Ranolazine

Do not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of ranolazine 3.2-fold

Ranolazine is a substrate and an inhibitor of the p-glycoprotein transport system; potential pharmacokinetic interactions with p-glycoprotein inhibitors (increased absorption of ranolazine). When ranolazine is co-administered with other substrates, dosage of such drugs may have to be reduced.

Potential pharmacodynamic interaction (possible additive effects on QT interval). Ranolazine should be avoided in patients receiving drugs that are known to prolong the QT interval (eg, class Ia (eg, quinidine) or III (eg, dofetilide, sotalol) antiarrhythmic agents, antipsychotic agents (eg, thioridazine, ziprasidone)).

Potential pharmacokinetic interaction (increased plasma ranolazine concentrations). Ranolazine should not be used with ketoconazole (a potent CYP3A inhibitor) or itraconazole.

For more Interactions (Complete) data for Ranolazine (17 total), please visit the HSDB record page.

In large preregistration clinical trials, ranolazine was not associated with serum aminotransferase and alkaline phosphatase elevations during treatment and no instances of symptomatic acute liver injury were reported. Since its approval and more wide spread use, ranolazine has been linked to a single instance of mildly symptomatic, rapidly reversible, anicteric liver injury (Case 1). Immunoallergic and autoimmune features were not present. Recovery was rapid once ranolazine was discontinued.

The most commonly reported adverse events include dizziness, headaches, nausea, confusion, tinnitus, vertigo, blurred vision, dyspnea, palpitations, abdominal pain, dry mouth, vomiting, anorexia, dyspepsia, peripheral edema, and constipation. More severe adverse effects include QT prolongation, syncope, hematuria, bradycardia, hypotension, orthostatic hypotension, thrombocytopenia, leukopenia, angioedema, renal failure, eosinophilia, pulmonary fibrosis, and pancytopenia. Although rare, isolated cases of ranolazine-induced myopathy have been reported; prognosis is generally favorable following discontinuation of the drug.

/SIGNS AND SYMPTOMS/ High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope.

/CASE REPORTS/ A 77-year-old white man with chronic renal insufficiency was evaluated for moderate dyspnea on exertion (DOE). Cardiac and pulmonary workup revealed nonobstructive coronary artery disease and mild obstructive lung disease. The patient had been taking ranolazine 500 mg daily for possible angina for the past 2 months. Given the temporal association of his symptoms with drug initiation, ranolazine was discontinued during the hospitalization. One month after discontinuing ranolazine, the patient's DOE had completely resolved; the only intervention had been discontinuation of ranolazine. The patient's Naranjo algorithm score was 3, indicating a possible adverse drug reaction. ... Ranolazine may be associated with DOE in this elderly man.

/OTHER TOXICITY INFORMATION/ Ranolazine was shown to improve exercise parameters in patients with chronic angina. It works by switching myocardial energy metabolism from fatty acids to glucose, thus increasing the efficiency of ATP production under hypoxic conditions. Tumors are hypoxic and may also respond to ranolazine. ... These findings have implications for the use of ranolazine in patients with a history of malignant neoplasms or adenomatous polyps.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ranolazine

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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/sq m/day) and 50 mg/kg/day for 24 months in mice (150 mg/sq m/day).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... Ranolazine caused a dose-dependent increase in tumor number in APC(Min/+) mice, a model of spontaneous intestinal tumorigenesis. Tumors from drug-treated mice were also more dysplastic and invasive than those from untreated mice. ...

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Ranolazine has been reported to promote tumor formation and progression to malignancy in a study of mice with a heterozygous, dominant mutation in the tumor suppressor gene adenomatous polyposis coli (APC); the manufacturer states that the clinical importance of these results have not been established.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). These doses in rats were associated with an increased maternal mortality rate.

For more Non-Human Toxicity Excerpts (Complete) data for Ranolazine (6 total), please visit the HSDB record page.

In patients with varying degrees of renal impairment, ranolazine plasma levels increased up to 50%. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.

Ranolazine is contraindicated in patients with clinically significant hepatic impairment. Plasma concentrations of ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment.

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, 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.

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.

In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ranolazine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Use (kg; approx.) in Germany (2009): >750