HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Tasigna® safely and effectively. See full prescribing information for
`Tasigna®.
`Tasigna® (nilotinib) Capsules
`Initial U.S. Approval: 2007
`WARNING: QT PROLONGATION AND SUDDEN DEATHS
`See full prescribing information for complete boxed warning.
`Tasigna prolongs the QT interval (5.2). Sudden deaths have been
`reported in patients receiving nilotinib (5.3). Tasigna should not be used
`in patients with hypokalemia, hypomagnesemia, or long QT syndrome
`(4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna
`administration and should be periodically monitored (5.2). Drugs known
`to prolong the QT interval and strong CYP3A4 inhibitors should be
`avoided (5.7). Patients should avoid food 2 hours before and 1 hour after
`taking dose (5.8). Use with caution in patients with hepatic impairment
`(5.9). ECGs should be obtained to monitor the QTc at baseline, seven
`days after initiation, and periodically thereafter, as well as following any
`dose adjustments. (5.2, 5.3, 5.6, 5.12)
`
`--------------INDICATIONS AND USAGE---------------------
`Tasigna is a kinase inhibitor indicated for the treatment of chronic
`phase and accelerated phase Philadelphia chromosome positive chronic
`myelogenous leukemia (CML) in adult patients resistant to or intolerant to
`prior therapy that included imatinib.(1)
`------------DOSAGE AND ADMINISTRATION-------------
`400 mg orally twice daily, approximately 12 hours apart and should not
`be taken with food. (2)
`
`•
`
`•
`
`•
`
`The capsules should be swallowed whole with water. No food should be
`consumed for at least 2 hours before the dose is taken and no food
`should be consumed for at least one hour after. (2)
`Dose adjustment may be required for hematologic and non-hematologic
`toxicities, and drug interactions. (2)
`-----------DOSAGE FORMS AND STRENGTHS------------
`200 mg hard capsules (3)
` - - - - - - - - -CONTRAINDICATIONS- - - - - - - - -- - - - - -
`Do not use in patients with hypokalemia, hypomagnesemia, or long QT
`syndrome. (4)
`---------------WARNINGS AND PRECAUTIONS------------
`Myelosuppression: Associated with neutropenia, thrombocytopenia and
`anemia. CBC should be done every 2 weeks for the first 2 months, then
`monthly. Reversible by withholding dose. Dose reduction may be
`required. (5.1)
`QT Prolongation: Tasigna prolongs the QT interval. Correct
`hypokalemia or hypomagnesemia prior to administration and monitor
`periodically (5.2). Avoid drugs known to prolong the QT interval and
`strong CYP3A4 inhibitors. (5.7) Use caution in patients with hepatic
`impairment. Obtain ECGs at baseline, seven days after initiation, and
`periodically thereafter, as well as following any dose adjustments. (5.2,
`5.3, 5.6, 5.12)
`Sudden deaths: There were sudden deaths reported in the safety
`population and the expanded access program. Ventricular repolarization
`abnormalities may have contributed to their occurrence. (5.3)
`
`•
`
`•
`
`•
`
`2
`
`•
`
`•
`
`•
`
`•
`
`Elevated serum lipase: Caution is recommended in patients with history
`of pancreatitis. Check serum lipase periodically. (5.4)
`Liver function abnormality: Tasigna may result in elevations in
`bilirubin, AST/ALT, and alkaline phosphatase. Check hepatic function
`tests periodically. (5.5)
`Electrolyte abnormalities: Tasigna can cause hypophosphatemia,
`hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct
`electrolyte abnormalities prior to initiating Tasigna and monitor
`periodically during therapy. (5.6, 5.12)
`Hepatic impairment: Tasigna has not been investigated in patients with
`hepatic impairment. Caution is recommended in these patients and QT
`interval should be monitored closely. (5.9)
`(cid:131) Drug interactions: Avoid concomitant use of strong inhibitors or
`inducers of CYP3A4. If patients must be co-administered a strong
`CYP3A4 inhibitor, dose reduction should be considered and the QT
`interval should be monitored closely. (5.7)
`(cid:131) Food Effects: Food increases blood levels of Tasigna.
`(cid:131) Avoid food 2 hours before and 1 hour after a dose. (5.8)
`(cid:131) Pregnancy: Fetal harm can occur when administered to a pregnant
`woman. Women should be advised not to become pregnant when taking
`Tasigna. (5.11, 8.1)
`-------------------ADVERSE REACTIONS--------------
`In CML-CP patients, the most commonly reported drug-related adverse
`reactions (>10%) were rash, pruritis, nausea, fatigue, headache, constipation,
`diarrhea and vomiting. The common serious drug-related adverse reactions
`were thrombocytopenia and neutropenia. In CML-AP patients, the most
`commonly reported drug-related adverse reactions (>10%) were rash, pruritus
`and constipation. The common serious drug-related adverse reactions were
`thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia,
`intracranial hemorrhage, elevated lipase and pyrexia. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact
`Novartis Pharmaceuticals Corporation at 1-888-NOW-NOVA or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`-------------------DRUG INTERACTIONS--------------
`CYP3A4 inhibitors may affect serum concentration (7.1)
`CYP3A4 inducers may affect serum concentration (7.2)
`Tasigna is an inhibitor of CYP3A4, CYP2C8, CYP2C9, and CYP2D6. It may
`also induce CYP2B6, CYP2C8 and CYP2C9. Therefore, Tasigna may alter
`serum concentration of other drugs (7.3)
`-------------USE IN SPECIFIC POPULATIONS-------------
`Should not be used during pregnancy (8.1)
`
`•
`
`•
`
`•
`
`•
`
`Sexually active female patients should use effective contraception
`during treatment (8.1)
`Should not breast feed (8.3)
`
`No data to support use in pediatrics (8.4)
`
`Use with caution in patients with hepatic impairment (8.6)
`•
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`Revised: October/2007
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`

`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`WARNING- QT PROLONGATION AND SUDDEN DEATHS
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`
`2.2 Dose Adjustments or Modifications
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Myelosuppression
`
`5.2 QT Prolongation
`
`5.3 Sudden Deaths
`
`5.4 Elevated Serum Lipase
`
`5.5 Hepatotoxicity
`
`5.6 Electrolyte Abnormalities
`
`5.7 Drug Interactions
`
`5.8 Food Effects
`
`5.9 Hepatic Impairment
`
`5.10 Lactose
`
`5.11 Pregnancy
`
`5.12 Monitoring Laboratory Tests
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Additional Data from Clinical Trials
`7 DRUG INTERACTIONS
`
`7.1 Effects of Nilotinib on Drug Metabolizing Enzymes
`
` and Drug Transport Systems
`
`7.2 Drugs That Inhibit or Induce Cytochrome P450 3A4
`
` Enzymes
`
`
`
`
`
`
`
`
`
`3
`
`
`
`7.3 Drugs That Inhibit Drug Transport Systems
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Cardiac Disorders
`8.7 Hepatic Impairment
`
`
`8.8 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`12.4 QT/QTc Prolongation
`
`12.5 Pharmacogenetics
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
` Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Taking Tasigna
`
`17.2 Drug interactions
`
`17.3 Pregnancy
`
`17.4 Compliance
`
`17.5 Medication Guide
`
`
`
`Sections or subsections omitted from Full Prescribing Information
`*
`are not listed.
`_________________________________________________________
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`

`
`FULL PRESCRIBING INFORMATION
`
`
`4
`
`WARNING: QT PROLONGATION AND SUDDEN DEATHS
`Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should
`not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must
`be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT
`interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after
`taking dose (5.8). Use with caution in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at
`baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments (5.2, 5.3, 5.6, 5.12).
`
`
`1 INDICATIONS AND USAGE
`Tasigna (nilotinib) is indicated for the 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. The effectiveness of Tasigna is based on hematologic and cytogenetic response
`rates [See Clinical Studies (14)]. There are no controlled trials demonstrating a clinical benefit, such as
`improvement in disease-related symptoms or increased survival.
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. [See Clinical Pharmacology
`(12.3)]. Treatment should continue as long as the patient does not show evidence of progression or
`unacceptable toxicity.
`Tasigna should be taken twice daily at approximately 12 hour intervals and should not be taken with
`food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours
`before the dose is taken and no food should be consumed for at least one hour after the dose is taken. [See
`Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) and Clinical Studies (14).
`If a dose is missed, the patient should not take a make-up dose, but should resume taking the next
`prescribed daily dose.
`Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-
`CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.
`2.2 Dose Adjustments or Modifications
`
`QT interval prolongation:
`Dose Adjustments for QT prolongation
`Table 1
`1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium,
`and if below lower limit of normal, correct with supplements to within normal
`limits. Concomitant medication usage must be reviewed.
`2. Resume within 2 weeks at prior dose if QTcF returns to <450msec and to within
`20 msec of baseline.
`3. If QTcF is between 450 msec and 480 msec after 2 weeks reduce the dose to
`400 mg once daily.
`4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec,
`Tasigna should be discontinued.
`5. An ECG should be repeated approximately 7 days after any dose adjustment.
`
`ECGs with a QTc >
`480 msec
`
`
`
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`

`Myelosuppression: Tasigna may need to be withheld and/or dose reduced for hematological toxicities
`(neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2)
`
`
`5
`
`Dose Adjustments for Neutropenia and Thrombocytopenia
`Table 2
`ANC* < 1.0 x 109/L and/or platelet
`1.
`Stop Tasigna, and monitor blood counts
`counts < 50 x 109/L
`2. Resume within 2 weeks at prior dose if ANC >1.0
`x 109/L and platelets >50 x 109/L
`3.
`If blood counts remain low for > 2 weeks, reduce
`the dose to 400 mg once daily
`
`Chronic
`Phase or
`Accelerated
`Phase CML
`at 400 mg
`twice daily
`*ANC = absolute neutrophil count
`
`See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic
`transaminases. [See Adverse Reactions (6.1)]
`
`Table 3
`Elevated serum
`lipase or amylase ≥
`Grade 3
`
`Dose Adjustments for selected non-hematologic laboratory abnormalities
`1. Withhold Tasigna, and monitor serum lipase or amylase
`2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤
`Grade 1
`1. Withhold Tasigna, and monitor bilirubin
`2. Resume treatment at 400 mg once daily if bilirubin return to ≤ Grade 1
`1. Withhold Tasigna, and monitor hepatic transaminases
`2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤
`Grade 1
`
`Elevated bilirubin ≥
`Grade 3
`
`Elevated hepatic
`transaminases ≥
`Grade 3
`
`Other non-hematologic toxicities: If other clinically significant moderate or severe non-hematologic
`toxicity develops, dosing should be withheld, and may be resumed at 400 mg once daily when the toxicity has
`resolved. If clinically appropriate, escalation of the dose back to 400 mg twice daily should be considered. [See
`Warnings and Precautions (5) and Use in Specific Populations (8)].
`
`Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be
`avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir,
`ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations
`of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended
`that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based
`on pharmacokinetic studies, 400 mg once daily (a dose reduction to 1/2 of the original daily dose) is predicted
`to adjust the nilotinib AUC to the AUC observed without inhibitors. However, there are no clinical data with
`this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a
`washout period should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close
`monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4
`inhibitors. [See Boxed Warning, Warnings and Precautions (5.2 and 5.7) and Drug Interactions (7.2)].
`Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be
`avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital).
`Patients should also refrain from taking St. John’s Wort. If patients must be co-administered a strong CYP3A4
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`

`6
`
`inducer, the dose of Tasigna 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. [See Drug Interactions (7.2)]
`
`3 DOSAGE FORMS AND STRENGTHS
`200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.
`4 CONTRAINDICATIONS
`Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. [See Boxed Warning]
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Myelosuppression
`Treatment with Tasigna (nilotinib) can cause Grade 3/4 thrombocytopenia, neutropenia and anemia.
`Complete blood counts should be performed every two weeks for the first 2 months and then monthly
`thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by
`withholding Tasigna temporarily or dose reduction. [See Dosage and Administration (2)]
`
`5.2 QT Prolongation
`Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on
`the surface ECG in a concentration-dependent manner. Prolongation of the QT interval can result in a type of
`ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.
`Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome.
`Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be
`monitored periodically during therapy. Avoid drugs known to prolong the QT interval and strong CYP3A4
`inhibitors. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated
`and following dose adjustments. [See Clinical Pharmacology (12.4)]
`
`Sudden Deaths
`5.3
`There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867;
`
`0.6%). A similar incidence was also reported in the expanded access program. The relative early occurrence of
`some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization
`abnormalities may have contributed to their occurrence.
`
`5.4 Elevated Serum Lipase
`The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a
`previous history of pancreatitis. Serum lipase should be checked periodically.
`
`5.5 Hepatotoxicity
`The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic
`function tests should be checked periodically.
`
`5.6 Electrolyte Abnormalities
`The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and
`hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes
`should be monitored periodically during therapy.
`
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`

`7
`
`5.7
`
`Drug Interactions
`The administration of Tasigna with agents that are strong CYP3A4-inhibitors or prolong QT should be
`avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be
`interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug
`that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval.
`[See Boxed Warning, Dosage and Administration (2), and Drug Interactions (7.2)]
`5.8
`Food Effects
`The bioavailability of nilotinib is increased with food. Tasigna should not be taken with food. No food
`should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and
`other foods that are known to inhibit CYP3A4 should be avoided. [See Boxed Warning, Drug Interactions (7.2)
`and Clinical Pharmacology (12.3)].
`
`5.9 Hepatic Impairment
`Tasigna has not been investigated in patients with hepatic impairment. Clinical studies have excluded
`patients with ALT and/ or AST >2.5 (or >5, if related to disease) times the upper limit of the normal range
`and/or total bilirubin >1.5 times the upper limit of the normal range. Metabolism of nilotinib is mainly hepatic.
`Caution is recommended in patients with hepatic impairment. These patients should be closely monitored for
`QT interval prolongation. [See Boxed Warning, Dosage and Administration (2) and Use in Specific Populations
`(8.7)].
`
`5.10 Lactose
`Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary
`problems of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption.
`
`5.11 Pregnancy
`Pregnancy Category D
`Tasigna can cause fetal harm when administered to a pregnant woman.
`Nilotinib was studied for effects on embryo-fetal development in pregnant rats (GD 6-17) and rabbits (GD 7-20)
`given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively. In rats, nilotinib at doses of 100
`mg/kg/day (approximately 5.7 fold the AUC in patients at the recommended human dose) was associated with
`maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib
`at doses ≥ 30 mg/kg/day resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss,
`and at 100 mg/kg/day a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-
`half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and
`decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed
`at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic.
`There are no adequate and well-controlled studies with Tasigna in pregnant women. Women should be
`advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant
`while taking this drug, the patient should be apprised of the potential hazard to the fetus.
`
`5.12 Monitoring Laboratory Tests
`Complete blood counts should be performed every two weeks for the first two months and then monthly
`thereafter. Chemistry panels should be checked periodically. ECGs should be obtained at baseline, seven days
`after initiation and periodically thereafter, as well as following dose adjustments [See Warnings and
`Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or
`less frequently at the physician’s discretion.
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`

`8
`
`
`6 ADVERSE REACTIONS
`The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in
`other sections of the package insert [See Boxed Warning and Warnings and Precautions (5)].
`QT prolongation and Sudden Deaths [See Boxed Warning, Warnings and Precautions (5.2, 5.3)]
`Myelosuppression [See Warnings and Precautions (5.1)]
`Elevated serum lipase [See Warnings and Precautions (5.4)]
`Hepatotoxicity [See Warnings and Precautions (5.5)]
`Electrolyte abnormalities [See Boxed Warning and Warnings and Precautions (5.6)]
`
`
`6.1
`
`Clinical Trials 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.
`In the single open-label multicenter clinical trial, a total of 438 patients were treated (CML-CP=318;
`CML-AP=120).
`The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and
`138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145 – 1149) was similar for
`both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing.
`The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-
`185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1 – 163).
`In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash,
`pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drug-related
`adverse reactions were thrombocytopenia and neutropenia.
`In CML-AP patients, the most commonly reported drug-related adverse reactions (>10%) were rash,
`pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia,
`neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.
`Sudden deaths and QT prolongation were reported. [See Boxed Warning and Warnings and Precautions
`(5.2 and 5.3)]
`Discontinuation for drug related adverse reactions was observed in 11% of CML-CP and 8% of CML-
`AP patients.
`
`Table 4 shows the percentage of patients experiencing treatment-emergent adverse reactions (excluding
`laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in at least 10% of
`patients who received at least one dose of Tasigna are listed.
`
`
`Table 4
`
`Treatment-emergent Adverse Reactions Reported in ≥10% of Patients in the Clinical
`Studya
`
`
`Body System and preferred term
`
`Skin and subcutaneous tissue disorders:
`
`Rash
`
` CML-CP
`n=318
`
`All
`Grades
`(%)
`
`33
`
`CTC
`Gradesb
`3 / 4
`(%)
`2
`
`CML-AP
`n=120
`
`All
`Grades
`(%)
`
`28
`
`CTC
`Gradesb
`3 / 4
`(%)
`0
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`

`
`Gastrointestinal disorders:
`
`
`
`
`Nervous system disorders
`General disorders and administration site
`conditions
`
`
`
`
`Pruritus
`Nausea
`Diarrhea
`Constipation
`Vomiting
`Abdominal pain
`Headache
`
`Fatigue
`
`Pyrexia
`Asthenia
`Edema,
`peripheral
`
`Arthralgia
`
`Myalgia
`Pain in extremity
`Bone pain
`Muscle spasms
`Back pain
`
`Cough
`
`Dyspnea
`Nasopharyngitis
`
`29
`31
`22
`21
`21
`11
`31
`
`28
`
`14
`14
`
`11
`
`18
`
`14
`13
`11
`11
`10
`
`17
`
`11
`16
`
`1
`1
`3
`<1
`<1
`1
`3
`
`1
`
`1
`0
`
`0
`
`2
`
`2
`1
`<1
`<1
`<1
`
`<1
`
`1
`<1
`
`20
`18
`19
`18
`10
`13
`21
`
`16
`
`24
`12
`
`11
`
`16
`
`14
`16
`13
`14
`12
`
`13
`
`8
`11
`
`9
`
`0
`<1
`2
`0
`0
`3
`2
`
`<1
`
`2
`2
`
`0
`
`0
`
`<1
`2
`<1
`0
`<1
`
`0
`
`3
`0
`
`Musculoskeletal and connective tissue
`disorders
`
`
`
`
`
`Respiratory, thoracic and mediastinal
`disorders
`
`Infections and infestations
`Excluding laboratory abnormalities
`NCI Common Terminology Criteria for Adverse Events, Version 3.0
`
`a
`
`b
`
`Table 5 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities
`in patients who received at least one dose of Tasigna.
`
`Table 5
`
`
`Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities
`CML-AP
`CML-CP
`N=120
`N=318
`
`
`Grades
`Grades
`3/4 *
`3/4 *
`Hematologic Parameters
`
`
`
`
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`10
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`37%2
`37%3
`23%
`
`17%
`4%
`10%
`
`10%
`
`2%
`
`3%
`
`9%
`
`4%
`
`4%
`3%
`1%
`1%
`1%
`1%
`
`1%
`
`6.2
`
`3%
`3%
`5%
`1%
`1%
`4%
`
`28%1
`-Thrombocytopenia
`-Neutropenia2
`28%
`8%
`-Anemia
`Biochemistry Parameters
`-Elevated lipase
`15%
`-Hyperglycemia
`11%
`-Hypophosphatemia
`10%
`-Elevated Bilirubin
`(total)
`-Elevated SGPT
`(ALT)
`-Hyperkalemia
`-Hyponatremia
`-Hypokalemia
`-Elevated SGOT (AST)
`-Decreased albumin
`-Hypocalcemia
`-Elevated alkaline
`phosphatase
`0%
`<1%
`-Elevated creatinine
`*NCI Common Terminology Criteria for Adverse Events, version 3.0
`1CML-CP: Thrombocytopenia: 11% were grade 3, 17% were grade 4
`2CML-AP: Thrombocytopenia: 7% were grade 3, 30% were grade 4
`3CML-AP: Neutropenia: 12% were grade 3, 25% were grade 4
`
`
`Additional Data from Clinical Trials
`The following drug related adverse reactions are ranked under a heading of frequency, the most frequent
`first using the following convention: common (1% -10%), and uncommon (0.1%-1%) adverse reactions single
`events are captured as unknown frequency. For laboratory abnormalities, very common events (≥1/10) not
`included in Table 4 are also reported. These adverse reactions are included based on clinical relevance, and
`ranked in order of decreasing seriousness within each category.
`Infections and Infestations: Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis.
`Unknown frequency: sepsis, bronchitis, herpes simplex, candidiasis.
`Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia.
`Unknown frequency: thrombocytosis, leukocytosis.
`Endocrine Disorders: Uncommon: hyperthyroidism.
`Unknown frequency: hypothyroidism, thyroiditis.
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`Metabolism and Nutrition Disorders: Common: hypomagnesemia, hyperkalemia, hyperglycemia, anorexia.
`Uncommon: hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration, decreased appetite,
`increased appetite.
`Unknown frequency: diabetes mellitus, hypercalcemia, hyperphosphatemia.
`Psychiatric Disorders: Common: Insomnia.
`Uncommon: depression, anxiety.
`Unknown frequency: disorientation, confusional state.
`Nervous System Disorders: Common: dizziness, paresthesia
`Uncommon: intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia.
`Unknown frequency: brain edema, loss of consciousness, optic neuritis, peripheral neuropathy.
`Eye Disorders: Uncommon: eye hemorrhage, visual acuity reduced, periorbital edema, conjunctivitis, eye
`irritation, dry-eye.
`Unknown frequency: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain.
`Ear and Labyrinth Disorders: Common: vertigo.
`Unknown frequency: hearing impaired, ear pain.
`Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged.
`Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease,
`cardiomegaly, cardiac murmur, bradycardia.
`Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasysoles,
`Vascular Disorders: Common: hypertension, flushing.
`Uncommon: hypertensive crisis, hematoma.
`Unknown frequency: shock hemorrhagic, hypotension, thrombosis.
`Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, cough, dysphonia.
`Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, epistaxis,
`pharyngolaryngeal pain, throat irritation.
`Unknown frequency: pulmonary hypertension.
`Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence.
`Uncommon: pancreatitis, gastrointestinal hemorrhage, melena, abdominal distension, mouth ulceration,
`gastroesophageal reflux, stomatitis, dry mouth
`Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer,
`esophagitis ulcerative, subileus.
`Hepatobiliary Disorders: Uncommon: hepatitis
`Unknown frequency: hepatotoxicity, hepatomegaly, jaundice.
`Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, alopecia, erythema,
`hyperhidrosis, dry skin.
`Uncommon: exfoliative rash, ecchymosis, swelling face,
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`Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity.
`Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest pain, musculoskeletal pain.
`Uncommon: muscular weakness.
`Unknown frequency: Arthritis, joint swelling.
`Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia, pollakiuria.
`Unknown frequency: renal failure, hematuria, urinary incontinence.
`Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.
`General Disorders and Administration Site Conditions: Common: pyrexia.
`Uncommon: chest pain, face edema, gravitational edema, influenza-like illness, chills, malaise.
`Investigations: Very common: lipase increased.
`Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased,
`blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood
`creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased.
`Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood
`urea increased.
`Unknown frequency: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased.
`
` 7
`
` DRUG INTERACTIONS
`7.1
`Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems
`Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro,
`potentially increasing the concentrations of drugs eliminated by these enzymes. In addition, single-dose
`administration of Tasigna with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam
`exposure by 30%. Caution should be exercised when co-administering Tasigna with substrates for these
`enzymes that have a narrow therapeutic index. Since warfarin is metabolized by CYP2C9 and CYP3A4 it
`should be avoided if possible.
`In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and thereby has
`the potential to decrease the concentrations of drugs which are eliminated by these enzymes.
`Nilotinib inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp,
`increased concentrations of the substrate drug are likely, and caution should be exercised.
`7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes
`Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or
`inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly.
`Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for
`6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold. [See Box Warning and
`Warnings and Precautions (5.7)]
`Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days,
`systemic exposure (AUC) to nilotinib was decreased approximately 80%.
`7.3 Drugs that Inhibit Drug Transport Systems
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`8.3
`
`8.4
`
`Nilotinib is a substrate of the efflux