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Ranexa

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Ranexa

Ranexa

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.

Patient Counseling Information

See FDA-Approved Patient Labeling (PATIENT 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)
  • to inform their physician if they are receiving P-gp inhibitors (e.g., cyclosporine)
  • that grapefruit juice or grapefruit products should be limited when taking RANEXA
  • that RANEXA should not be used in patients with liver cirrhosis
  • 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

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 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]. The clinical significance of this finding is unclear.

Use In Specific Populations

Pregnancy

Pregnancy Category C

In animal studies, ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate [see Nonclinical Toxicology]. 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, decide whether to discontinue nursing or to discontinue RANEXA, taking into account the importance of the drug to the mother.

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

Compared to patients with no renal impairment, Cmax was increased between 40% and 50% in patients with mild, moderate or severe 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.

Last reviewed on RxList: 11/25/2013
This monograph has been modified to include the generic and brand name in many instances.

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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.


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