Ranexa Description

Ranexa® (ranolazine) is available as an extended-release tablet for oral administration.

Ranolazine is a racemic mixture and chemically described as 1-piperazineacetamide, N -(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C24 H33 N3 O4 , a molecular weight of 427.54 g/mole, and the following structural formula:

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 is available for oral administration as film-coated, extended-release tablets containing 500 mg or 1000 mg of ranolazine. Inactive ingredients of the 500 mg tablet include carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium hydroxide, titanium dioxide, and FD&C Yellow #6 Lake.

Inactive ingredients of the 1000 mg tablet include carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, triacetin, and Iron Oxide Yellow.

Ranexa Indications And Usage

Ranexa is indicated for the treatment of chronic angina. Because Ranexa prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs. Ranexa should be used in combination with amlodipine, beta-blockers or nitrates. The effect on angina rate or exercise tolerance appeared to be smaller in women than men.

Ranexa Contraindications

Ranexa is contraindicated in patients:

• With pre-existing QT prolongation
• With hepatic impairment (Child-Pugh Classes A [mild], B [moderate] or C [severe]) (see CLINICAL PHARMACOLOGY, Hepatic Insufficiency, and Electrocardiographic Effects)
• On QT-prolonging drugs
• On potent and moderately potent CYP3A inhibitors, including diltiazem

Ranexa Side Effects

Qt Prolongation

Ranolazine has been shown to prolong the QTc interval in a dose-related manner. While the clinical significance of the QTc prolongation in the case of ranolazine is unknown, other drugs with this potential have been associated with torsades de pointes-type arrhythmias and sudden death.

With repeat dosing, the mean effect on QTc of ranolazine 1000 mg b.i.d., at Tmax , is about 6 msec. However, in 5% of the population the prolongation of QTc is 15 msec. Age, weight, gender, race, heart rate, CHF NYHA Class I to IV, and diabetes have no significant effect on the relationship between ranolazine plasma level and increase in QTc. The relationship between ranolazine levels and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by 1000 mg b.i.d., and is not affected by changes in heart rate. Doses > 1000 mg b.i.d. should not be used.

There are no studies examining the effects of ranolazine in patients with pre-existing QT prolongation or receiving other QT-prolonging drugs. Because of possible additive effects on the QT interval, ranolazine should be avoided in patients with known QT prolongation (including congenital long QT syndrome, uncorrected hypokalemia), known history of ventricular tachycardia and in patients receiving drugs that prolong the QTc interval, such as Class Ia (e.g., quinidine) and Class III (e.g. , dofetilide, sotalol) antiarrhythmics, and antipsychotics (e.g., thioridazine, ziprasidone).

Because the QTc-prolonging effect is increased approximately 3-fold in patients with hepatic dysfunction, ranolazine is contraindicated in patients with mild, moderate or severe liver disease (see Special Populations and Hepatic Insufficiency ).

Ranolazine is primarily metabolized by CYP3A. Use of ranolazine with potent or moderately potent inhibitors of CYP3A should be avoided because concomitant administration will increase ranolazine plasma levels and QTc prolongation. These inhibitors include ketoconazole and other azole antifungals, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors and grapefruit juice or grapefruit-containing products.

Tumor Promotion

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 ). The clinical significance of this finding is unclear (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility ).

Ranexa Precautions

Co-administration of ranolazine and digoxin increases the plasma concentrations of digoxin by approximately 1.5-fold and the dose of digoxin may have to be reduced accordingly. The dose of other P-gp substrates may have to be reduced as well when ranolazine is co-administered.

Ranolazine can inhibit the activity of CYP2D6 and thus the metabolism of drugs that are mainly metabolized by this enzyme, for example tricyclic antidepressants and some antipsychotics, may be impaired and exposure to these drugs increased. The dose of such drugs may have to be reduced when ranolazine is co-administered.

In vitro studies indicate that ranolazine is a P-gp substrate. Caution should be exercised when co-administering ranolazine and P-gp inhibitors such as ritonavir or cyclosporine.

Use In Patients With Congestive Heart Failure

No dosage adjustment for Ranexa is required in patients with CHF (NYHA Class I to IV) (see CLINICAL PHARMACOLOGY and Special Populations ).

Use In Patients With Diabetes Mellitus

No dosage adjustment is required in patients with diabetes (see CLINICAL PHARMACOLOGY and Special Populations ).

Use In Patients With Severe Renal Impairment

Ranexa increases blood pressure by about 15 mm Hg in patients with severe renal impairment. Blood pressure should be monitored regularly after initiation of Ranexa in such patients.

Laboratory Tests

Average elevations of serum creatinine by 0.1 mg/dL have been observed in angina patients treated with ranolazine. In patients with renal impairment, the percentage increase in creatinine from pretreatment values was of the same magnitude as in angina patients; BUN did not increase. These elevations have a rapid onset, show no signs of progression during long-term therapy, and are reversible after discontinuation of ranolazine. The results of a special renal function study in healthy volunteers receiving Ranexa 1000 mg b.i.d. showed that the glomerular filtration rate was not affected by ranolazine. The elevated creatinine levels are likely due to a blockage of creatinine?s tubular secretion by ranolazine or one of its metabolites. Urinalysis results are unaffected by ranolazine.

Transient eosinophilia was observed infrequently on ranolazine. Small mean decreases in hematocrit (1.2%) were also observed on ranolazine in controlled studies; however, there was no evidence of occult fecal blood loss.

Information For Patients

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 is only for patients not responding adequately to other antianginal drugs
• 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 proarrhythmic conditions such as hypokalemia
• that Ranexa should be avoided in patients receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone)
• that Ranexa should be avoided in patients receiving drugs that are potent or moderately potent inhibitors of CYP3A, including, for example, ketoconazole, HIV protease inhibitors, macrolide antibiotics, diltiazem, and verapamil
• that grapefruit juice or grapefruit products should be avoided when taking Ranexa
• that doses of Ranexa higher than 1000 mg twice a day should not be used
• that if a dose of Ranexa is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled
• that Ranexa will not abate an acute angina episode
• that Ranexa should generally be avoided in patients with mild, moderate or severe liver impairment
• that Ranexa should generally be avoided in patients with severe renal impairment
• to inform their physician of any other medications when taken concurrently with Ranexa, including over-the-counter medications
• to contact their physician if they experience palpitations or 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
• that Ranexa may be taken with or without meals
• that Ranexa tablets should be swallowed whole and not crushed, broken, or chewed

Drug-drug Interactions

(also see CLINICAL PHARMACOLOGY, Drug-Drug Interactions, and DOSAGE AND ADMINISTRATION )

Ketoconazole

As a potent inhibitor of CYP3A, ketoconazole (200 mg b.i.d.) increases average steady-state plasma concentrations of ranolazine 3.2-fold. Ranexa should not be used during treatment with ketoconazole (see CONTRAINDICATIONS ).

Diltiazem

As a moderate inhibitor of CYP3A, diltiazem (180 to 360 mg daily) causes dose-dependent mean increases in average ranolazine steady-state concentrations of about 1.8- to 2.3-fold.

Verapamil

Verapamil 120 mg t.i.d. increases ranolazine steady-state plasma concentrations about 2-fold.

Cimetidine

Co-administration of cimetidine does not increase the plasma concentrations of ranolazine. No dose adjustment of Ranexa is required in patients treated with cimetidine.

Digoxin

Co-administration of digoxin does not increase the plasma concentration of ranolazine. No dose adjustment of Ranexa is required in patients treated with digoxin.

Paroxetine

Paroxetine, a potent inhibitor of CYP2D6, increased average steady-state plasma concentrations of ranolazine 1.2-fold. No dose adjustment of Ranexa is required in patients treated with paroxetine or other CYP2D6 inhibitors.

Digoxin

As a result of an interaction at the P-gp level, co-administration of ranolazine and digoxin results in a 1.5-fold elevation of digoxin plasma concentrations. The dose of digoxin may have to be adjusted when ranolazine is co-administered with digoxin.

Simvastatin

Co-administration of ranolazine and simvastatin results in about a 2-fold increase in plasma concentrations of simvastatin, and its active metabolite.

Warfarin

Ranolazine has no significant effect on the pharmacokinetics of (+) R- and (-) S- warfarin.

Drug/Laboratory Test Interactions

Ranolazine is not known to interfere with any laboratory test.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ranolazine demonstrated no mutagenic 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 21 to 24 month studies 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 doses are equivalent to 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a mg/m2 basis and represent the maximum tolerated doses in these species (see WARNINGS, Tumor Promotion ).

There are no adequate studies assessing the effect of ranolazine on fertility or reproductive capacity.

Pregnancy

There are no adequate studies assessing the effect of ranolazine on the developing fetus.

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.

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, a decision should be made whether to discontinue nursing or to discontinue Ranexa, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the chronic angina patients treated with ranolazine 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 ranolazine, compared to placebo, appeared to have a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In controlled ranolazine studies, the placebo-subtracted incidence of any adverse event in patients ? 75 years old treated with ranolazine was 23%, and 11% discontinued ranolazine due to unacceptable adverse events. In CARISA and ERICA, the most commonly reported placebo-subtracted adverse events in patients ? 75 years old on ranolazine included constipation (19%), nausea (6%), and dizziness (6%). In general, dose selection for an elderly patient should be cautious, usually starting 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.

Ranexa Overdosage

No cases of intentional or accidental overdose with ranolazine have been reported. In the event of overdose, the expected symptoms would be dizziness, nausea/vomiting, diplopia, paresthesia, and confusion. Syncope with prolonged loss of consciousness may develop. Because the QTc interval increases with ranolazine plasma concentration, continuous ECG monitoring may be warranted in the event of overdose. If required, general supportive measures should be initiated.

Since ranolazine is about 62% bound to plasma proteins, complete clearance of ranolazine by hemodialysis is not likely.

Ranexa Information For Patients

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 is only for patients not responding adequately to other antianginal drugs
• 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 proarrhythmic conditions such as hypokalemia
• that Ranexa should be avoided in patients receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone)
• that Ranexa should be avoided in patients receiving drugs that are potent or moderately potent inhibitors of CYP3A, including, for example, ketoconazole, HIV protease inhibitors, macrolide antibiotics, diltiazem, and verapamil
• that grapefruit juice or grapefruit products should be avoided when taking Ranexa
• that doses of Ranexa higher than 1000 mg twice a day should not be used
• that if a dose of Ranexa is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled
• that Ranexa will not abate an acute angina episode
• that Ranexa should generally be avoided in patients with mild, moderate or severe liver impairment
• that Ranexa should generally be avoided in patients with severe renal impairment
• to inform their physician of any other medications when taken concurrently with Ranexa, including over-the-counter medications
• to contact their physician if they experience palpitations or 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
• that Ranexa may be taken with or without meals
• that Ranexa tablets should be swallowed whole and not crushed, broken, or chewed