Aspruzyo Sprinkle Drug Information

ASPRUZYO Sprinkle is indicated for the treatment of chronic angina. ASPRUZYO Sprinkle may be used with beta-blockers, nitrates, calcium channel blockers, anti‑platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

Dosing Information Initiate ASPRUZYO

Sprinkle dosing at 500 mg orally twice daily and increase to 1000 mg orally twice daily, as needed, based on clinical symptoms. The maximum recommended daily dose of ASPRUZYO Sprinkle is 1000 mg twice daily. If a dose of ASPRUZYO Sprinkle is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

Directions for use with soft food (e.g., applesauce and yogurt) Sprinkle granules on one tablespoonful of soft food and consume immediately. Do not crush or chew the granules. Direction for nasogastric and gastric tube administration Nasogastric (NG) tube: Add the content of a sachet to a plastic catheter tip syringe and add 50 mL of water.

Gently shake the syringe for approximately 15 seconds. Promptly deliver through a 12 French or larger NG tube. Ensure no granules are left in the syringe.

Rinse with additional water (about 15 mL) if needed. Gastrostomy/Gastric (G) tube: Add the content of a sachet to a plastic catheter tip syringe and add 30 mL of water. Rinse with 20 mL of water in the syringe.

Dose Modification

Dose adjustments may be needed when ASPRUZYO Sprinkle is taken in combination with other drugs. Limit the maximum dose of ASPRUZYO Sprinkle to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of ASPRUZYO Sprinkle with strong CYP3A inhibitors and CYP3A inducers is contraindicated.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with ranolazine, 1026 were enrolled in three double‑blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration.

At recommended doses, about 6% of patients discontinued treatment with ranolazine because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. Doses above 1000 mg twice daily are poorly tolerated. Dizziness may be dose-related.

In open-label, long-term treatment studies, a similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with ranolazine and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders- bradycardia, palpitations Ear and Labyrinth Disorders- tinnitus, vertigo Eye Disorders- blurred vision Gastrointestinal Disorders- abdominal pain, dry mouth, vomiting, dyspepsia General Disorders and Administrative Site Adverse Events- asthenia, peripheral edema Metabolism and Nutrition Disorders- anorexia Nervous System Disorders- syncope (vasovagal) Psychiatric Disorders- confusional state Renal and Urinary Disorders- hematuria Respiratory, Thoracic, and Mediastinal Disorders- dyspnea Skin and Subcutaneous Tissue Disorders- hyperhidrosis Vascular Disorders- hypotension, orthostatic hypotension Other (< 0.5%) but potentially medically important adverse reactions observed more frequently with ranolazine than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia. A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for ranolazine, but there was no apparent proarrhythmic effect in these high-risk patients.

Laboratory Abnormalities: Ranolazine produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine's tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of ranolazine, and is not accompanied by changes in BUN. In healthy volunteers, ranolazine 1000 mg twice daily had no effect upon the glomerular filtration rate.

More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of ranolazine in patients with severe renal impairment.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of ranolazine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Nervous System Disorders - Abnormal coordination, myoclonus, paresthesia, tremor, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking ranolazine. The onset of events was often associated with an increase in ranolazine dose or exposure.

Many patients reported symptom resolution following drug discontinuation or dose decrease. Metabolism and Nutrition Disorders - Cases of hypoglycemia have been reported in diabetic patients on antidiabetic medication. Psychiatric Disorders - hallucination Renal and Urinary Disorders - dysuria, urinary retention Skin and Subcutaneous Tissue Disorders - angioedema, pruritus, rash

Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors

Concomitant use of ASPRUZYO Sprinkle with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir is contraindicated. 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. P-gp Inhibitors 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. CYP3A Inducers Concomitant use of ASPRUZYO Sprinkle with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort is contraindicated.

Alcohol 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.

Effects of Ranolazine on Other Drugs 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. 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. 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.

Pregnancy Risk Summary 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 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.

Pediatric Use Safety and effectiveness have not been established in pediatric patients.

ASPRUZYO Sprinkle is contraindicated in patients: Taking strong inhibitors of CYP3A Taking inducers of CYP3A With liver cirrhosis Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) Liver cirrhosis

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.