Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 16 April 2018

Indication(s)

1 INDICATIONS AND USAGE 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. (1.1) Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. (1.2) Pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy. (1.3) 1.1 Adult and Pediatric Patients with Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) 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. 1.2 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. 1.3 Pediatric Patients with Resistant or Intolerant Ph+ CML-CP Tasigna is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy.

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Advisory information

contraindications
4 CONTRAINDICATIONS Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of labeling: Myelosuppression [see Warnings and Precautions (5.1)] QT Prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden Deaths [see Boxed Warning, Warnings and Precautions (5.3)] Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions (5.4)] Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions (5.5)] Hepatotoxicity [see Warnings and Precautions (5.6)] Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions (5.7)] Hemorrhage [see Warnings and Precautions (5.9)] Fluid Retention [see Warnings and Precautions (5. 13 )] The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult and pediatric patients were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia and anemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Adult Patients with Newly Diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the Tasigna 300 mg twice daily group was 61 months (range 0.1 to 71 months). The median actual dose intensity was 593 mg/day in the Tasigna 300 mg twice daily group. The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or equal to 10% and greater than 5%) and have been of mild-to-moderate severity, manageable and generally did not require dose reduction. Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of greater than 500 msec while on study drug. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (8%). See Table 9 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients. In Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively 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 20 (range 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients and QTcF of greater than 500 msec was observed in 4 patients (less than 1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.2)]. Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 7 and 8 show the percentage of adult patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of adult patients who received at least 1 dose of Tasigna are listed. Table 7: Most Frequently Reported Non-Hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Adult Patients with Newly Diagnosed Ph+ CML-CP (Greater than or equal to 10% in Tasigna 300 mg Twice Daily or Imatinib 400 mg Once Daily Groups) 60-Month Analysisa Patients with Newly Diagnosed Ph+ CML-CP TASIGNA 300 mg t wice daily Imatinib 400 mg o nce daily TASIGNA 300 mg t wice daily Imatinib 400 mg o nce daily N=279 N=280 N=279 N=280 Body System and Adverse Reaction All Grades (%) CTC Grades b 3/ 4 (%) Skin and subcutaneous tissue disorders Rash 38 19 <1 2 Pruritus 21 7 <1 0 Alopecia 13 7 0 0 Dry skin 12 6 0 0 Gastrointestinal disorders Nausea 22 41 2 2 Constipation 20 8 <1 0 Diarrhea 19 46 1 4 Vomiting 15 27 <1 <1 Abdominal pain upper 18 14 1 <1 Abdominal pain 15 12 2 0 Dyspepsia 10 12 0 0 Nervous system disorders Headache 32 23 3 <1 Dizziness 12 11 <1 <1 General disorders and administration site conditions Fatigue 23 20 1 1 Pyrexia 14 13 <1 0 Asthenia 14 12 <1 0 Peripheral edema 9 20 <1 0 Face edema <1 14 0 <1 Musculoskeletal and connective tissue disorders Myalgia 19 19 <1 <1 Arthralgia 22 17 <1 <1 Muscle spasms 12 34 0 1 Pain in extremity 15 16 <1 <1 Back pain 19 17 1 1 Respiratory, thoracic and mediastinal disorders Cough 17 13 0 0 Oropharyngeal pain 12 6 0 0 Dyspnea 11 6 2 <1 Infections and infestations Nasopharyngitis 27 21 0 0 Upper respiratory tract infection 17 14 <1 0 Influenza 13 9 0 0 Gastroenteritis 7 10 0 <1 Eye disorders Eyelid edema 1 19 0 <1 Periorbital edema <1 15 0 0 Psychiatric disorders Insomnia 11 9 0 0 Vascular disorder Hypertension 10 4 1 <1 aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 8: Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients with Resistant or Intolerant Ph+ CML Receiving TASIGNA 400 mg Twice Daily (Regardless of Relationship to Study Drug) (Greater than or equal to 10% in any Group) 24-Month Analysisa Body System and Adverse Reaction CML-CP CML-AP N=321 N=137 All Grades (%) CTC Grades b 3/ 4 (%) All Grades (%) CTC Grades b 3 / 4 (%) Skin and subcutaneous tissue disorders Rash 36 2 29 0 Pruritus 32 <1 20 0 Night sweat 12 <1 27 0 Alopecia 11 0 12 0 Gastrointestinal disorders Nausea 37 1 22 <1 Constipation 26 <1 19 0 Diarrhea 28 3 24 2 Vomiting 29 <1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 <1 12 <1 Dyspepsia 10 <1 4 0 Nervous system disorders Headache 35 2 20 1 General disorders and administration site conditions Fatigue 32 3 23 <1 Pyrexia 22 <1 28 2 Asthenia 16 0 14 1 Peripheral edema 15 <1 12 0 Musculoskeletal and connective tissue disorders Myalgia 19 2 16 <1 Arthralgia 26 2 16 0 Muscle spasms 13 <1 15 0 Bone pain 14 <1 15 2 Pain in extremity 20 2 18 1 Back pain 17 2 15 <1 Musculoskeletal pain 11 <1 12 1 Respiratory, thoracic and mediastinal disorders Cough 27 <1 18 0 Dyspnea 15 2 9 2 Oropharyngeal pain 11 0 7 0 Infections and infestations Nasopharyngitis 24 <1 15 0 Upper respiratory tract infection 12 0 10 0 Metabolism and nutrition disorders Decreased appetitec 15 <1 17 <1 Psychiatric disorders Insomnia 12 1 7 0 Vascular disorders Hypertension 10 2 11 <1 aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 cAlso includes preferred term anorexia Laboratory Abnormalities Table 9 shows the percentage of adult patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna. Table 9: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Newly Diagnosed Adult Ph+ CML-CP Resistant or Intolerant Adult Ph+ CML-CP CML-AP TASIGNA 300 mg twice daily N=279 (%) Imatinib 400 mg once daily N=280 (%) TASIGNA 400 mg twice daily N=321 (%) TASIGNA 400 mg twice daily N=137 (%) Hematologic Parameters Thrombocytopenia 10 9 301 423 Neutropenia 12 22 312 424 Anemia 4 6 11 27 Biochemistry Parameters Elevated lipase 9 4 18 18 Hyperglycemia 7 <1 12 6 Hypophosphatemia 8 10 17 15 Elevated bilirubin (total) 4 <1 7 9 Elevated SGPT (ALT) 4 3 4 4 Hyperkalemia 2 1 6 4 Hyponatremia 1 <1 7 7 Hypokalemia <1 2 2 9 Elevated SGOT (AST) 1 1 3 2 Decreased albumin 0 <1 4 3 Hypocalcemia <1 <1 2 5 Elevated alkaline phosphatase 0 <1 <1 1 Elevated creatinine 0 <1 <1 <1 *NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4 2CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4 3CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4 4CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4 Elevated total cholesterol (all grades) occurred in 28% (Tasigna 300 mg twice daily) and 4% (imatinib). Elevated triglycerides (all grades) occurred in 12% and 8% of patients in the Tasigna and imatinib arms, respectively. Hyperglycemia (all Grades) occurred in 50% and 31% of patients in the Tasigna and imatinib arms, respectively. Most common biochemistry laboratory abnormalities (all grades) were alanine aminotransferase increased (72%), blood bilirubin increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood cholesterol increased (28%), and blood triglyceride increased (12%). Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained molecular response (MR4.5) In eligible patients who discontinued Tasigna therapy after attaining a sustained molecular response (MR4.5), musculoskeletal symptoms (e.g. myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as noted in Table 10. The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation. In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time during the TFR phase, 23/53 (43.4%) had not resolved by the TFR end date or data cut-off date. In the population previously treated with imatinib in whom musculoskeletal events occurred at any time during the TFR phase, 32/57 (56.1%) had not resolved by the data cut-off date. The rate of musculoskeletal symptoms decreased in patients who entered the Tasigna treatment reinitiation (NTRI) phase, at 11/88 (12.5%) in the newly diagnosed population and 14/56 (25%) in the population previously treated with imatinib. Other adverse reactions observed in the Tasigna re-treatment phase were similar to those observed Tasigna use in patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP. Table 10: Musculoskeletal symptoms occurring upon treatment discontinuation in the context of treatment-free remission (TFR) Entire TFR period in all TFR patients By time interval, in subset of patients in TFR greater than 48 weeks Ph+ CML-CP patients N Median follow-up in TFR Patients with musculoskeletal symptoms N Year prior to TASIGNA discontinuation 1st year after TASIGNA discontinuation 2nd year after TASIGNA discontinuation All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Newly Diagnosed 190 76 weeks 28% 1% 100 17% 0% 34% 2% 9% 0% Previously treated with imatinib 126 99 weeks 45% 2% 73 14% 0% 48% 3% 15% 1% Additional Data from Clinical Trials The following adverse drug reactions were reported in adult patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (greater than or equal to 1% and less than 10%), uncommon (greater than or equal to 0.1% and less than 1%), and unknown frequency (single events). For laboratory abnormalities, very common events (greater than or equal to 10%), which were not included in Tables 7 and 8, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies: 1. Adult patients with newly diagnosed Ph+ CML-CP 60 month analysis and, 2. Adult patients with resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis. Infections and Infestations: Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis). Unknown frequency: hepatitis B reactivation, sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant , and Unspecified : Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia. Blood and Lymphatic System Disorders: Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia. Psychiatric Disorders: Common: depression, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: basilar artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Eye Disorders: Common: eye hemorrhage, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilledema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery stenosis, myocardial ischemia, pericardial effusion, cyanosis. Unknown frequency: ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis, peripheral artery stenosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea exertional, epistaxis, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing. Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Hepatobiliary Disorders: Very Common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform). Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis. Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness. Uncommon: musculoskeletal stiffness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema. Investigations: Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including very low density and high density) increased, total cholesterol increased, blood triglycerides increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, globulins decreased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased. In Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP The data below reflect exposure to Tasigna from two studies in pediatric patients from 2 to less than 18 years of age with either newly diagnosed Ph+ CML-CP or imatinib/dasatinib resistant or intolerant Ph+ CML-CP treated at the recommended dose of 230 mg/m2 twice daily (n=69) [see Clinical Studies (14.5)]. The median time on treatment with Tasigna was 13.8 months (range: 0.7 to 30.9 months). The median actual dose intensity was 435.5 mg/m2/day (range: 149 to 517 mg/m2/day), and the median relative dose intensity was 94.7% (range: 32 to 112%). Forty patients (58.0%) had relative dose intensity superior to 90%. In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse drug reactions were headache, rash, hyperbilirubinemia, alanine aminotransferase increased, pyrexia, nausea, upper respiratory tract infection, aspartate aminotransferase increased, and vomiting. The most common (greater than 5%) Grade 3/4 non-hematologic adverse drug reactions were alanine aminotransferase increased and hyperbilirubinemia. Laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%) and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), were reported at a higher frequency than in adult patients. The most common hematological adverse drug reactions (greater than or equal to 30% of patients, of all grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (41%), absolute lymphocytes (32%), and hemoglobin (30%). Discontinuation due to adverse reactions occurred in 9 patients (13%). The adverse reactions leading to discontinuation were hyperbilirubinemia (6%) and rash (4%). Increase in QTcF greater than 30 msec from baseline was observed in 17 patients (25%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 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. (2.1) Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). (2.1) See Dosage and Administration (2.1) for full dosing instructions and dose-reduction instructions for toxicity. Reduce starting dose in patients with baseline hepatic impairment. (2.7) 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 Dosing Tasigna should be taken twice daily at approximately 12-hour intervals and must be taken 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 [see Boxed Warning, Clinical Pharmacology (12.3)]. 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 [see Clinical Pharmacology (12.3)]. 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 dose of Tasigna is 300 mg orally twice daily. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dose 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 The recommended dose of Tasigna for pediatric patients is 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). 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/m2 twice daily, maximum single dose of 400 mg) Body Surface Area (BSA) Single Dose Total Daily Dose Up to 0.32 m2 50 mg 100 mg 0.33 - 0.54 m2 100 mg 200 mg 0.55 - 0.76 m2 150 mg 300 mg 0.77 - 0.97 m2 200 mg 400 mg 0.98 - 1.19 m2 250 mg 500 mg 1.20 - 1.41 m2 300 mg 600 mg 1.42 - 1.63 m2 350 mg 700 mg ≥1.64 m2 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 [see Clinical Studies (14.3, 14.4)]. 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 (i.e., 13a2/b2a2 or e14a2/b3a2) who achieve the sustained MR4.5 criteria are eligible for discontinuation of Tasigna treatment. 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 of treatment 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 of treatment in patients with Ph+ CML-CP that are resistant or intolerant to treatment with 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 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 [see Warnings and Precautions (5.16)]. 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. 2.3 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 [see Warnings and Precautions ( 5.1 6) ]. 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 [see Warnings and Precautions (5.16)]. 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. 2.4 Dosage Modification for QT Interval Prolongation See Table 2 for dose adjustments for QT interval prolongation [see Clinical Pharmacology (12.2)]. Table 2: Dose Adjustments for Adult and Pediatric Patients with QT Prolongation Degree of QTc Prolongation Dose 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/m2 once daily in pediatric patients. 4. Discontinue Tasigna if, following dose-reduction to 400 mg once daily in adults and 230 mg/m2 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. 2.5 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: Dose Adjustments for Neutropenia and Thrombocytopenia *ANC=absolute neutrophil count Diagnosis Degree of Myelosuppression Dose 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 109/L and/or platelet counts less than 50 x 109/L 1. Stop Tasigna, and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC greater than 1.0 x 109/L and platelets greater than 50 x 109/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/m2 twice daily - Resistant or intolerant Ph+ CML in chronic phase at 230 mg/m2 twice daily ANC* less than 1.0 x 109/L and/or platelet counts less than 50 x 109/L 1. Stop Tasigna and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC greater than 1.5 x 109/L and/or platelets greater than 75 x 109/L 3. If blood counts remain low for greater than 2 weeks, a dose reduction to 230 mg/m2 once daily may be required 4. If event occurs after dose reduction, consider discontinuing treatment See Table 4 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see Adverse Reactions (6.1)]. Table 4: Dose Adjustments for Selected Non-Hematologic Laboratory Abnormalities Degree of Non-Hematologic Laboratory Abnormalities Dose 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/m2 once daily if prior dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 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/m2 once daily if prior dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 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/m2 once daily if prior dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days 2.6 Dosage Modification for Other Non-Hematologic Toxicities If clinically significant moderate or severe non-hematologic toxicity develops (including medically severe fluid retention), see Table 5 for dose adjustments [see Adverse Reactions (6.1)]. Table 5: Dose Adjustments for Other Non-hematologic Laboratory Abnormalities Degree of “Other Non-Hematologic Toxicity” Dose 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/m2 once daily if previous dose was 230 mg/m2 twice daily; discontinue treatment if prior dose was 230 mg/m2 once daily. 3. If clinically appropriate, consider re-escalation of the dose to 230 mg/m2 twice daily. 2.7 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 [see Use in Specific Populations (8.7)]. 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. 2.8 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 [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.1, 7.2), and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, Tasigna can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal lethality, fetal effects, and fetal variations in rats and rabbits at maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis. In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses ≥ 30 mg/kg/day. At ≥ 30 mg/kg/day skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 mg/kg/day. Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day. In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity. Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at this dose. At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72700 ng*hr/mL and 17100 ng*hr/mL respectively, representing approximately 2 and 0.5 times the exposure in humans at the highest recommended dose 400 mg twice daily. When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 60 mg/kg (i.e., 360 mg/m2, approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 20 mg/kg (i.e., 120 mg/m2, approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups. 8.2 Lactation Risk Summary No data are available regarding the presence of nilotinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, nilotinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, advise lactating women not to breastfeed during treatment with Tasigna and for at least 14 days after the last dose. Animal Data After a single 20 mg/kg of [14C] nilotinib dose to lactating rats, the transfer of parent drug and its metabolites into milk was observed. The overall milk-to-plasma exposure ratio of total radioactivity was approximately 2, based on the AUC0-24h or AUC0-∞ values. No rat metabolites of nilotinib were detected that were unique to milk. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with Tasigna. Contraception Females Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Tasigna and for at least 14 days after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In studies in rats and rabbits, the fertility in males and females was not affected [see Nonclinical Toxicology (13 .1 )]. 8.4 Pediatric Use The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase [see Clinical Studies (14.5)]. There are no data for pediatric patients under 2 years of age. Use of Tasigna in pediatric patients 1 to less than 2 years of age is supported by efficacy in pediatric patients 2 to 6 years of age. Use of Tasigna in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials [see Clinical Studies (14.5)]. The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years). All pediatric patients received Tasigna treatment at a dose of 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). No differences in efficacy or safety were observed between the different age subgroups in the two trials. The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%) and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), which were reported at a higher frequency in pediatric patients than in adults [see Adverse Reactions (6.1)]. The long-term effects of prolonged treatment with Tasigna in pediatric patients are unknown. 8.5 Geriatric Use In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over respectively. Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged less than 65 years and those greater than or equal to 65 years. Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged less than 65 years and those greater than or equal to 65 years. Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients less than 65 years of age and 29% in patients greater than or equal to 65 years. No major differences for safety were observed in patients greater than or equal to 65 years of age as compared to patients less than 65 years. 8.6 Cardiac Disorders In the clinical trials, patients with a history of uncontrolled or significant cardiovascular disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, were excluded. Caution should be exercised in patients with relevant cardiac disorders [see Boxed Warning, Warnings and Precautions (5.2)]. 8.7 Hepatic Impairment Reduce the Tasigna dosage in patients with hepatic impairment and monitor the QT interval closely in these patients [see Dosage and Administration (2.7), and Clinical Pharmacology (12.3)].

Interactions

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

More information

Category Value
Authorisation number NDA022068
Agency product number F41401512X
Orphan designation No
Product NDC 0078-0526,0078-0592
Date Last Revised 22-03-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Novartis Pharmaceuticals Corporation
Warnings WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments (5.2, 5.3, 5.7, 5. 12 ). Sudden deaths have been reported in patients receiving Tasigna (5.3). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2). Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors (7.1, 7.2). Avoid food 2 hours before and 1 hour after taking the dose (2.1). WARNING: QT PROLONGATION AND SUDDEN DEATHS See full prescribing information for complete boxed warning. Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies ( 5.2 ). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments ( 5.2 , 5.3 , 5.7 , 5.12 ). Sudden deaths have been reported in patients receiving Tasigna ( 5.3 ). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome ( 4 , 5.2 ). Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors ( 7.1, 7.2 ). A void food 2 hours before and 1 hour after taking the dose ( 2.1 ).