QT Prolongation

Ranolazine has been shown to prolong the QTc interval in a dose-related manner. While the clinical significance of the QTc prolongation in the case of ranolazine is unknown, other drugs with this potential have been associated with torsades de pointes-type arrhythmias and sudden death.

With repeat dosing, the mean effect on QTc of ranolazine 1000 mg b.i.d., at Tmax, is about 6 msec. However, in 5% of the population the prolongation of QTc is 15 msec. Age, weight, gender, race, heart rate, CHF NYHA Class I to IV, and diabetes have no significant effect on the relationship between ranolazine plasma level and increase in QTc. The relationship between ranolazine levels and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by 1000 mg b.i.d., and is not affected by changes in heart rate. Doses > 1000 mg b.i.d. should not be used.

There are no studies examining the effects of ranolazine in patients with pre-existing QT prolongation or receiving other QT-prolonging drugs. Because of possible additive effects on the QT interval, ranolazine should be avoided in patients with known QT prolongation (including congenital long QT syndrome, uncorrected hypokalemia), known history of ventricular tachycardia and in patients receiving drugs that prolong the QTc interval, such as Class Ia (e.g., quinidine) and Class III (e.g., dofetilide, sotalol) antiarrhythmics, and antipsychotics (e.g., thioridazine, ziprasidone).

Because the QTc-prolonging effect is increased approximately 3-fold in patients with hepatic dysfunction, ranolazine is contraindicated in patients with mild, moderate or severe liver disease (see Special Populations and Hepatic Insufficiency).

Ranolazine is primarily metabolized by CYP3A. Use of ranolazine with potent or moderately potent inhibitors of CYP3A should be avoided because concomitant administration will increase ranolazine plasma levels and QTc prolongation. These inhibitors include ketoconazole and other azole antifungals, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice or grapefruit-containing products.

Tumor Promotion

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 (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility).

Co-administration of ranolazine and digoxin increases the plasma concentrations of digoxin by approximately 1.5-fold and the dose of digoxin may have to be reduced accordingly. The dose of other P-gp substrates may have to be reduced as well when ranolazine is co-administered.

Ranolazine can inhibit the activity of CYP2D6 and thus the metabolism of drugs that are mainly metabolized by this enzyme (e.g., tricyclic antidepressants and some antipsychotics) may be impaired and exposure to these drugs increased. The dose of such drugs may have to be reduced when ranolazine is co-administered.

In vitro studies indicate that ranolazine is a P-gp substrate. Caution should be exercised when co-administering ranolazine and P-gp inhibitors such as ritonavir or cyclosporine.

Ranolazine is primarily metabolized by CYP3A and is a substrate of P-gp. Co-administration of Ranexa and an inducer of CYP3A metabolism and P-gp (e.g., rifampin and structurally related rifabutin and rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort) should be avoided (see Drug-DRUG INTERACTIONS).

Use in Patients with Congestive Heart Failure

No dosage adjustment for Ranexa is required in patients with CHF (NYHA Class I to IV) (see CLINICAL PHARMACOLOGY and Special Populations).

Use in Patients with Diabetes Mellitus

No dosage adjustment is required in patients with diabetes (see CLINICAL PHARMACOLOGY and Special Populations).

Use in Patients with Severe Renal Impairment

Ranexa increases blood pressure by about 15 mm Hg in patients with severe renal impairment. Blood pressure should be monitored regularly after initiation of Ranexa in such patients.

Laboratory Tests

Average elevations of serum creatinine by 0.1 mg/dL have been observed in angina patients treated with ranolazine. In patients with renal impairment, the percentage increase in creatinine from pretreatment values was of the same magnitude as in angina patients; BUN did not increase. These elevations have a rapid onset, show no signs of progression during long-term therapy, and are reversible after discontinuation of ranolazine. The results of a special renal function study in healthy volunteers receiving Ranexa 1000 mg b.i.d. showed that the glomerular filtration rate was not affected by ranolazine. The elevated creatinine levels are likely due to a blockage of creatinine's tubular secretion by ranolazine or one of its metabolites. Urinalysis results are unaffected by ranolazine.

Transient eosinophilia was observed infrequently on ranolazine. Small mean decreases in hematocrit (1.2%) were also observed on ranolazine in controlled studies; however, there was no evidence of occult fecal blood loss.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ranolazine demonstrated no mutagenic 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 21 to 24 month studies 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 doses are equivalent to 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a mg/m² basis and represent the maximum tolerated doses in these species (see WARNINGS, Tumor Promotion).

There are no adequate studies assessing the effect of ranolazine on fertility or reproductive capacity.

Pregnancy - Pregnancy Category C

There are no adequate studies assessing the effect of ranolazine on the developing fetus.

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, a decision should be made whether to discontinue nursing or to discontinue Ranexa, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the chronic angina patients treated with ranolazine 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, appeared to have a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In controlled ranolazine studies, the placebo- subtracted incidence of any adverse event in patients ≥ 75 years old treated with ranolazine was 23%, and 11% discontinued ranolazine due to unacceptable adverse events. In CARISA and ERICA, the most commonly reported placebo-subtracted adverse events in patients ≥ 75 years old on ranolazine included constipation (19%), nausea (6%), and dizziness (6%). In general, dose selection for an elderly patient should be cautious, usually starting 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.

REFERENCES

1. M.A. Suckow et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(min/+) mice. Cancer Letters 209(2004):165–169.

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