Ranolazine

Trade Names:Ranexa- Tablets, ER 500 mg- Tablets, ER 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.

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 from oral solution is about 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

Plasma levels increase up to 50%.

Increased plasma levels in patients with mild and moderate hepatic function impairment.

Indications and Usage

Treatment of chronic angina.

Contraindications

Patients taking strong CYP3A inhibitors; patients taking CYP3A inducers; clinically important hepatic function impairment.

Dosage and Administration

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

PO Limit the max dosage to 500 mg twice daily in patients receiving diltiazem, verapamil, and other moderate CYP3A inhibitors. Down-titrate the dose based on clinical response in patients receiving P-glycoprotein inhibitors (eg, cyclosporine).

General Advice

• May be used in combination with amlodipine, beta-blockers, or nitrates.
• Administer without regard to meals. Administer with food if GI upset occurs.
• Advise patient to swallow tablet whole and not to crush, chew, or break.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Drug Interactions

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

Plasma levels may be increased by ranolazine; however, dosage adjustments do not appear to be necessary.

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

Ranolazine plasma concentrations may be decreased. Avoid coadministration with ranolazine.

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

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

Ranolazine plasma concentrations may be increased. Down-titrate the ranolazine dose based on clinical response.

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

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Bradycardia, hypotension, orthostatic hypotension, palpitations (2% or less); dose-related QTc interval prolongation.

CNS

Dizziness, headache (6%).

EENT

Tinnitus, vertigo (2% or less).

GI

Constipation (5%); nausea (4%); abdominal pain, dry mouth, vomiting (2% or less).

Hematologic-Lymphatic

Leukopenia, pancytopenia, thrombocytopenia.

Hypersensitivity

Angioedema.

Respiratory

Dyspnea (2% or less).

Miscellaneous

Peripheral edema (2% or less).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

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.

Renal Function

Plasma concentrations may be increased up to 50%.

Hepatic Function

Plasma concentrations may increase in patients with mild and moderate hepatic function impairment by 30% and 60%, respectively. Contraindicated in patients with clinically significant hepatic function impairment.

QT prolongation

Ranolazine prolongs the QTc interval in a dose-related manner. There is little experience with dosages above 1,000 mg twice daily, high exposure, other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval.

Tumor promotion

Ranolazine has been reported to promote tumor formation and progression to malignancy in mice.

Overdosage

Symptoms

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

Patient Information

• Ensure that patient understands that ranolazine is taken daily to reduce the frequency of angina attacks and is not to be used to treat an acute angina episode.
• Advise patient to review the Patient Information leaflet carefully before starting therapy and to reread and check for new information each time the medication is refilled.
• Advise patient that ranolazine may be used in combination with at least 1 other antianginal medication and to continue to take other antianginal medications as prescribed by health care provider.
• Caution patient to take exactly as prescribed and not to change the dose or stop taking unless advised by health care provider.
• Caution patient that max daily dosage is 1,000 mg twice daily and to never exceed that amount because of the risk of serious toxicity.
• Advise patient to take each dose without regard to meals, but to take with food if GI upset occurs.
• Caution patient to swallow tablets whole and not to crush, chew, or break.
• Caution patient to avoid grapefruit juice and grapefruit-containing products while taking ranolazine.
• Review with patient and family the signs and symptoms of angina (eg, acute onset of pressure-like chest pain that may radiate down the left arm and/or into the neck or jaw, often associated with sweating and shortness of breath or difficulty breathing).
• Ensure that patient has SL nitroglycerin available at all times, knows when and how to use SL nitroglycerin, and knows what to do if angina pain worsens or fails to respond to SL nitroglycerin.
• Advise patient to notify health care provider if angina symptoms increase in frequency or severity, or if there is a sudden increase in the frequency of use of SL nitroglycerin.
• Caution patient that medication may cause dizziness or light-headedness, and to use caution while driving or performing other tasks requiring alertness or coordination until tolerance is determined.
• Advise patient to discontinue therapy and contact health care provider immediately if any of the following occur: difficulty breathing, fainting, hives, itching, palpitations, skin rash, or unexplained shortness of breath.

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