May 30, 2016
Recommended Topic Related To:

Ranexa

"Having close biological relatives with heart disease can increase your risk of developing this disease. Family health history offers important information to help you and your family members understand health risks and prevent disease.

"...

A A A

Ranexa




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

QT Interval Prolongation

Ranolazine blocks IKr 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]. However, there is little experience with high doses ( > 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.

Renal Failure

Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking RANEXA. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue RANEXA and treat appropriately [see Use in Specific Populations].

Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Inform patients that RANEXA will not abate an acute angina episode.

Strong CY3PA Inhibitors, CYP3A Inducers, Liver Cirrhosis
  • Inform patients that RANEXA should not be used with drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir) [(see CONTRAINDICATIONS, DRUG INTERACTIONS].
  • Inform patients that RANEXA should not be used with drugs that are inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort) [(see CONTRAINDICATIONS, DRUG INTERACTIONS].
  • Inform patients that RANEXA should not be used in patients with liver cirrhosis [(see CONTRAINDICATIONS, Use in Specific Populations].
Moderate CYP3A Inhibitors, P-gp Inhibitors, Grapefruit Products
  • Advise patients to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) [see DRUG INTERACTIONS].
  • Advise patients to inform their physician if they are receiving drugs that are P-gp inhibitors (e.g., cyclosporine) [see DRUG INTERACTIONS].
  • Advise patients to limit grapefruit juice or grapefruit products when taking RANEXA [see DRUG INTERACTIONS].
QT Interval Prolongation
  • Inform patients that RANEXA may produce changes in the electrocardiogram (QTc interval prolongation) [see WARNINGS AND PRECAUTIONS].
  • Advise patients 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) [see WARNINGS AND PRECAUTIONS].
Use in Patients with Renal Impairment

Patients with severe renal impairment may be at risk of renal failure while on RANEXA. Advise patients to inform their physician if they have impaired renal function before or while taking RANEXA [see WARNINGS AND PRECAUTIONS].

Dizziness, Fainting
  • Inform patients that RANEXA may cause dizziness and lightheadedness. Patients should know how they react to RANEXA before they operate an automobile or machinery, or engage in activities requiring mental alertness or coordination [see ADVERSE REACTIONS].
  • Advise patients to contact their physician if they experience fainting spells while taking RANEXA.
Administration
  • Instruct patients to swallow RANEXA tablets whole, with or without meals, and not to crush, break, or chew tablets. Inform patients that if a dose is missed, to take the usual dose at the next scheduled time. The next dose should not be doubled. Inform patients that doses of RANEXA higher than 1000 mg twice daily should not be used [see DOSAGE AND ADMINISTRATION].
  • Advise patients to inform their physician of any other medications taken concurrently with RANEXA, including over-the-counter medications.

Nonclinical Toxicology

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 daily maximum recommended human dose (MRHD) of 2000 mg 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]. The clinical significance of this finding is unclear.

In male and female rats, oral administration of ranolazine that produced exposures (AUC) approximatelty 3-fold or 5-fold higher, respectively, than the MRHD had no effect on fertility.

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data on RANEXA use in pregnant women to inform any drug-associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures 4 times the maximum recommended human dose (MRHD) (see Data).

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Embryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine during organogenesis. In rats, decreased fetal weight and reduced ossification were observed at doses (corresponding to 4-fold the AUC for the MRHD) that caused maternal weight loss. No adverse fetal effects were observed in either species exposed (AUC) to ranolazine at exposures (AUC) equal to the MRHD.

Lactation

Risk Summary

There are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk [see Use In Specific Populations]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RANEXA and any potential adverse effects on the breastfed infant from RANEXA or from the underlying maternal condition.

Adult female rats were administered ranolazine orally from gestation day 6 through postnatal day 20. No adverse effects on pup development, behavior, or reproduction parameters were observed at a maternal dosage level of 60 mg/kg/day (equal to the MHRD based on AUC). At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via the maternal milk.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

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 RANEXA, 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.

Use In Patients With Hepatic Impairment

RANEXA is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [see CLINICAL PHARMACOLOGY].

Use In Patients With Renal Impairment

A pharmacokinetic study of RANEXA in subjects with severe renal impairment (CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving RANEXA 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation [see WARNINGS AND PRECAUTIONS]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue RANEXA if acute renal failure develops.

In a separate study, Cmax was increased between 40% and 50% in patients with mild, moderate, or severe renal impairment compared to patients with no renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.

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.

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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 1/10/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Heart Health

Get the latest treatment options.

Atrial Fibrillation Quiz