEZ5M406) (ranolazine - UNII:A6IEZ5M406) ranolazine 500 mg
    Inactive Ingredients
    Ingredient Name Strength
    carnauba wax (UNII: R12CBM0EIZ)  
    hypromelloses (UNII: 3NXW29V3WO)  
    magnesium stearate (UNII: 70097M6I30)  
    methacrylic acid - Ethyl Acrylate Copolymer (1:1) Type A (UNII: NX76LV5T8J)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    sodium hydroxide (UNII: 55X04QC32I)  
    polyvinyl alcohol (UNII: 532B59J990)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycol 3350 (UNII: G2M7P15E5P)  
    talc (UNII: 7SEV7J4R1U)  
    ferric oxide yellow (UNII: EX438O2MRT)  
    ferric oxide red (UNII: 1K09F3G675)  
    water (UNII: 059QF0KO0R)  
    Product Characteristics
    Color ORANGE (Light orange) Score no score
    Shape OVAL (oblong-shaped) Size 17mm
    Flavor Imprint Code GSI500
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:55154-4428-4 60 in 1 CARTON
    1 NDC:55154-4428-6 1 in 1 POUCH; Type 0: Not a Combination Product
    2 NDC:55154-4428-0 10 in 1 BAG
    2 NDC:55154-4428-6 1 in 1 POUCH; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021526 01/27/2006
    Labeler - Cardinal Health (188557102)
    Establishment
    Name Address ID/FEI Business Operations
    Cardinal Health 188557102 REPACK(55154-4428)
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