Nilotinib

Trade Names:
Tasigna
- Capsules 200 mg

Pharmacology

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Binds to and stabilizes the inactive conformation of the kinase domain of Abl protein.

Pharmacokinetics

Absorption

C _max is 3 h after oral administration. Bioavailability is increased when given with a meal. Compared with fasting, the AUC is increased 82% when given 30 min after a high-fat meal.

Distribution

Serum protein binding is approximately 98%.

Metabolism

Main metabolic pathways are oxidation and hydroxylation. The metabolites are inactive.

Elimination

Elimination t _½ is approximately 17 h. Steady state is reached in about 8 days. Approximately 93% of the administered dose is eliminated in feces within 7 days.

Special Populations

Has not been investigated but a decrease in total body Cl is not anticipated.

Has not been investigated.

Do not affect the pharmacokinetics.

Indications and Usage

Treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Contraindications

Hypokalemia; hypomagnesemia; long QT syndrome.

Dosage and Administration

PO 400 mg twice daily.

PO

Withhold dose and perform an analysis of serum potassium and magnesium. If below lower limit of normal, correct with supplements to within normal limits. Review concomitant medication usage. If QTcF returns to less than 450 msec and to within 20 msec of baseline, resume treatment within 2 wk at prior dose. If QTcF is between 450 and 480 msec after 2 wk, reduce dosage to 400 mg once daily. If, following dosage reduction to 400 mg once daily, the QTcF returns to more than 480 msec, discontinue nilotinib. An ECG should be repeated approximately 7 days after any dose adjustment.

PO

If absolute neutrophil count (ANC) less than 1 times 10 ⁹ /L and/or platelet counts less than 50 times 10 ⁹ /L, stop nilotinib and monitor blood cell counts. Resume within 2 wk at prior dose if ANC is more than 1 times 10 ⁹ /L and platelets are more than 50 times 10 ⁹ /L. If blood cell counts remain low for longer than 2 wk, reduce dosage to 400 mg once daily.

PO

Withhold nilotinib and monitor serum lipase or amylase. Resume treatment at 400 mg once daily if serum lipase or amylase returns to grade 1 or less.

Withhold nilotinib and monitor bilirubin. Resume treatment at 400 mg once daily if bilirubin returns to grade 1 or less.

Withhold nilotinib and monitor hepatic transaminases. Resume treatment at 400 mg once daily if hepatic transaminases return to grade 1 or less.

PO If moderate or severe nonhematologic toxicity occurs, withhold nilotinib and resume treatment at 400 mg once daily when toxicity resolves. Escalation of dosage to 400 mg twice daily should be considered.

PO If a strong CYP3A4 inhibitor cannot be avoided, a dosage reduction to 400 mg once daily is predicted to adjust the AUC to the value observed without administration of an inhibitor. However, there are no clinical data with this dose adjustment. If the strong inhibitor is discontinued, after a washout period, the nilotinib dose should be adjusted upward to the indicated dose. Closely monitor for prolongation of the QT interval.

PO If a strong CYP3A4 inducer cannot be avoided, the nilotinib dose may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the nilotinib dose should be reduced to the indicated dose.

General Advice

• Treatment should be continued as long as there is no evidence of progression or unacceptable toxicity.
• Do not administer with food. Food should not be consumed for at least 2 h before or at least 1 h after a dose is taken.
• Administer twice daily at approximately 12 h intervals.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Concentrations of drugs that are substrates for these enzymes may be reduced; administer with caution.

Concentrations of drugs that are substrates for these enzymes may be elevated; administer with caution. Avoid warfarin because it is a substrate for CYP2C9 and CYP3A4.

Because nilotinib concentrations may be elevated, avoid grapefruit juice.

Concentrations of drugs that are a substrate for P-glycoprotein may be increased; administer with caution.

Because nilotinib concentrations may be reduced, avoid St. John's wort.

Nilotinib concentrations may be reduced, leading to subtherapeutic levels.

Nilotinib concentrations may be elevated, increasing the risk of toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Flushing, hypertension, palpitations, prolonged QT (1% to 10%); atrial fibrillation, cardiac failure, cardiac murmur, cardiomegaly, coronary artery disease, hemorrhagic shock, hypertensive crisis, MI, pericardial effusion, pericarditis, thrombosis, ventricular dysfunction.

CNS

Headache (31%); fatigue (28%); pyrexia (24%); asthenia (14%); dizziness, insomnia, paresthesia, vertigo (1% to 10%); intracranial hemorrhage.

Dermatologic

Rash (33%); pruritus (29%); alopecia, dry skin, eczema, erythema, hyperhidrosis, night sweats, urticaria (1% to 10%); exfoliative rash.

EENT

Nasopharyngitis (16%).

GI

Nausea (31%); diarrhea (22%); constipation, vomiting (21%); abdominal pain (13%); abdominal discomfort, anorexia, dyspepsia, flatulence (1% to 10%); GI hemorrhage, GI ulcer perforation, hematemesis, retroperitoneal hemorrhage.

Genitourinary

Hematuria, renal failure.

Hematologic-Lymphatic

Neutropenia, thrombocytopenia (37%); anemia (23%); febrile neutropenia, pancytopenia (1% to 10%); leukocytosis, thrombocytosis.

Hepatic

Hepatitis, hepatomegaly, hepatotoxicity, jaundice.

Lab Tests

Elevated lipase (17%); hyperglycemia (11%); elevated bilirubin, hypophosphatemia (10%); hypokalemia (5%); elevated ALT, hyperkalemia, hypocalcemia (4%); elevated alkaline phosphatase, hyponatremia (3%); hypomagnesemia, increased blood amylase, increased blood creatine phosphokinase, increased gamma-glutamyltransferase (1% to 10%); decreased albumin, elevated AST (1%).

Musculoskeletal

Arthralgia (18%); pain in extremities (16%); muscle spasm, myalgia (14%); bone pain (13%); back pain (12%); musculoskeletal chest pain, musculoskeletal pain (1% to 10%).

Respiratory

Cough (17%); dyspnea (11%); dysphonia (1% to 10%); interstitial lung disease, plural effusion, pulmonary edema.

Miscellaneous

Peripheral edema (11%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Galactose intolerance

Since the capsules contain lactose, nilotinib therapy is not recommended in patients with hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Hepatotoxicity

Elevations in AST/ALT, bilirubin, and alkaline phosphatase may occur.

Myelosuppression

Grade 3/4 thrombocytopenia, neutropenia, and anemia can occur.

Serum electrolytes

Hyperkalemia, hypokalemia, hypocalcemia, hyponatremia, and hypophosphatemia may occur.

Serum lipase

Elevation may occur; use with caution in patients with a history of pancreatitis.

Overdosage

Symptoms

No cases of overdose have been reported.

Patient Information

• Advise patients to take on an empty stomach. Food should not be consumed for at least 2 h before or at least 1 h after a dose is taken.
• Advise patients to take medication twice daily at approximately 12-h intervals.
• Advise patient to avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract.
• Instruct patients to contact health care provider immediately if they feel faint or have an irregular heartbeat.
• Instruct patients to inform health care provider if they have any heart problems, irregular heartbeat, liver problems, pancreatitis, low magnesium or potassium levels, QTc prolongation or family history of QTc prolongation, or a severe problem with lactose or other sugars.
• Instruct patient not to open capsules and to swallow them whole.
• Women of child-bearing potential should use effective contraceptives.

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