ASPRUZYO SPRINKLE

ASPRUZYO SPRINKLE- ranolazine granule
SUN PHARMACEUTICAL INDUSTRIES, INC.

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

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)

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Sprinkle granules on one tablespoonful of soft food and consume immediately.

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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)].

3 DOSAGE FORMS AND STRENGTHS

ASPRUZYO Sprinkle (ranolazine) is supplied as unit-dose sachets containing 500 or 1000 mg of white to off-white, coated, extended-release granules.

4 CONTRAINDICATIONS

ASPRUZYO Sprinkle is contraindicated in patients:

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Taking strong inhibitors of CYP3A [see Drug Interactions (7.1)]

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Taking inducers of CYP3A [see Drug Interactions (7.1)]

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With liver cirrhosis [see Use in Specific Populations (8.6)]

5 WARNINGS AND PRECAUTIONS

5.1 QT Interval Prolongation

Ranolazine blocks I_Kr and prolongs the QT_c interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death [see Clinical Studies (14.2)]. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT‑prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.

5.2 Renal Failure

Acute renal failure has been observed in patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking ranolazine. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue ASPRUZYO Sprinkle and treat appropriately [see Use in Specific Populations (8.7)].

Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.

6 ADVERSE REACTIONS

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