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Ranolazine

Pronunciation

Pronunciation: ra-NOE-la-zeen
Class: Antianginal agent

Trade Names

Ranexa
- Tablets, ER, oral 500 mg
- Tablets, ER, oral 1,000 mg

Pharmacology

Mechanism of action unknown. Ranolazine has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or BP.

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Pharmacokinetics

Absorption

T max is 2 to 5 h. Mean steady-state C max is 2,600 ng/mL (range, 400 to 6,100 ng/mL), and is usually attained within 3 days of twice-daily dosing. Bioavailability is approximately 76%.

Distribution

Protein binding is approximately 62%.

Metabolism

Extensively metabolized in the gut and the liver with less than 5% excreted unchanged. Primarily metabolized by CYP3A and, to a lesser extent, by CYP2D6.

Elimination

Apparent terminal half-life is 7 h. Approximately 75% is excreted in the urine and 25% in the feces.

Special Populations

Renal Function Impairment

Plasma levels increase up to 50%.

Hepatic Function Impairment

C max is increased by 30% in mild (Child-Pugh class A) hepatic impairment and 80% in cirrhotic patients with moderate (Child-Pugh class B) hepatic impairment.

Elderly

Pharmacokinetics unaffected by age.

Gender

Pharmacokinetics unaffected by gender.

Heart failure

Heart failure (New York Heart Association [NYHA] class I to IV) had no significant effect on ranolazine pharmacokinetics.

Diabetes

No effect of diabetes on ranolazine pharmacokinetics.

Indications and Usage

For the treatment of chronic angina.

Contraindications

Concomitant use with strong CYP3A inhibitors or CYP3A inducers; liver cirrhosis.

Dosage and Administration

Adults

PO 500 mg twice daily. May increase to 1,000 mg twice daily, based on symptoms (max, 2,000 mg/day).

Concomitant therapy
Adults

PO Use with strong CYP3A inhibitors is contraindicated. Limit the max dosage to 500 mg twice daily in patients receiving diltiazem, verapamil, erythromycin, and other moderate CYP3A inhibitors. Downtitrate the dose based on clinical response in patients receiving P-glycoprotein (P-gp) inhibitors (eg, cyclosporine).

General Advice

  • May be used with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers
  • Administer without regard to meals. Swallow tablet whole; do not crush, chew, or break.
  • If a dose is missed, the prescribed dose should be taken at the next scheduled time. The next dose should not be doubled.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Dextromethorphan

In extensive metabolizers of dextromethorphan, a CYP2D6 substrate, ranolazine partially inhibits the formation of the main metabolite, dextrorphan. Dextromethorphan concentrations may be elevated, increasing the risk of adverse reactions. Monitor for dextromethorphan adverse reactions and adjust the dose as needed.

Drugs metabolized by CYP2D6 (eg, antipsychotics [eg, risperidone], tricyclic antidepressants [eg, amitriptyline])

Studies have not been conducted; however, ranolazine may inhibit metabolism of these agents, necessitating a decrease in dose of CYP2D6 substrates.

Drugs metabolized by CYP3A (eg, simvastatin)

Plasma levels may be increased by ranolazine. Limit the simvastatin dosage to 20 mg once daily in patients receiving ranolazine.

Drugs transported by P-gp (eg, digoxin)

Plasma levels may be elevated by ranolazine. Dosage adjustment may be needed.

Inducers of CYP3A (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) and P-gp (eg, rifampin, St. John's wort)

Ranolazine plasma concentrations may be decreased. Coadministration is contraindicated.

Inhibitors of CYP2D6 (eg, paroxetine)

Ranolazine plasma concentrations may be increased. However, ranolazine dosage adjustment does not appear to be necessary.

Lovastatin, metoprolol, sirolimus, tacrolimus

Plasma concentrations of these agents may be elevated, increasing the risk of adverse reactions. Dose adjustments may be needed. Monitor for adverse reactions.

Moderate CYP3A inhibitors (eg, diltiazem, erythromycin, fluconazole, grapefruit juice or grapefruit-containing products, verapamil)

Ranolazine plasma concentrations may be increased. Limit the ranolazine dosage to 500 mg twice daily.

P-gp inhibitors (eg, cyclosporine)

Ranolazine plasma concentrations may be increased. Downtitrate the ranolazine dose based on clinical response. Cyclosporine plasma concentrations may be increased by ranolazine. Cyclosporine dose adjustments may be needed.

Strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir)

Ranolazine plasma concentrations may be increased. Coadministration with ranolazine is contraindicated.

Adverse Reactions

Cardiovascular

Bradycardia, hypotension, orthostatic hypotension, palpitations, syncope (vasovagal) (up to 4%); dose-related QTc interval prolongation.

CNS

Dizziness, headache (6%); asthenia, confusional state, vertigo (up to 4%); hallucination, hypoesthesia, paresthesia, tremor (postmarketing).

Dermatologic

Angioedema, pruritus, rash (postmarketing).

EENT

Blurred vision, tinnitus (up to 4%).

GI

Constipation (5%); nausea (4%); abdominal pain, anorexia, dry mouth, dyspepsia, vomiting (up to 4%).

Genitourinary

Hematuria (up to 4%).

Lab Tests

Elevated serum creatinine; reduced hemoglobin A 1c (HbA 1c ).

Respiratory

Dyspnea (up to 4%).

Miscellaneous

Hyperhidrosis, peripheral edema (up to 4%).

Precautions

Monitor

Obtain baseline and follow-up ECGs to evaluate effects of ranolazine on QT interval.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Patients 75 y and older had a higher incidence of adverse reactions, serious adverse reactions, and drug discontinuations because of adverse reactions. Use caution when selecting dose, usually starting at the lower end of the dosing range, reflecting the greater frequency of hepatic and renal function impairment and comorbidity.

Hepatic Function

Contraindicated in patients with liver cirrhosis.

Diabetes

Ranolazine produces small reductions in HbA 1c in patients with diabetes; the clinical significance is unknown. Ranolazine should not be considered a treatment for diabetes.

Heart failure

Ranolazine had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA class I to IV.

QT prolongation

Ranolazine prolongs the QTc interval in a dose-related manner.

Overdosage

Symptoms

Confusion, diplopia, dizziness, nausea, paresthesia, syncope, vomiting.

Patient Information

  • Advise patients that ranolazine will not abate an acute angina episode.
  • Advise patients to inform their health care provider of any other medications taken concurrently with ranolazine, including nonprescription medications.
  • Advise patients that ranolazine may produce changes in the ECG (QTc interval prolongation).
  • Advise patients to inform their health care provider of any personal or family history of QTc prolongation or 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, amiodarone, dofetilide, sotalol) antiarrhythmic agents, erythromycin, or certain antipsychotics (eg, thioridazine, ziprasidone).
  • Advise patients not to use ranolazine if they are receiving drugs that are strong CYP3A inhibitors (eg, clarithromycin, ketoconazole, nefazodone, ritonavir).
  • Advise patients to avoid initiation of treatment with ranolazine during administration of inducers of CYP3A (eg, rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort).
  • Advise patients to inform their health care provider if they are receiving drugs that are moderate CYP3A inhibitors (eg, diltiazem, verapamil, erythromycin) or P-gp inhibitors (eg, cyclosporine).
  • Advise patients that grapefruit juice or grapefruit products should be limited when taking ranolazine.
  • Advise patients that ranolazine should generally not be used in patients with liver cirrhosis.
  • Advise patients not to use dosages of ranolazine higher than 1,000 mg twice daily.
  • Advise patients that if a dose is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled.
  • Inform patients that ranolazine may be taken with or without meals and that the tablets should be swallowed whole and not crushed, broken, or chewed.
  • Advise patients to contact their health care provider if they experience fainting spells while taking ranolazine.
  • Advise patients that ranolazine may cause dizziness and light-headedness; 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.

Copyright © 2009 Wolters Kluwer Health.

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