Ranexa

— THERAPEUTIC CATEGORIES —
  • Angina
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Ranexa Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ranolazine 500mg, 1000mg; ext-rel tabs.

    Pharmacological Class

    Antianginal.

    How Supplied

    Tabs—60

    How Supplied

    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
      • Bottles of 60
    • 1000 mg tablets are pale yellow, with GSI1000 on one side
      • Bottles of 60

    Storage

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

    Manufacturer

    Gilead Sciences, Inc.

    Generic Availability

    YES

    Mechanism of Action

    The antianginal effects of ranolazine have not been determined. Its 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.

    Ranexa Indications

    Indications

    Chronic angina; may be used with beta-blockers, nitrates, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, anti-platelet and lipid-lowering therapies.

    Ranexa Dosage and Administration

    Adult

    Swallow whole. Initially 500mg twice daily, may increase to max 1g twice daily. Concomitant moderate CYP3A inhibitors (eg, diltiazem, verapamil, erythromycin, fluconazole, grapefruit-containing products): max 500mg twice daily. Concomitant P-gp inhibitors (eg, cyclosporine): titrate ranolazine dose based on response. Concomitant simvastatin: limit simvastatin to 20mg once daily. Concomitant metformin: give max metformin 1.7g/day if taking ranolazine 1g twice daily.

    Children

    Not established.

    Renal Impairment

    A pharmacokinetic study of Ranexa in patients with severe renal impairment (CrCL <30 mL/min) was stopped when 2 out of 4 patients 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 patient and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 patients during the 500 mg lead-in phase. One patient required hemodialysis, while the other 2 patients improved upon drug discontinuation. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue Ranexa if acute renal failure develops.

    Hepatic Impairment

    Ranexa is contraindicated in patients with liver cirrhosis. In a clinical study, 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 those 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.

    Other Modifications

    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

    • Data from a population pharmacokinetic evaluation of 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.

    Ranexa Contraindications

    Contraindications

    Liver cirrhosis. Concomitant strong CYP3A inhibitors (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir) or CYP3A inducers (eg, rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, St. John's wort).

    Ranexa Boxed Warnings

    Not Applicable

    Ranexa Warnings/Precautions

    Warnings/Precautions

    Not for acute angina episodes or for treating diabetes. History of or congenital long QT syndrome. Monitor renal function after initiation and periodically in moderate to severe renal impairment. Discontinue if acute renal failure develops. Elderly. Pregnancy. Nursing mothers.

    Warnings/Precautions

    QT Interval Prolongation

    • Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner.
    • Clinical evaluation in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. 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 those with known acquired QT interval prolongation.

    Renal Failure

    • Acute renal failure has been observed in some patients with severe renal impairment (CrCl <30 mL/min) while taking Ranexa.
    • If acute renal failure develops, discontinue Ranexa and treat appropriately.
    • 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.

    Pregnancy Considerations

    There are no available data on Ranexa use in pregnant women to inform any drug-associated risks.

    Nursing Mother Considerations

    There are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk.

    The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ranexa and any potential adverse effects on the breastfed infant from Ranexa or from the underlying maternal condition.

    Pediatric Considerations

    Safety and effectiveness have not been established in pediatric patients.

    Geriatric Considerations

    No overall differences in efficacy were observed between elderly and younger patients in controlled studies. 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.

    Renal Impairment Considerations

    A pharmacokinetic study of Ranexa in patients with severe renal impairment (CrCL <30 mL/min) was stopped when 2 out of 4 patients 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 patient and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 patients during the 500 mg lead-in phase. One patient required hemodialysis, while the other 2 patients improved upon drug discontinuation. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue Ranexa if acute renal failure develops.

    Hepatic Impairment Considerations

    Ranexa is contraindicated in patients with liver cirrhosis. In a clinical study, 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 those 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.

    Other Considerations for Specific Populations

    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

    • Data from a population pharmacokinetic evaluation of 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.

    Ranexa Pharmacokinetics

    Absorption

    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%.

    Distribution

    Plasma protein bound: ~62%.

    Metabolism

    Hepatic (primarily CYP3A and, to a lesser extent, by CYP2D6).

    Elimination

    Following a single oral dose of ranolazine solution, ~75% of the dose is excreted in urine and 25% in feces. Half-life: range 6–22 hours.

    Ranexa Interactions

    Interactions

    See Contraindications. Potentiates metformin; monitor glucose levels. May potentiate drugs metabolized by CYP3A (eg, simvastatin, lovastatin, cyclosporine, tacrolimus, sirolimus), P-gp transporters (eg, digoxin), CYP2D6 (eg, antipsychotics, tricyclic antidepressants); adjust doses of these drugs. May be potentiated by P-gp inhibitors (eg, cyclosporine). Caution with drugs that cause QT prolongation (eg, Class IA, Class III antiarrhythmics, thioridazine, ziprasidone).

    Ranexa Adverse Reactions

    Adverse Reactions

    Dizziness, headache, constipation, nausea; QT prolongation.

    Ranexa Clinical Trials

    Clinical Trials

    Chronic Stable Angina

    The CARISA (Combination Assessment of Ranolazine In Stable Angina) study involved 823 chronic angina patients who were randomly assigned to receive 12 weeks of treatment with twice-daily Ranexa 750 mg, 1000 mg, or placebo, and were also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg; sublingual nitrates were used 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. Results showed no increase in effect on exercise at the 1000 mg dose vs the 750 mg dose during the treadmill exercise.

    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 randomly assigned 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. Moreover, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Statistically significant decreases in angina attack frequency (P =0.028) and nitroglycerin use (P =0.014) were seen with Ranexa compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.

    Lack of Benefit in Acute Coronary Syndrome

    In a large (n=6560) 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, and there was no difference between Ranexa and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99; upper 95% confidence limit of 1.22).

    Ranexa Note

    Not Applicable

    Ranexa Patient Counseling

    Patient Counseling

    Inform patients that Ranexa will not abate an acute angina episode.

    Strong CY3PA Inhibitors, CYP3A Inducers, Liver Cirrhosis

    • Inform patients that Ranexa should not be used with drugs that are strong CYP3A inhibitors (eg, ketoconazole, clarithromycin, nefazodone, ritonavir). 
    • Inform patients that Ranexa should not be used with drugs that are inducers of CYP3A (eg, rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort).
    • Inform patients that Ranexa should not be used in patients with liver cirrhosis. 

    Moderate CYP3A Inhibitors, P-gp Inhibitors, Grapefruit Products

    • Advise patients to inform their health care provider if they are receiving drugs that are moderate CYP3A inhibitors (eg, diltiazem, verapamil, erythromycin).
    • Advise patients to inform their health care provider if they are receiving drugs that are P-gp inhibitors (eg, cyclosporine).
    • Advise patients to limit grapefruit juice or grapefruit products when taking Ranexa.

    QT Interval Prolongation

    • Inform patients that Ranexa may produce changes in the electrocardiogram (QTc interval prolongation).
    • Advise patients to inform their health care provider 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 (eg, quinidine) or Class III (eg, dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, thioridazine, ziprasidone).

    Use in Patients with Renal Impairment

    • Patients with severe renal impairment may be at risk of renal failure while on Ranexa.
    • Advise patients to inform their health care provider if they have impaired renal function before or while taking Ranexa.

    Dizziness, Fainting

    • Inform patients that Ranexa may cause dizziness and lightheadedness. Patients should know how they react to Ranexa before they operate an automobile or machinery, or engage in activities requiring mental alertness or coordination.
    • Advise patients to contact their health care provider if they experience fainting spells while taking Ranexa.

    Administration

    • Advise patients to inform their health care provider of any other medications taken concurrently with Ranexa, including over-the-counter medications.

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