"By Megan Brooks
Medscape Medical News
The US Food and Drug Administration (FDA) will require makers of prescription testosterone products to clarify the approved uses of these medications on the product label and add information"...
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, placebocontrolled, 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 doserelated. 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 and were more frequent than the incidence observed in placebo-treated patients:
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 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, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies].
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.
The following adverse reactions have been identified during postapproval use of RANEXA. 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 ranolazine. The onset of events was often associated with an increase in ranolazine 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
Read the Ranexa (ranolazine) Side Effects Center for a complete guide to possible side effects
Effects of Other Drugs on Ranolazine
Strong CYP3A Inhibitors
Do not use RANEXA with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].
Moderate CYP3A Inhibitors
Limit the dose of RANEXA to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruitcontaining products [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Concomitant use of RANEXA and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate RANEXA based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see DOSAGE AND ADMINISTRATION].
Effects of Ranolazine on Other Drugs
Drugs Metabolized by CYP3A
Limit the dose of simvastatin in patients on any dose of RANEXA to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as RANEXA may increase plasma concentrations of these drugs [see CLINICAL PHARMACOLOGY].
Drugs Transported by P-gp
Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see CLINICAL PHARMACOLOGY].
Drugs Metabolized by CYP2D6
The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with RANEXA, and lower doses of these drugs may be required.
Drugs Transported by OCT2
In subjects with type 2 diabetes mellitus, concomitant use of RANEXA 1000 mg twice daily and metformin results in increased plasma levels of metformin. When RANEXA 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with RANEXA 500 mg twice daily [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 11/25/2013
Additional Ranexa Information
Report Problems to the Food and Drug Administration
Get the latest treatment options.