ASPRUZYO SPRINKLE

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 C 24 H 33 N 3 O 4 , 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. structural-formula

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. ASPRUZYO Sprinkle is an antianginal indicated for the treatment of chronic angina. (1)

500 mg orally twice daily and increase to 1000 mg orally twice daily, based on clinical symptoms (2.1) 2.1 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. Gently shake the syringe for approximately 15 seconds. Promptly deliver through a 12 French or larger G-tube. Rinse with 20 mL of water in the syringe. Ensure no granules are left in the syringe. Rinse with additional water (about 15 mL) if needed. 2.2 Dose Modification Dose adjustments may be needed when ASPRUZYO Sprinkle is taken in combination with other drugs [see Drug Interactions (7.1)]. 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 [see Contraindications (4), Drug Interactions (7.1)].

ASPRUZYO Sprinkle is contraindicated in patients: Taking strong inhibitors of CYP3A [see Drug Interactions (7.1)] Taking inducers of CYP3A [see Drug Interactions (7.1)] With liver cirrhosis [see Use in Specific Populations (8.6)] Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4, 7.1) CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) (4, 7.1) Liver cirrhosis (4, 8.6)

Most common adverse reactions (> 4% and more common than with placebo) are dizziness, headache, constipation, nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. In addition, upon study completion, 1251 patients received treatment with ranolazine in open-label, long-term studies; 1227 patients were exposed to ranolazine for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years. 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. The most common adverse events that led to discontinuation more frequently on ranolazine than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported treatment‑emergent adverse reactions (> 4% and more common on ranolazine than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). 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 [see Clinical Studies (14.2)]. 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 [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)]. 6.2 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

Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit ASPRUZYO Sprinkle to 500 mg twice daily. (7.1) P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate ASPRUZYO Sprinkle based on clinical response. (7.1) CYP3A substrates: Limit simvastatin to 20 mg when used with ASPRUZYO Sprinkle. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with ASPRUZYO Sprinkle. (7.2) OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with ASPRUZYO Sprinkle 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses. (7.2) Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with ASPRUZYO Sprinkle. (7.2) 7.1 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 [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)]. 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 [see Dosage and Administration (2.2)]. 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 [see Contraindications (4), Clinical Pharmacology (12.3)]. 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 [see Clinical Pharmacology (12.3)] . 7.2 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 [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)].