FDA Label for Ranexa

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.

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 diltiazem, verapamil, and other moderate CYP3A inhibitors. Down-titrate Ranexa based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.

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 CVT500 on one side
• 1000 mg tablets are pale yellow, with CVT1000 on one side

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 clinically significant hepatic impairment [see Use in Specific Populations (8.6)]

5.1 Qt Interval Prolongation

Ranolazine blocks I_Kr 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, or potassium channel variants resulting in a long QT interval.

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 2.0% 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

Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting

General Disorders and Administrative Site Adverse Events – peripheral edema

Respiratory, Thoracic, and Mediastinal Disorders – dyspnea

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, blurred vision, confusional state, hematuria, 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.

7.1 Effects Of Other Drugs On Ranolazine

Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).

7.2 Effects Of Ranolazine On Other Drugs

In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. Ranolazine and its most abundant metabolites are not known to inhibit the metabolism of substrates for CYP 1A2, 2C8, 2C9, 2C19, or 2E1 in human liver microsomes, suggesting that ranolazine is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.

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 ranolazine, 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 clinically significant hepatic impairment. Plasma concentrations of ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment [see Contraindications (4)].

8.7 Use In Patients With Renal Impairment

In patients with varying degrees of renal impairment, ranolazine plasma levels increased up to 50%. 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.

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.

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 - ranexa 01

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 polysorbate 80 and FD&C Yellow No. 6 Lake; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow.

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 (I_Na). 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 I_Kr, which prolongs the ventricular action potential.

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 C_max 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, C_max and AUC_0–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.

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.

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.

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

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.

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).

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.

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 CVT500 on one side
• 1000 mg tablets are pale yellow, with CVT1000 on one side

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

	Strength	NDC
Unit-of-Use Bottle (60 Tablets)	500 mg	61958-1001-1
Unit-of-Use Bottle (60 Tablets)	1000 mg	61958-1002-1

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) or P-gp inhibitors (e.g., cyclosporine)
• that grapefruit juice or grapefruit products should be limited when taking Ranexa
• that Ranexa should generally not be used in patients with clinically significant liver impairment
• 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