Nilotinib Capsules — Package Insert

Drug Name: Nilotinib Capsules

Trade Names: Tasigna, Ninlib

English Name: Nilotinib Capsules

Specification: 200 mg × 30 capsules/box

Manufacturer: Hetero Healthcare Limited

Drug Class: Antineoplastic Agent; BCR-ABL Kinase Inhibitor

I. Composition

The active ingredient is nilotinib.

II. Description

Capsules; the contents consist of a white to yellow powder.

III. Indications

1. Newly diagnosed adult and pediatric patients (aged 1 year and older) with Philadelphia chromosome-positive (Ph+) Chronic Myeloid Leukemia (CML) in the chronic phase.

2. Adult patients with Ph+ CML in the chronic or accelerated phase who are resistant to or intolerant of prior therapy (including imatinib).

3. Pediatric patients (aged 1 year and older) with Ph+ CML in the chronic or accelerated phase who are resistant to or intolerant of prior tyrosine kinase inhibitor (TKI) therapy.

V. Dosage and Administration

(I) Adult Dosage

1. Newly diagnosed Ph+ CML (Chronic Phase): 300 mg orally, twice daily, approximately 12 hours apart.

2. Resistant/Intolerant Ph+ CML (Chronic or Accelerated Phase): 400 mg orally, twice daily, approximately 12 hours apart.

(II) Pediatric Dosage (Ages 1 year and older)

Newly diagnosed or resistant/intolerant Ph+ CML (Chronic or Accelerated Phase): 230 mg/m² orally, twice daily. The dose should be rounded to the nearest 50 mg, with a maximum single dose not exceeding 400 mg.

(III) Administration Method

1. Take on an empty stomach: Do not consume food for at least 2 hours before taking the medication and for at least 1 hour after taking it.

2. The capsules must be swallowed whole; they should not be chewed, sucked on, or opened. For patients unable to swallow the capsules whole, the contents may be mixed with 1 teaspoon of applesauce and taken immediately (within 15 minutes); the mixture must not be stored for later use. 3. Missed Dose: Do not take a missed dose; resume the regular dosing schedule with the next scheduled dose.

4. Duration of Therapy: Treatment should be continued as long as the patient continues to derive clinical benefit.

(IV) Dosage Adjustments for Specific Populations

1. Hepatic Impairment: For mild to moderate hepatic impairment, the starting dose is 300 mg twice daily; for severe hepatic impairment, the starting dose is 200 mg twice daily, with subsequent adjustments based on tolerability.

2. Concomitant Use with Strong CYP3A4 Inhibitors: Concomitant use should be avoided. If unavoidable, reduce the dose to 200 mg once daily for newly diagnosed patients, and to 300 mg once daily for patients with resistance or intolerance. Upon discontinuation of the inhibitor, resume the original dose and monitor the QT interval closely.

3. Renal Impairment: No dosage adjustment is required.

4. Elderly Patients (≥65 years): No dosage adjustment is required.

VI. Adverse Reactions

(I) Common Adverse Reactions (≥10%)

Hematologic: Thrombocytopenia, neutropenia, anemia, eosinophilia, pancytopenia.

Non-hematologic: Rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, myalgia, arthralgia, pyrexia, night sweats, cough, nasopharyngitis.

(II) Important Adverse Reactions

1. QT Interval Prolongation: May lead to Torsades de Pointes, and in severe cases, sudden death.

2. Myelosuppression: Grade 3/4 thrombocytopenia, neutropenia, and anemia; these are more frequently observed during the accelerated phase.

3. Cardiovascular Events: Hypertension, angina pectoris, arrhythmia, peripheral arterial occlusive disease, ischemic heart disease/cerebrovascular events.

4. Hepatic Function Abnormalities: Elevated bilirubin, ALT/AST, and alkaline phosphatase levels.

5. Electrolyte Disturbances: Hypophosphatemia, hypokalemia, hypomagnesemia, hypocalcemia, hyperkalemia, etc.

6. Elevated Serum Lipase: May precipitate pancreatitis.

VII. Contraindications

1. Hypersensitivity to nilotinib or to any of the excipients. 2. Patients with hypokalemia or hypomagnesemia.

3. Patients with Long QT Syndrome.

VIII. Precautions

(I) Cardiac Monitoring

Perform electrocardiograms (ECGs) prior to treatment, 7 days after initiating treatment, following any dose adjustments, and periodically thereafter to monitor the QTc interval.

Monitor electrolytes (potassium, magnesium, calcium, and phosphorus) prior to and periodically during treatment; promptly correct any electrolyte abnormalities.

Avoid concomitant use with medications known to prolong the QT interval or with strong CYP3A4 inhibitors.

(II) Hematologic Monitoring

Perform a complete blood count (CBC) every 2 weeks during the first 2 months of treatment, and monthly thereafter, or as clinically indicated.

Myelosuppression is reversible and can be managed by temporarily interrupting treatment or reducing the dosage.

(III) Hepatic Function Monitoring

Monitor liver function periodically; use is not recommended in patients with transaminase levels > 2.5 times the upper limit of normal (ULN) or bilirubin levels > 1.5 times the ULN.

(IV) Other Considerations

1. Use with caution in patients with a history of pancreatitis; monitor lipase levels periodically.

2. Assess cardiovascular risk and manage pre-existing hypertension and hyperlipidemia; patients should seek immediate medical attention if acute cardiovascular symptoms occur.

3. This product contains lactose; it is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

4. Men and women of childbearing potential must use effective contraception during treatment and for at least 2 weeks after discontinuing the medication; use is contraindicated in breastfeeding women.

5. May be used in combination with hematopoietic growth factors (e.g., EPO, G-CSF), hydroxyurea, or anagrelide.

IX. Drug Interactions

1. Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir): Increase nilotinib plasma concentrations and increase the risk of QT interval prolongation; avoid concomitant use.

2. Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort): Decrease nilotinib exposure; avoid concomitant use.

3. QT-Prolonging Medications (e.g., amiodarone, disopyramide, moxifloxacin, methadone): Increase the risk of cardiac arrhythmias; avoid concomitant use. 4. H2 Receptor Blockers/Antacids: H2 receptor blockers should be taken 10 hours before and 2 hours after administering Nilotinib; antacids should be taken 2 hours before or after administration.

5. Proton Pump Inhibitors (PPIs): May slightly reduce absorption; if co-administration is necessary, monitor therapeutic efficacy closely.

6. Food: High-fat meals significantly increase bioavailability; the medication must be taken strictly on an empty stomach. Avoid grapefruit juice.

X. Pharmacological Action

Nilotinib is a BCR-ABL kinase inhibitor that binds to and stabilizes the inactive conformation of ABL kinase. It inhibits BCR-ABL kinase activity, blocks the proliferation of Ph+ CML cells, and induces apoptosis; it is capable of overcoming most imatinib-resistant mutations.

XI. Pharmacokinetics

1. Absorption: Following oral administration on an empty stomach, peak plasma concentrations are reached within 3 hours, with a bioavailability of approximately 30%. Food can significantly increase absorption.

2. Distribution: Plasma protein binding is approximately 98%, and the volume of distribution is approximately 174 L.

3. Metabolism: Primarily metabolized via the hepatic CYP3A4 pathway; the parent compound constitutes the major component in serum (87.5%).

4. Elimination: The elimination half-life is approximately 17 hours. Excretion occurs primarily via feces (>90%), with less than 5% excreted in urine.

XII. Storage

Store below 30°C. Protect from light and moisture. Keep in the original packaging.

Product Specifications

Product Name: Nilotinib Capsules 200 mg × 30 Capsules/Box (Ninlib Nilotinib Capsules)

Common Name: Nilotinib Capsules

Composition: Nilotinib

Dosage Form: Capsules

Specification: 200 mg × 30 Capsules/Box

Manufacturer: Hetero Healthcare Limited

Indications: 1. Newly diagnosed adult and pediatric patients (aged 1 year and older) with Philadelphia chromosome-positive (Ph+) Chronic Myeloid Leukemia (CML) in the chronic phase. 2. Adult patients with Ph+ CML in the chronic or accelerated phase who are resistant to or intolerant of prior therapy (including imatinib).

3. Pediatric patients aged 1 year and older with Ph+ CML in the chronic or accelerated phase who are resistant to or intolerant of prior tyrosine kinase inhibitor (TKI) therapy.

Dosage and Administration: (I) Adult Dosage

1. Newly diagnosed Ph+ CML (Chronic Phase): 300 mg orally, twice daily, approximately 12 hours apart.

2. Resistant/Intolerant Ph+ CML (Chronic or Accelerated Phase): 400 mg orally, twice daily, approximately 12 hours apart.

(II) Pediatric Dosage (Ages 1 year and older)

Newly diagnosed or resistant/intolerant Ph+ CML (Chronic or Accelerated Phase): 230 mg/m² orally, twice daily; the dose should be rounded to the nearest 50 mg, with a maximum single dose not exceeding 400 mg.

(III) Method of Administration

1. Administration on an Empty Stomach: Do not consume food for at least 2 hours before taking the medication and for at least 1 hour after taking it.

2. Capsules must be swallowed whole; they should not be chewed, sucked, or opened. For patients unable to swallow the capsules whole, the contents may be mixed with 1 teaspoon of applesauce and administered immediately (within 15 minutes); the mixture should not be stored for later use.

3. Missed Dose: Do not take a missed dose; resume the regular dosing schedule with the next scheduled dose.

4. Duration of Therapy: Treatment should be continued as long as the patient continues to derive clinical benefit.