Generic Name: Nilotinib
Class: Antineoplastic Agents
Chemical Name: 4 - methyl - N - [3 - (4 - methyl - 1H - imidazol - 1 - yl) - 5 - (trifluoromethyl)phenyl] - 3 - [[4 - (3 - pyridinyl) - 2 - pyrimidinyl]amino] - benzamide, monohydrochloride, monohydrate
Molecular Formula: C28H22F3N7O • HCl • H2O

Warning(s)

  • QT Interval Prolongation and Sudden Death
  • Prolongs QT interval.1 ECG monitoring recommended at baseline, 7 days after initiation, following any dosage adjustments, and periodically thereafter.1 (See Prolongation of QT Interval under Cautions.)

  • Sudden deaths reported in patients receiving nilotinib.1

  • Contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.1 Correct hypokalemia or hypomagnesemia prior to administration; periodically monitor electrolytes.1

  • Avoid concomitant administration of drugs known to prolong the QT interval and potent CYP3A4 inhibitors.1 (See Interactions.)

  • Avoid food 2 hours before and 1 hour after taking dose.1 (See Absorption under Pharmacokinetics.)

  • Dosage reduction recommended in patients with hepatic impairment.1 (See Hepatic Impairment under Cautions and also under Dosage and Administration.)

Introduction

Antineoplastic agent; inhibitor of Bcr-Abl tyrosine kinase.1 3 4 5 6 7 8 9 11

Uses for Tasigna

Chronic Myelogenous Leukemia (CML)

Treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adults who are in chronic phase of the disease.1 16 Efficacy based on molecular and cytogenetic response rates at 12 months; additional data needed to establish long-term efficacy.1 16

Slideshow: Parkinson’s Disease - 10 Clinical Fast Facts

Treatment of Ph+ CML in adults who are in chronic or accelerated phase of the disease, after failure (secondary to resistance or intolerance) of prior therapy that included imatinib.1 4 20 Efficacy based on hematologic and cytogenetic response rates.1

Designated an orphan drug by FDA for use in the treatment of CML.2

Tasigna Dosage and Administration

General

  • ECG monitoring recommended before initiation of therapy, 7 days after initiation, approximately 7 days following any dose adjustments, and periodically thereafter.1

  • Prior to administration, correct hypokalemia or hypomagnesemia; periodically monitor electrolytes during therapy.1

  • Perform CBCs every 2 weeks for first 2 months and then monthly (or as clinically indicated) thereafter.1

  • May be administered with hydroxyurea or anagrelide; may also be used concurrently with hematopoietic growth factors (e.g., erythropoietin, filgrastim, sargramostim).1

Administration

Oral Administration

Administer orally twice daily (approximately 12 hours apart in the morning and evening).1

Administer on an empty stomach, at least 1 hour before or 2 hours after any food.1

Swallow capsules whole with water.1 Alternatively, patients who are unable to swallow capsules may open nilotinib capsules, disperse the contents of each capsule in one teaspoonful of applesauce, and swallow the mixture immediately (within 15 minutes).1 Do not store mixture for later use.1 Do not use foods other than applesauce.1 Do not mix contents of each capsule with more than one teaspoonful of applesauce.1

Dosage

Adults

CML
Newly Diagnosed Chronic Phase CML
Oral

300 mg twice daily.1 16 Manufacturer recommends 200 mg once daily if concomitant use of a potent CYP3A4 inhibitor is required (see Interactions).1

In clinical trial, median duration of treatment was 18.6 months.1

Chronic or Accelerated Phase CML Following Failure of Prior Therapy That Included Imatinib
Oral

400 mg twice daily.1 3 6 Manufacturer recommends 300 mg once daily if concomitant use of a potent CYP3A4 inhibitor is required (see Interactions).1

In clinical trial, median duration of treatment was 18.4 or 8.7 months for patients in chronic or accelerated phase, respectively.1

Dosage Modification for Toxicity
Prolongation of QT Interval
Oral

If QTc is >480 msec, withhold nilotinib.1 Resume treatment within 2 weeks at prior dosage (300 mg twice daily in patients receiving nilotinib as first-line therapy for CML or 400 mg twice daily in those receiving nilotinib following failure of prior therapy that included imatinib) if QTcF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline.1 If QTcF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 400 mg once daily.1 If QTcF >480 msec following this dosage reduction, discontinue nilotinib.1

Adverse Hematologic Effects
Oral

Adjust dosage if neutropenia and/or thrombocytopenia (unrelated to leukemia) occurs.1

If ANC <1000/mm3 and/or platelets <50,000/mm3, withhold nilotinib.1 Resume treatment within 2 weeks at prior dosage (300 mg twice daily in patients receiving nilotinib as first-line therapy for CML or 400 mg twice daily in those receiving nilotinib following failure of prior therapy that included imatinib) if ANC >1000/mm3 and platelets >50,000/mm3.1 If blood counts remain low for >2 weeks, reduce dosage to 400 mg once daily.1

Other Nonhematologic Adverse Effects
Oral

Withhold therapy in patients with elevated lipase, amylase, bilirubin, and/or hepatic transaminase concentrations of grade 3 or higher (as defined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]).1 13 If toxicity decreases to grade 1 or less, resume treatment at a reduced dosage of 400 mg once daily (in patients receiving nilotinib either as first-line therapy for CML or following failure of prior therapy that included imatinib).1

Withhold therapy if other moderate or severe nonhematologic toxicities (NCI grade 2 or higher) occur;1 13 once toxicity resolves, resume therapy, as appropriate, at a reduced dosage of 400 mg once daily.1 If clinically appropriate, consider escalation of dosage back to 300 mg twice daily (in patients receiving nilotinib as first-line therapy for CML) or 400 mg twice daily (in those receiving nilotinib following failure of prior therapy that included imatinib).1

Special Populations

Hepatic Impairment

If possible, consider alternative therapy.1 If use of nilotinib is required, consider reducing initial dosage.1 (See Hepatic Impairment under Cautions.)

Newly Diagnosed Chronic Phase CML
Oral

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): 200 mg twice daily initially, followed by dosage escalation to 300 mg twice daily as tolerated.1

Chronic or Accelerated Phase CML Following Failure of Prior Therapy That Included Imatinib
Oral

Mild or moderate hepatic impairment (Child-Pugh class A or B): 300 mg twice daily initially, followed by dosage escalation to 400 mg twice daily as tolerated.1

Severe hepatic impairment (Child-Pugh class C): 200 mg twice daily initially, followed by dosage escalation as tolerated to 300 mg twice daily and then to 400 mg twice daily.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Tasigna

Contraindications

  • Hypokalemia, hypomagnesemia, or long QT syndrome.1 11

Warnings/Precautions

Warnings

Prolongation of QT Interval

Plasma concentration-dependent QT interval prolongation has occurred; may be associated with torsades de pointes, leading to syncope, seizure, and/or sudden death.1 (See Sudden Death under Cautions.)

ECG monitoring is recommended at baseline, 7 days after initiation of drug, approximately 7 days after any dosage adjustments, and periodically during therapy to monitor for QT interval effects.1 (See Prolongation of QT Interval under Dosage and Administration.)

Contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.1

Concomitant use of potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit) or antiarrhythmics or other drugs that prolong QT interval (e.g., amiodarone, chloroquine, clarithromycin, disopyramide, haloperidol, methadone, moxifloxacin, pimozide, procainamide, quinidine, sotalol) may result in substantial prolongation of QT interval; avoid concomitant use of these agents.1 (See Interactions.)

Administration with food may result in substantial prolongation of QT interval; do not administer with food.1 (See Oral Administration under Dosage and Administration.)

Sudden Death

Sudden deaths reported in patients receiving nilotinib.1 Possibility that ventricular repolarization abnormalities may have contributed to their occurrence.1 (See Prolongation of QT Interval under Cautions.)

Other Warnings and Precautions

Hematologic Effects

Grade 3 or 4 myelosuppression (neutropenia, anemia, and thrombocytopenia) reported; usually reversible by withholding or reducing the dosage.1 (See Adverse Hematologic Effects under Dosage and Administration.)

Perform CBCs every 2 weeks during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.1

Elevated Serum Lipase

Grade 3 or 4 elevations in serum lipase reported.1 Caution in patients with a previous history of pancreatitis.1 Monitor serum lipase monthly or as clinically indicated; interruption of therapy and/or dosage reduction may be required.1 (See Other Nonhematologic Adverse Effects under Dosage and Administration.)

If lipase elevations are accompanied by abdominal symptoms, interrupt therapy and consider diagnostic testing to exclude pancreatitis.1

Hepatic Effects

Grade 3 or 4 elevations of serum bilirubin, AST, ALT, and/or alkaline phosphatase reported.1 Monitor hepatic function tests monthly or as clinically indicated; interruption of therapy and/or dosage reduction may be required.1 (See Other Nonhematologic Adverse Effects under Dosage and Administration.)

Pharmacogenetic analysis evaluating potential association between genetic polymorphisms of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and nilotinib-associated hyperbilirubinemia found increased risk of hyperbilirubinemia with the (TA)7/(TA)7 genotype relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes; largest increases in bilirubin observed in patients with the (TA)7/(TA)7 genotype (UGT1A1*28).1

Electrolyte Abnormalities

Grade 3 or 4 electrolyte abnormalities (hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia) reported.1

Correct electrolyte abnormalities prior to administration of nilotinib; monitor electrolytes periodically during therapy.1

Total Gastrectomy

Nilotinib exposure is reduced in patients who have undergone total gastrectomy.1 Consider more frequent follow-up of these patients.1 If necessary, consider increasing nilotinib dosage or instituting alternative therapy.1

Lactose Intolerance

Contains lactose monohydrate; not recommended in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with severe intolerance to lactose-containing products, or glucose-galactose malabsorption.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; maternal and embryofetal toxicity demonstrated in animals.1 Avoid pregnancy during therapy.1 (See Advice to Patients.) If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Cardiac Disorders

Clinical trials excluded patients with a history of uncontrolled or clinically important cardiovascular disease, including recent MI, CHF, unstable angina, and clinically important bradycardia.1 Caution advised in such patients.1 (See Prolongation of QT Interval under Cautions.)

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether nilotinib is distributed into human milk.1 Discontinue nursing or drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In newly diagnosed chronic-phase CML patients, no difference in major molecular response rates between patients ≥65 years of age and younger adults.1

In chronic-phase CML patients receiving nilotinib after failure of prior therapy that included imatinib, no difference in major cytogenetic response rates between patients ≥65 years of age and younger adults.1

In accelerated-phase CML patients receiving nilotinib after failure of prior therapy that included imatinib, hematologic response rate was 29% in patients ≥65 years of age compared with 44% in patients <65 years of age.1

No major differences in safety relative to younger adults.1

Hepatic Impairment

Increased nilotinib exposure in patients with hepatic impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.) If possible, consider alternative therapy.1 If nilotinib therapy is required, reduce initial dosage and closely monitor QT interval.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied in patients with renal impairment; however, renal impairment not expected to decrease nilotinib clearance.1

Common Adverse Effects

Adverse nonhematologic effects: Rash, pruritus, headache, nausea, fatigue, myalgia, nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, pyrexia, upper respiratory infection, back pain, cough, asthenia.1

Grade 3/4 adverse hematologic effects: Thrombocytopenia, neutropenia, anemia.1 16

Interactions for Tasigna

Metabolized principally by CYP3A4.1

Inhibits CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1; induces CYP2B6, CYP2C8, and CYP2C9.1 Potential pharmacokinetic interactions with drugs metabolized by these isoenzymes.1

Substrate and inhibitor of efflux transporter Pgp (ABCB1).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased serum nilotinib concentrations).1 Avoid concomitant use; interrupt nilotinib therapy if use of a potent CYP3A4 inhibitor is required.1 If interruption is not possible, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML or 300 mg once daily following failure of prior therapy for CML that included imatinib) and closely monitor for QT interval prolongation.1 Recommended dosage adjustment based on pharmacokinetic studies, not on clinical experience.1 If the CYP3A4 inhibitor is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period.1 (See Specific Drugs and Foods under Interactions.)

Potent CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma nilotinib concentrations).1 Avoid concomitant use; select alternative drugs with less CYP34A induction potential.1 (See Specific Drugs and Foods under Interactions.) Nilotinib dosage adjustment unlikely to compensate for loss of exposure.1 (See Plasma Concentrations under Pharmacokinetics.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4, CYP2C8, CYP2C9, CYP2D6: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1 Caution if used concomitantly with substrates of these enzymes that have a narrow therapeutic index.1

Substrates of CYP2B6, CYP2C8, and CYP2C9: Potential pharmacokinetic interaction (decreased plasma substrate concentrations).1

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)

Substrates of UGT1A1: Potential pharmacokinetic interaction (increased concentrations of drugs metabolized by this enzyme).1 Caution when used concomitantly with drugs metabolized by UGT1A1 that have a narrow therapeutic index.1

Substrates or Inhibitors of P-Glycoprotein Transport Systems (Pgp)

Substrates of Pgp: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1 Use with caution.1

Pgp inhibitors: Potential pharmacokinetic interaction (increased plasma nilotinib concentrations).1 Use with caution.1

Drugs that Prolong QT Interval

Potential pharmacologic interactions (additive effect on QT interval prolongation).1 Avoid concomitant use of nilotinib with drugs known to prolong the QT interval.1 (See Prolongation of QT Interval under Cautions and see Specific Drugs and Foods under Interactions.) If use of such drugs is required, interrupt nilotinib therapy.1 If interruption is not possible, closely monitor patients for QT interval prolongation.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antacids

Possible decreased nilotinib bioavailability secondary to decreased solubility at higher pH1

Separate administration by at least several hours1

Antiarrhythmics (e.g., amiodarone, disopyramide, procainamide, quinidine, sotalol)

Potential for substantial prolongation of QT interval with antiarrhythmics that prolong the QT interval1

Avoid concomitant use; interrupt nilotinib therapy if use of such antiarrhythmics is required; if interruption is not possible, closely monitor for QT interval prolongation1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased plasma nilotinib concentrations1

Avoid concomitant use; select alternative therapy with less enzyme induction potential1

Nilotinib dosage adjustment unlikely to compensate for loss of exposure1

Antifungals, azoles (itraconazole, ketoconazole, voriconazole)

Possible increased plasma nilotinib concentrations1

Ketoconazole: Increased nilotinib AUC approximately threefold1

Avoid concomitant use; interrupt nilotinib therapy if use of antifungal with potent CYP3A4 inhibitory activity is required1

If interruption is not possible, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML or 300 mg once daily following failure of prior CML therapy that included imatinib) and closely monitor for QT interval prolongation1

If antifungal is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Possible decreased plasma nilotinib concentrations1

Rifampin: Decreased nilotinib AUC approximately 80%1

Avoid concomitant use; select alternative therapy with less enzyme induction potential1

Nilotinib dosage adjustment unlikely to compensate for loss of exposure1

Antipsychotic agents (haloperidol, pimozide)

Potential for substantial prolongation of QT interval with antipsychotic agents that prolong the QT interval1

Avoid concomitant use; interrupt nilotinib therapy if use of such antipsychotics is required; if interruption is not possible, closely monitor for QT interval prolongation1

Chloroquine

Potential for substantial prolongation of QT interval1

Avoid concomitant use; interrupt nilotinib therapy if use of chloroquine is required; if interruption is not possible, closely monitor for QT interval prolongation1

Clarithromycin

Potential for substantial prolongation of QT interval1

(see also Macrolides entry in this table)

Avoid concomitant use; interrupt nilotinib therapy if use of clarithromycin is required; if interruption is not possible, closely monitor for QT interval prolongation1

Dexamethasone

Possible decreased plasma nilotinib concentrations1

Avoid concomitant use; select alternative therapy with less enzyme induction potential1

Nilotinib dosage adjustment unlikely to compensate for loss of exposure1

Grapefruit

Possible increased plasma nilotinib concentrations1

Avoid grapefruit products1

Histamine H2-receptor antagonists

Possible decreased nilotinib bioavailability secondary to decreased solubility at higher pH1

Separate administration by at least several hours1

HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased plasma nilotinib concentrations1

Avoid concomitant use1

If concomitant therapy necessary, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML or 300 mg once daily following failure of prior CML therapy that included imatinib) and closely monitor for QT interval prolongation1

If HIV protease inhibitor is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period1

Imatinib

Increase in nilotinib and imatinib exposure1

Macrolides (clarithromycin, telithromycin)

Possible increased plasma nilotinib concentrations1

(see also Clarithromycin entry in this table)

Avoid concomitant use; interrupt nilotinib therapy if use of macrolide with potent CYP3A4 inhibitory activity is required1

If interruption is not possible, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML or 300 mg once daily following failure of prior CML therapy that included imatinib) and closely monitor for QT interval prolongation1

If macrolide is discontinued, increase nilotinib dosage to usual indicated dosage1

Methadone

Potential for substantial prolongation of QT interval1

Avoid concomitant use; interrupt nilotinib therapy if methadone is required; if interruption is not possible, closely monitor for QT interval prolongation1

Midazolam

Increased midazolam AUC1

Use with caution1

Moxifloxacin

Potential for substantial prolongation of QT interval1

Avoid concomitant use; interrupt nilotinib therapy if moxifloxacin is required; if interruption is not possible, closely monitor for QT interval prolongation1

Nefazodone

Possible increased plasma nilotinib concentrations1

Avoid concomitant use; interrupt nilotinib therapy if use of nefazodone is required1

If interruption is not possible, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML or 300 mg once daily following failure of prior therapy that included imatinib) and closely monitor for QT interval prolongation1

If nefazodone is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period1

Proton-pump inhibitors

Decreased nilotinib bioavailability and exposure secondary to decreased solubility at higher pH1 18

Esomeprazole: Decreased nilotinib AUC by 34%1 18

Use with caution1

Increased nilotinib dosage unlikely to compensate for loss of exposure; separation of administration times unlikely to eliminate interaction because proton-pump inhibitors cause prolonged acid suppression1

St. John’s wort (Hypericum perforatum)

Possible decreased nilotinib concentrations1

Avoid concomitant use; nilotinib dosage adjustment unlikely to compensate for loss of exposure1

Warfarin

In healthy individuals, single nilotinib dose did not alter warfarin pharmacokinetics or pharmacodynamics1

Use with caution1

Tasigna Pharmacokinetics

Absorption

Bioavailability

Peak concentrations are attained 3 hours following oral administration.1

Single-dose administration of two intact 200-mg nilotinib capsules is bioequivalent to single-dose administration of two 200-mg capsules when the contents of each capsule are dispersed in a teaspoonful of applesauce and ingested within 15 minutes following dispersal.1

Food

Food increases oral bioavailability.1 When administered 30 minutes after a high-fat meal, AUC increased by 82% relative to administration in the fasted state.1

Plasma Concentrations

Steady-state exposure is dose dependent; at dosages >400 mg once daily, increase in exposure is less than proportional to increase in dose.1 Steady-state exposure at dosage of 400 mg twice daily is about 13% higher than exposure at dosage of 300 mg twice daily.1

Special Populations

In individuals with mild to moderate hepatic impairment (Child-Pugh class A or B), AUC increased 35%; in those with severe hepatic impairment (Child-Pugh class C), AUC increased 56%.1

In patients having undergone total gastrectomy, median steady-state trough concentrations reduced by 53%.1

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 98%.1

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4, to inactive metabolites.1 Undergoes oxidation and hydroxylation.1

Elimination Route

Eliminated principally in feces (93%) mainly as unchanged drug.1

Half-life

Approximately 17 hours.1

Special Populations

Renal impairment not expected to reduce clearance.1

No clinically relevant effects of age, body weight, gender, or ethnic origin on pharmacokinetics.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits Bcr-Abl tyrosine kinase, an abnormal protein created by the Philadelphia chromosome abnormality in CML.1 3 8

  • Competitively inhibits the ATP-binding site of Bcr-Abl tyrosine kinase, leading to inhibition of tyrosine phosphorylation of proteins involved in the intracellular signal transduction that Bcr-Abl mediates.4 5

  • Binds to and stabilizes the inactive conformation of the Abl kinase; inhibits proliferation of murine leukemic cells as well as human cell lines derived from Ph+ CML patients.1

  • Overcomes imatinib resistance resulting from Bcr-Abl kinase domain mutations in vitro.1

Advice to Patients

  • A copy of the manufacturer’s patient information (medication guide) for nilotinib should be provided to all patients with each prescription of the drug.1 19 Importance of patients reading the medication guide prior to initiation of therapy and each time the prescription is refilled.1

  • Risk of QT interval prolongation.1 Importance of informing clinician immediately if feelings of lightheadedness or faintness or an irregular heartbeat occurs.1

  • Importance of advising patients that nilotinib is a long-term therapy.1 Importance of taking only as prescribed; do not alter the dosage or discontinue therapy without first consulting clinician.1

  • Importance of advising patients to swallow nilotinib capsules whole with water.1 Alternatively, instruct patients who cannot swallow capsules to open nilotinib capsules, sprinkle the contents of each capsule on one teaspoonful of applesauce, and swallow the mixture immediately (within 15 minutes).1 Advise patients that foods other than applesauce should not be used and that no more than one teaspoonful of applesauce should be mixed with the contents of each capsule.1

  • Importance of advising patients that if a dose is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.1

  • Importance of advising patients to take nilotinib on an empty stomach (at least 1 hour before and at least 2 hours after eating any food); advise patients receiving nilotinib twice daily to take doses approximately 12 hours apart.1

  • Importance of advising patients to separate doses of nilotinib and doses of antacids or H2-receptor antagonists by at least several hours.1

  • Importance of informing clinicians if patient is lactose intolerant.1

  • Importance of advising patients to avoid any grapefruit products or any other foods that inhibit CYP3A4 while taking nilotinib.1

  • Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, and advise pregnant women of risk to the fetus.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., long QT syndrome).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Nilotinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

150 mg

Tasigna

Novartis

200 mg

Tasigna

Novartis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 26, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals Corporation. Tasigna (nilotinib) capsules prescribing information. East Hanover, NJ; 2011 Jan.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD; 2008 May 16. From FDA website (). Accessed 2008 Aug 11.

3. Kantarjian HM, Giles F, Gattermann N et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007; 110:3540-6. [PubMed 17715389]

4. Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood. 2007; 110:2828-37. [PubMed 17626839]

5. Kantarjian H, Giles F, Wunderle L et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006; 354:2542-51. [PubMed 16775235]

6. le Coutre P, Ottmann FG, Giles F et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008; 111:1834-9. [PubMed 18048643]

7. Jabbour E, Cortes JE, Giles FJ et al. Current and emerging treatment options in chronic myeloid leukemia. Cancer. 2007; 109:2171-81. [PubMed 17431887]

8. Kantarjian HM, Talpaz M, Giles F et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006; 145:913-23. [PubMed 17179059]

9. Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med. 2007; 357:258-65. [PubMed 17634461]

10. Novartis Pharmaceuticals Corporation., East Hanover, NJ: Personal communication.

11. Anon. Nilotinib (Tasigna) for CML. Med Lett Drugs Ther. 2008; 50:26-27. [PubMed 18391899]

13. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS. From: http://ctep.cancer.gov., 2006 August 9.

14. Rix U, Hantschel O, Dürnberger G et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007; 110:4055-63. [PubMed 17720881]

15. Cortes J, Jabbour E, Kantarjian H et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood. 2007; 110:4005-11. [PubMed 17785585]

16. Saglio G, Kim DW, Issaragrisil S et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010; 362:2251-9. [PubMed 20525993]

17. Sokal JE, Cox EB, Baccarani M et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984; 63:789-99. [PubMed 6584184]

18. Yin OQ, Gallagher N, Fischer D et al. Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib. J Clin Pharmacol. 2010; 50:960-7. [PubMed 20498287]

19. Food and Drug Administration. Tasigna (nilotinib) Risk Evaluation and Mitigation Strategy (REMS) document (modified 2011 Jan 7). From FDA website. Accessed 2011 Apr 22.

20. Kantarjian HM, Giles FJ, Bhalla KN et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011; 117:1141-5. [PubMed 21098399]

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