Strong CYP3A Inhibitors
Concomitant use of ASPRUZYO Sprinkle with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)].
Moderate CYP3A Inhibitors
Limit the dose of ASPRUZYO Sprinkle to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Concomitant use of ASPRUZYO Sprinkle and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate ASPRUZYO Sprinkle based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2)].
Concomitant use of ASPRUZYO Sprinkle with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)].
An in-vitro dissolution study was conducted to evaluate the impact of alcohol on extended-release characteristics of ASPRUZYO Sprinkle. The in-vitro study showed that alcohol causes a rapid release of ranolazine from ASPRUZYO Sprinkle that may increase the risk of adverse events associated with ASPRUZYO Sprinkle. Patients should not consume alcohol when taking ASPRUZYO Sprinkle [see Clinical Pharmacology (12.3)].
Drugs Metabolized by CYP3A
Limit the dose of simvastatin in patients on any dose of ASPRUZYO Sprinkle to 20 mg once daily, when ASPRUZYO Sprinkle 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 ASPRUZYO Sprinkle may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].
Drugs Transported by P-gp
Concomitant use of ASPRUZYO Sprinkle and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3)].
Drugs Metabolized by CYP2D6
The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with ASPRUZYO Sprinkle, and lower doses of these drugs may be required.
Drugs Transported by OCT2
In subjects with type 2 diabetes mellitus, concomitant use of ASPRUZYO Sprinkle 1000 mg twice daily and metformin results in increased plasma levels of metformin. When ASPRUZYO Sprinkle 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 ranolazine 500 mg twice daily [see Clinical Pharmacology (12.3)].
There are no available data on ranolazine 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 to 4% and 15 to 20%, respectively.
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.
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 (8.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ranolazine and any potential adverse effects on the breastfed infant from ranolazine 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.
Safety and effectiveness have not been established in pediatric patients.
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.
ASPRUZYO Sprinkle 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 200% increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [see Clinical Pharmacology (12.2)].
A pharmacokinetic study of ranolazine in subjects with severe renal impairment (CrCL< 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine 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 [s ee Warnings and Precautions (5.2)]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue ASPRUZYO Sprinkle 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.
Hypotension, QT prolongation, bradycardia, myoclonic activity, severe tremor, unsteady gait/incoordination, dizziness, nausea, vomiting, dysphasia, and hallucinations have been seen in cases of oral overdose of ranolazine. In cases of extreme overdose of ranolazine fatal outcomes have been reported. In clinical studies, high intravenous exposure resulted in diplopia, paresthesia, confusion, and syncope.
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.
ASPRUZYO Sprinkle contains ranolazine, an antianginal available as white to off-white coated extended-release granules filled in a sachet for oral administration.
Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N ‑(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-(±)-. It has a molecular formula of C24 H33 N3 O4 , a molecular weight of 427.54 g/mole, and the following structural formula:
Ranolazine is off-white to white powder. Ranolazine is soluble in dichloromethane and methanol.
ASPRUZYO Sprinkle contains 500 mg or 1000 mg of ranolazine and the following inactive ingredients: amino methacrylate copolymer, dibutyl sebacate, ethyl cellulose, hypromellose, magnesium stearate, methacrylic acid and ethyl acrylate copolymer, microcrystalline cellulose, and talc.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.