Tasigna contains nilotinib, which belongs to a pharmacologic class of drugs known as kinase inhibitors. Nilotinib drug substance, in the form of monohydrochloride monohydrate, is a white to slightly yellowish to slightly greenish yellow powder with the molecular formula and weight, respectively, of C 28 H 22 F 3 N 7 O•HCl • H 2 O and 584 g/mol (corresponding molecular formula and weight of nilotinib base, anhydrous are C 28 H 22 F 3 N 7 O and 529 g/mol, respectively). The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pK a 1 was determined to be 2.1; pK a 2 was estimated to be 5.4. The chemical name of nilotinib monohydrochloride monohydrate is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate. Its structure is shown below: Tasigna (nilotinib) capsules, for oral use, contain 50 mg, 150 mg, or 200 mg nilotinib base, anhydrous (equivalent to 55 mg, 166 mg, and 221 mg nilotinib monohydrochloride monohydrate respectively) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and poloxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide. chemical structure of nilotinib

Tasigna is a kinase inhibitor indicated for the treatment of: Adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. Pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP and CML-AP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy

Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP Tasigna is indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase

Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) resistant or intolerant to prior therapy that included imatinib

Pediatric Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy.

Capsules: 50 mg red opaque cap and light-yellow opaque body hard gelatin capsules with black radial imprint “NVR/ABL.” 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR.” 200 mg light-yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.” Capsules: 50 mg, 150 mg, and 200 mg

Recommended Adult Dose: Newly diagnosed Ph+ CML-CP: 300 mg orally twice daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg orally twice daily. Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP and CML-AP resistant or intolerant to prior TKI therapy: 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. Reduce starting dose in patients with baseline hepatic impairment. Eligible newly diagnosed adult patients with Ph+ CML-CP who have received Tasigna for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received Tasigna for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. ( 2.2 , 2.3 , 5.16 ) 2.1 Recommended Dosage Dose Tasigna twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water . For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use . 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. Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of Tasigna is 300 mg orally twice daily. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of Tasigna is 400 mg orally twice daily. Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of Tasigna for pediatric patients is 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) . If needed, attain the desired dose by combining different strengths of Tasigna capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Table 1: Pediatric Dosing of Tasigna (230 mg/m 2 Twice Daily, Maximum Single Dose of 400 mg) Body surface area Single dose Total daily dose Up to 0.32 m 2 50 mg 100 mg 0.33 – 0.54 m 2 100 mg 200 mg 0.55 – 0.76 m 2 150 mg 300 mg 0.77 – 0.97 m 2 200 mg 400 mg 0.98 – 1.19 m 2 250 mg 500 mg 1.20 – 1.41 m 2 300 mg 600 mg 1.42 – 1.63 m 2 350 mg 700 mg ≥ 1.64 m 2 400 mg 800 mg 2.2 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on Tasigna Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking Tasigna for a minimum of 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 0.0032% IS), may be eligible for treatment discontinuation . Information on FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at http://www.fda.gov/CompanionDiagnostics . Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of Tasigna. Patients must continue to be monitored for possible loss of molecular remission after treatment discontinuation. Use the same FDA-authorized test to consistently monitor molecular response levels while on and off treatment. Consider discontinuation in patients with newly diagnosed Ph+ CML-CP who have: been treated with Tasigna for at least 3 years maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) for one year prior to discontinuation of therapy achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) no history of accelerated phase or blast crisis no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Consider discontinuation in patients with Ph+ CML-CP that are resistant or intolerant to imatinib who have achieved a sustained molecular response (MR4.5) on Tasigna who have: been treated with Tasigna for a minimum of 3 years been treated with imatinib only prior to treatment with Tasigna achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL ≤ 0.0032% IS) sustained an MR4.5 for a minimum of one year immediately prior to discontinuation of therapy been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) no history of accelerated phase or blast crisis no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Monitor BCR-ABL transcript levels and complete blood count (CBC) with differential in patients who have discontinued Tasigna therapy monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter . Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) during the treatment-free phase, monitor BCR-ABL transcript levels every 2 weeks until BCR-ABL levels remain lower than major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS] for 4 consecutive measurements. The patient can then proceed to the original monitoring schedule

Reinitiation of Treatment in Patients Who Lose Molecular Response After Discontinuation of Therapy With Tasigna Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy . Patients who reinitiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until major molecular response is re-established and every 12 weeks thereafter. Patients resistant or intolerant to prior treatment that included imatinib with confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy . Patients who reinitiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4.0 is re-established and every 12 weeks thereafter

Dosage Modification for QT Interval Prolongation See Table 2 for dose adjustments for QT interval prolongation . Table 2: Dosage Adjustments for Adult and Pediatric Patients With QT Prolongation Abbreviation: ECG, electrocardiogram. Degree of QTc prolongation Dosage adjustment ECGs with a QTc greater than 480 msec 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 less than 450 msec 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 in adults and 230 mg/m 2 once daily in pediatric patients. 4. Discontinue Tasigna if, following dose-reduction to 400 mg once daily in adults and 230 mg/m 2 once daily in pediatric patients, QTcF returns to greater than 480 msec. 5. An ECG should be repeated approximately 7 days after any dose adjustment

Dosage Modifications for Myelosuppression Withhold or reduce Tasigna dosage for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 3) . Table 3: Dosage Adjustments for Neutropenia and Thrombocytopenia Abbreviations: ANC, absolute neutrophil count; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia. Diagnosis Degree of myelosuppression Dosage adjustment Adult patients with: Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L 1. Stop Tasigna, and monitor blood counts. 2. Resume within 2 weeks at prior dose if ANC greater than 1.0 x 10 9 /L and platelets greater than 50 x 10 9 /L. 3. If blood counts remain low for greater than 2 weeks, reduce the dose to 400 mg once daily. Pediatric patients with: Newly diagnosed Ph+ CML in chronic phase at 230 mg/m 2 twice daily Resistant or intolerant Ph+ CML in chronic phase at 230 mg/m 2 twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L 1. Stop Tasigna and monitor blood counts. 2. Resume within 2 weeks at prior dose if ANC greater than 1.5 x 10 9 /L and/or platelets greater than 75 x 10 9 /L. 3. If blood counts remain low for greater than 2 weeks, a dose reduction to 230 mg/m 2 once daily may be required. 4. If event occurs after dose reduction, consider discontinuing treatment

Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities See Table 4 for dosage adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases . Table 4: Dosage Adjustments for Selected Non-Hematologic Laboratory Abnormalities Degree of non-hematologic laboratory abnormality Dosage adjustment Elevated serum lipase or amylase greater than or equal to Grade 3 Adult patients: 1. Withhold Tasigna, and monitor serum lipase or amylase. 2. Resume treatment at 400 mg once daily if serum lipase or amylase returns to less than or equal to Grade 1. Pediatric patients: 1. Interrupt Tasigna until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily. Elevated bilirubin greater than or equal to Grade 3 in adult patients and greater than or equal to Grade 2 in pediatric patients Adult patients: 1. Withhold Tasigna, and monitor bilirubin. 2. Resume treatment at 400 mg once daily if bilirubin returns to less than or equal to Grade 1. Pediatric patients: 1. Interrupt Tasigna until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days. Elevated hepatic transaminases greater than or equal to Grade 3 Adult patients: 1. Withhold Tasigna, and monitor hepatic transaminases. 2. Resume treatment at 400 mg once daily if hepatic transaminases returns to less than or equal to Grade 1. Pediatric patients: 1. Interrupt Tasigna until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days. If clinically significant moderate or severe non-hematologic toxicity develops (including medically severe fluid retention), see Table 5 for dosage adjustments . Table 5: Dosage Adjustments for Other Non-Hematologic Toxicities Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. Degree of “other Non-hematologic toxicity” Dosage adjustment Other clinically moderate or severe non-hematologic toxicity Adult patients: 1. Withhold Tasigna until toxicity has resolved. 2. Resume treatment at 400 mg once daily if previous dose was 300 mg twice daily in adult patients newly diagnosed with CML-CP or 400 mg twice daily in adult patients with resistant or intolerant CML-CP and CML-AP. 3. Discontinue treatment if the prior dose was 400 mg once daily in adult patients. 4. If clinically appropriate, consider re-escalation of the dose to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily. Pediatric patients: 1. Interrupt Tasigna until toxicity has resolved. 2. Resume treatment at 230 mg/m 2 once daily if previous dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily. 3. If clinically appropriate, consider re-escalation of the dose to 230 mg/m 2 twice daily

Dosage Modification for Hepatic Impairment If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction : Table 6: Dose Adjustments for Adult Patients With Hepatic Impairment Diagnosis Degree of hepatic impairment Dosage adjustment Newly diagnosed Ph+ CML in chronic phase Mild (Child-Pugh A), Moderate (Child-Pugh B), or Severe (Child-Pugh C) Reduce dosage to 200 mg twice daily. Increase dosage to 300 mg twice daily based on tolerability. Resistant or intolerant Ph+ CML in chronic phase or accelerated phase Mild or Moderate Reduce dosage to 300 mg twice daily. Increase dosage to 400 mg twice daily based on tolerability. Severe Reduce dosage to 200 mg twice daily. Increase dosage to 300 mg twice daily and then to 400 mg twice daily based on tolerability

Dosage Modification With Concomitant Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors. Should treatment with any of these agents be required, interrupt therapy with Tasigna. If patients must be coadministered a strong CYP3A4 inhibitor, reduce dosage to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, allow a washout period before adjusting Tasigna dose upward to the indicated dose. For patients who cannot avoid use of strong CYP3A4 inhibitors, monitor closely for prolongation of the QT interval .

Myelosuppression: Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. Cardiac and Arterial Vascular Occlusive Events: Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during Tasigna therapy. Pancreatitis and Elevated Serum Lipase: Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis. Hepatotoxicity: Monitor hepatic function tests monthly or as clinically indicated. Electrolyte Abnormalities: Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy. Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. Hemorrhage: Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed. Fluid Retention: Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. Effects on Growth and Development in Pediatric Patients: Growth retardation has been reported in pediatric patients treated with Tasigna. Monitor growth and development in pediatric patients. Embryo-Fetal Toxicity: Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 ) Treatment Discontinuation: Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform CBCs every 2 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

QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface electrocardiogram (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. Electrocardiograms should be performed at baseline, 7 days after initiation of Tasigna, and periodically as clinically indicated and following dose adjustments . Tasigna should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating Tasigna and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy . Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided . The presence of hypokalemia and hypomagnesemia may further prolong the QT interval

Sudden Deaths Sudden deaths have been reported in 0.3% of patients with CML treated with Tasigna in clinical studies of 5661 patients. The relative early occurrence of some of these deaths relative to the initiation of Tasigna suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence

Cardiac and Arterial Vascular Occlusive Events Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the postmarketing reports of patients receiving Tasigna therapy . With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, occurred in 9% and 15% of patients in the Tasigna 300 and 400 mg twice daily arms, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events, including ischemic heart disease-related cardiac events (5% and 9% in the Tasigna 300 mg and 400 mg twice daily arms, respectively, and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 2.9% in the Tasigna 300 mg and 400 mg twice daily arms, respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.4% and 3.2% in the Tasigna 300 mg and 400 mg twice daily arms, respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to standard guidelines

Pancreatitis and Elevated Serum Lipase Tasigna can cause increases in serum lipase . Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis . Test serum lipase levels monthly or as clinically indicated

Hepatotoxicity Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Grade 3-4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated and following dose adjustments.

Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and during therapy. Monitor these electrolytes periodically during therapy

Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases. Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna

Hemorrhage Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with Tasigna. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Tasigna and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the Tasigna 300 mg twice daily arm, in 1.8% of patients in the Tasigna 400 mg twice daily arm, and 0.4% of patients in the imatinib arm. GI hemorrhage occurred in 2.9% and 5% of patients in the Tasigna 300 mg twice daily and 400 mg twice daily arms and in 1.4% of patients in the imatinib arm, respectively. Grade 3 or 4 events occurred in 0.7% and 1.4% of patients in the Tasigna 300 mg twice daily and 400 mg twice daily arms, respectively, and in no patients in the imatinib arm. Monitor for signs and symptoms of bleeding and medically manage as needed

Total Gastrectomy Since the exposure of Tasigna is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy

Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption

Monitoring Laboratory Tests Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose prior to therapy and periodically. Electrocardiograms should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments . Monitor lipid profiles and glucose periodically during the first year of Tasigna therapy and at least yearly during chronic therapy. Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to treat lipid elevations, evaluate the potential for a drug-drug interaction before initiating therapy as certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway . Assess glucose levels before initiating treatment with Tasigna and monitor during treatment as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines

Fluid Retention In the randomized trial in patients with newly diagnosed Ph+ CML in chronic phase, severe (Grade 3 or 4) fluid retention occurred in 3.9% and 2.9% of patients receiving Tasigna 300 mg twice daily and 400 mg twice daily, respectively, and in 2.5% of patients receiving imatinib. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema, were observed in 2.2% and 1.1% of patients receiving Tasigna 300 mg twice daily and 400 mg twice daily, respectively, and in 2.1% of patients receiving imatinib. Effusions were severe (Grade 3 or 4) in 0.7% and 0.4% of patients receiving Tasigna 300 mg twice daily and 400 mg twice daily, respectively, and in no patients receiving imatinib. Similar events were also observed in postmarketing reports. Monitor patients for signs of severe fluid retention (e.g., unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during Tasigna treatment; evaluate etiology and treat patients accordingly

Effects on Growth and Development in Pediatric Patients Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with Tasigna. In a pediatric trial with 58 patients with Ph+ CML in chronic phase with a median exposure of 56.7 months, growth deceleration (crossing at least two main height percentile lines from baseline) was observed in eight patients: five (9%) crossed two main percentile lines from baseline and three (5%) crossed three main percentile lines from baseline (percentile lines: 5 th , 10 th , 25 th , 50 th , 75 th , 90 th , and 95 th ). Growth deceleration was more pronounced in children who were less than age 12 at baseline. Adverse reactions associated with growth retardation were reported in 3 patients (5%). Monitor growth and development in pediatric patients receiving Tasigna treatment

Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, Tasigna can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal lethality/fetal effects (small renal papilla, fetal edema, and skeletal variations) in rats and increased resorptions of fetuses and fetal skeletal variations in rabbits at maternal area under the curve (AUCs) approximately 2 and 0.5 times, respectively, the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose

Monitoring of BCR-ABL Transcript Levels Monitoring of BCR-ABL Transcript Levels in Patients Who Discontinued Tasigna Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA authorized test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS). In patients who discontinue Tasigna therapy, assess BCR-ABL transcript levels monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation . Newly diagnosed patients must reinitiate Tasigna therapy within 4 weeks of a loss of major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS]. Patients resistant or intolerant to prior treatment which included imatinib must reinitiate Tasigna therapy within 4 weeks of a loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0, corresponding to = BCR-ABL/ABL ≤ 0.01% IS). For patients who fail to achieve MMR after three months of treatment reinitiation, BCR-ABL kinase domain mutation testing should be performed. Monitoring of BCR-ABL Transcript Levels in Patients Who Have Reinitiated Therapy After Loss of Molecular Response Monitor CBC and BCR-ABL transcripts in patients who reinitiate treatment with Tasigna due to loss of molecular response quantitation every 4 weeks until a major molecular response is re-established, then every 12 weeks.

5.8 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases. Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna.