Ranexa 375 mg

Excipients/Inactive Ingredients: Each tablet contains 0.04 mg azo colouring agent E102 and 12.0 mg lactose monohydrate.

Excipients for All Ranexa 375 mg Prolonged-Release Tablets: Carnauba wax, hypromellose, magnesium stearate, methacrylic acid-ethyl acrylate copolymer (1:1), microcrystalline cellulose, sodium hydroxide, titanium dioxide.

Additional Excipients for 375 mg Tablet: Macrogol, polysorbate 80, blue #2/indigo carmine Aluminium Lake (E132).

Additional Excipients for 500 mg Tablet: Macrogol, polyvinyl alcohol-part hydrolyzed, iron oxide yellow (E172), iron oxide red (E172), talc.

Additional Excipients for 750 mg Tablet: Glycerol triacetate, lactose monohydrate, blue #1/brilliant blue FCF Aluminum Lake (E133) and yellow #5/tartrazine, Aluminum Lake (E102) 0.04 mg, lactose monohydrate 12 mg.

Ranexa 375 mg is an anti-anginal medication. It works by improving blood flow to help the heart work more efficiently.

Ranexa 375 mg is used to treat chronic angina (chronic chest pain). It may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

Ranexa 375 mg is an anti-anginal medication. It works by improving blood flow to help the heart work more efficiently.

Ranexa 375 mg is used to treat chronic angina (chest pain). Ranexa 375 mg is not for use during an acute (emergency) attack of angina.

Ranexa 375 mg may also be used for purposes not listed in this medication guide.

Dosing Information

Initiate Ranexa 375 mg dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranexa 375 mg with or without meals. Swallow Ranexa 375 mg tablets whole; do not crush, break, or chew.

The maximum recommended daily dose of Ranexa 375 mg is 1000 mg twice daily.

If a dose of Ranexa 375 mg is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

Dose Modification

Dose adjustments may be needed when Ranexa 375 mg is taken in combination with certain other drugs. Limit the maximum dose of Ranexa 375 mg to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of Ranexa 375 mg with strong CYP3A inhibitors is contraindicated. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranexa 375 mg. Titrate Ranexa 375 mg based on clinical response.

How supplied

Dosage Forms And Strengths

Ranexa 375 mg 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
• 1000 mg tablets are pale yellow, with GSI1000 on one side

Storage And Handling

Ranexa 375 mg 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
• 1000 mg tablets are pale yellow, with GSI1000 on one side

Ranexa 375 mg (Ranexa 375 mg) extended-release tablets are available in:

Store Ranexa 375 mg tablets at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F).

Manufactured for: Gilead Sciences, Inc., Foster City, CA 94404. Revised: December 2015

See also:
What is the most important information I should know about Ranexa 375 mg?

You should not take Ranexa 375 mg if you have cirrhosis of the liver. There are many other drugs that should not be used together with Ranexa 375 mg. Tell your doctor about all other medicines you use.

Ranexa 375 mg is not for use during an acute (emergency) attack of angina. Continue using any other medicines prescribed by your doctor (such as nitroglycerin) to treat acute angina.

Before you take Ranexa 375 mg, tell your doctor about all of your medical conditions, especially if you have a personal or family history of Long QT syndrome.

Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.

Chronic angina is often treated with a combination of different drugs. To best treat your condition, use all of your medications as directed by your doctor. Do not change your doses or medication schedule without advice from your doctor.

Use Ranexa 375 mg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Ranexa 375 mg by mouth with or without food.
• Swallow Ranexa 375 mg whole. Do not break, crush, or chew before swallowing.
• Check with your doctor before you eat grapefruit or drink grapefruit juice while you are taking Ranexa 375 mg.
• If you miss a dose of Ranexa 375 mg, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Ranexa 375 mg.

Use: Labeled Indications

Chronic angina: Treatment of chronic angina

Note: According to the 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guidelines for patients with stable ischemic heart disease, Ranexa 375 mg may be useful when prescribed as a substitute for beta blockers for relief of symptoms if initial treatment with beta blockers leads to unacceptable side effects, is less effective, or if initial treatment with beta-blockers is contraindicated. May also be used in combination with beta-blockers, for relief of symptoms when initial treatment with beta-blockers is not successful (Fihn 2012).

Off Label Uses

Ventricular tachycardia

Data from small prospective studies and retrospective analysis suggest that Ranexa 375 mg may be beneficial for suppression of ventricular tachycardia. Additional data may be necessary to further define the role of Ranexa 375 mg in this condition.

Based on the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, Ranexa 375 mg is effective at suppressing ventricular tachycardia.

See also:
What other drugs will affect Ranexa 375 mg?

Effects of Other Medicinal Products on Ranexa 375 mg: CYP3A4 or P-gp Inhibitors: Ranexa 375 mg is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4 increase plasma concentrations of Ranexa 375 mg. The potential for dose-related adverse events (eg, nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment with ketoconazole 200 mg twice daily increased the AUC of Ranexa 375 mg by 3- to 3.9-fold during Ranexa 375 mg treatment. Combining Ranexa 375 mg with potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a potent CYP3A4 inhibitor.

Diltiazem (180-360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent increases in average Ranexa 375 mg steady state concentrations of 1.5- to 2.4-fold. Careful dose titration of Ranexa 375 mg is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (eg, erythromycin, fluconazole). Down-titration of Ranexa 375 mg may be required.

Ranexa 375 mg is a substrate for P-gp. Inhibitors of P-gp (eg, cyclosporin, verapamil) increase plasma levels of Ranexa 375 mg. Verapamil (120 mg 3 times daily) increases Ranexa 375 mg steady state concentrations 2.2-fold. Careful dose titration of Ranexa 375 mg is recommended in patients treated with P-gp inhibitors. Down-titration of Ranexa 375 mg may be required.

CYP3A4 Inducers: Rifampicin (600 mg once daily) decreases Ranexa 375 mg steady-state concentrations by approximately 95%. Initiation of treatment with Ranexa 375 mg should be avoided during administration of inducers of CYP3A4 (eg, rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort).

CYP2D6 Inhibitors: Ranexa 375 mg is partially metabolized by CYP2D6; therefore, inhibitors of this enzyme may increase plasma concentrations of Ranexa 375 mg. The potent CYP2D6 inhibitor paroxetine, at a dose of 20 mg once daily, increased steady state plasma concentrations of Ranexa 375 mg 1,000 mg twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in Ranexa 375 mg AUC of about 62%.

Effects of Ranexa 375 mg on Other Medicinal Products: Ranexa 375 mg is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are transported by P-gp may be increased.

Dose adjustment of sensitive CYP3A4 substrates (eg, simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporin, tacrolimus, sirolimus, everolimus) may be required as Ranexa 375 mg may increase plasma concentrations of these drugs.

Available data suggest that Ranexa 375 mg is a mild inhibitor of CYP2D6. Ranexa 375 mg 750 mg twice daily increased plasma concentrations of metoprolol by 1.8-fold. Therefore, the exposure to metoprolol or other CYP2D6 substrates (eg, propafenone and flecainide or to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during co-administration with Ranexa 375 mg, and lower doses of these medicinal products may be required.

The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during co-administration with CYP2B6 substrates (eg, bupropion, efavirenz, cyclophosphamide).

Digoxin: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported when Ranexa 375 mg and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranexa 375 mg therapy.

Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa 375 mg 1,000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2-fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranexa 375 mg and simvastatin, in post-marketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranexa 375 mg.

Atorvastatin: Ranexa 375 mg 1,000 mg twice daily increased C_max and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3-fold, respectively and changed the C_max and AUC of atorvastatin metabolites <35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking Ranexa 375 mg.

Dose limitation of other statins, metabolized by CYP3A4 (eg, lovastatin), may be considered when taking Ranexa 375 mg.

Tacrolimus, Cyclosporin, Sirolimus, Everolimus: Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients after Ranexa 375 mg administration. It is recommended that tacrolimus blood levels are monitored when co-administering Ranexa 375 mg and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporin, sirolimus, everolimus).

Drugs Transported by the Organic Cation Transporter-2 (OCT2): Plasma exposure of metformin (1,000 mg twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with Ranexa 375 mg 500 mg and 1,000 mg twice daily, respectively. The exposure of other OCT2 substrates, including but not limited to pindolol and varenicline, may be affected to a similar degree.

There is a theoretical risk that concomitant treatment of Ranexa 375 mg with other drugs known to prolong the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (eg, terfenadine, astemizole, mizolastine), certain antiarrhythmics (eg, quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants (eg, imipramine, doxepin, amitriptyline).

See also:
What are the possible side effects of Ranexa 375 mg?

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 2018 patients with chronic angina were treated with Ranexa 375 mg in controlled clinical trials. Of the patients treated with Ranexa 375 mg, 1026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration. In addition, upon study completion, 1251 patients received treatment with Ranexa 375 mg in open-label, long-term studies; 1227 patients were exposed to Ranexa 375 mg 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 375 mg 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 375 mg 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 375 mg 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 4.0% in patients treated with Ranexa 375 mg and were more frequent than the incidence observed in placebo-treated patients:

Cardiac Disorders – bradycardia, palpitations

Ear and Labyrinth Disorders – tinnitus, vertigo

Eye Disorders – blurred vision

Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia

General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema

Metabolism and Nutrition Disorders – anorexia

Nervous System Disorders – syncope (vasovagal)

Psychiatric Disorders – confusional state

Renal and Urinary Disorders – hematuria

Respiratory, Thoracic, and Mediastinal Disorders – dyspnea

Skin and Subcutaneous Tissue Disorders – hyperhidrosis

Vascular Disorders – hypotension, orthostatic hypotension

Other ( < 0.5%) but potentially medically important adverse reactions observed more frequently with Ranexa 375 mg than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, 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 375 mg, but there was no apparent proarrhythmic effect in these high-risk patients.

Laboratory Abnormalities

Ranexa 375 mg produces small reductions in hemoglobin A1c. Ranexa 375 mg is not a treatment for diabetes.

Ranexa 375 mg produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine's tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of Ranexa 375 mg, and is not accompanied by changes in BUN. In healthy volunteers, Ranexa 375 mg 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of Ranexa 375 mg in patients with severe renal impairment.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Ranexa 375 mg. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Nervous System Disorders – Tremor, paresthesia, abnormal coordination, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking Ranexa 375 mg. The onset of events was often associated with an increase in Ranexa 375 mg dose or exposure. Many patients reported symptom resolution following drug discontinuation or dose decrease.

Psychiatric Disorders – hallucination

Renal and Urinary Disorders – dysuria, urinary retention

Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash