Danziten Drug Information

• The following clinically significant adverse reactions can occur with DANZITEN and are discussed in greater detail in other sections of labeling:
• Myelosuppression [ see Warnings and Precautions ( 5.2 ) ]
• QT Prolongation [ see Boxed Warning, Warnings and Precautions ( 5.3 ) ]
• Sudden Deaths [ see Boxed Warning, Warnings and Precautions ( 5.4 ) ]
• Cardiac and Arterial Vascular Occlusive Events [ see Warnings and Precautions ( 5.5 ) ]
• Pancreatitis and Elevated Serum Lipase [ see Warnings and Precautions ( 5.6 ) ]
• Hepatotoxicity [ see Warnings and Precautions ( 5.7 ) ]
• Electrolyte Abnormalities [ see Boxed Warning, Warnings and Precautions ( 5.8 ) ]
• Hemorrhage [ see Warnings and Precautions ( 5.10 ) ]
• Fluid Retention [ see Warnings and Precautions ( 5.13 ) ] The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult patients are 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 Azurity Pharmaceuticals, Inc., at 1-800-461-7449 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. The safety of DANZITEN (nilotinib) tablets has been established from adequate and well-controlled studies of Tasigna ® (nilotinib) capsules, which has different recommended dosages than DANZITEN, in adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) and adult patients with CP and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib [see Clinical Studies ( 14 )] . Below is a display of the adverse reactions of Tasigna ® (nilotinib) capsules in these adequate and well-controlled studies. In Adult Patients With Newly Diagnosed Ph+ CML-CP The data below reflect exposure to nilotinib from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the equivalent recommended dosage of DANZITEN 142 mg twice daily (n = 279). The median time on treatment at the equivalent recommended dosage of DANZITEN 142 mg twice daily group was 61 months (range, 0.1 to 71 months). 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%). Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) at the equivalent recommended dosage of DANZITEN 142 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 10 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-arm, 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 equivalent recommended dosage of DANZITEN 190 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 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 ( 5.3 , 5.4 ), 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 Nilotinib 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 (≥ 10% in nilotinib 300 mg twice daily* or imatinib 400 mg once daily groups) 60-Month Analysis a Patients With Newly Diagnosed Ph+ CML-CP nilotinib 300 mg Twice Daily* imatinib 400 mg Once Daily nilotinib 300 mg Twice Daily* imatinib 400 mg Once 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 Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria (CTC) for Adverse Events, version 3.0. *Equivalent to the recommended dosage of DANZITEN 142 mg twice daily. Table 8. Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients with Resistant or Intolerant Ph+ CML Receiving Nilotinib 400 mg Twice Daily* (regardless of relationship to study drug) (≥ 10% in any group) 24-Month Analysis a 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 appetite c 15 < 1 17 < 1 Psychiatric disorders Insomnia 12 1 7 0 Vascular disorders Hypertension 10 2 11 < 1 Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria for Adverse Events, version 3.0. c Also includes preferred term anorexia. *Equivalent to the recommended dosage of DANZITEN 190 mg twice daily. 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 nilotinib. 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 nilotinib 300 mg a imatinib 400 mg nilotinib 400 mg b nilotinib 400 mg b Twice Daily Once Daily Twice Daily Twice Daily N = 279 N = 280 N = 321 N = 137 (%) (%) (%) (%) Hematologic Parameters Thrombocytopenia 10 9 30 1 42 3 Neutropenia 12 22 31 2 42 4 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 Abbreviations: ALT alanine aminotransferase; AST, aspartate aminotransferase; CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. *NCI Common Terminology Criteria for Adverse Events, version 3.0. 1 CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4. 2 CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4. 3 CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4. 4 CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4. a Equivalent to the recommended dosage of DANZITEN 142 mg twice daily. b Equivalent to the recommended dosage of DANZITEN 190 mg twice daily. Elevated total cholesterol (all Grades) occurred in 28% (equivalent recommended dosage of DANZITEN 142 mg twice daily) and 4% (imatinib). Elevated triglycerides (all Grades) occurred in 12% and 8% of patients in the nilotinib and imatinib arms, respectively. Hyperglycemia (all Grades) occurred in 50% and 31% of patients in the nilotinib 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 Patients With Ph+ CML-CP Who Have Achieved a Sustained Molecular Response (MR4.5) In eligible patients who discontinued nilotinib 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 9. 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%) 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%) had not resolved by the data cut-off date. The rate of musculoskeletal symptoms decreased in patients who entered the nilotinib treatment reinitiation (NTRI) phase, at 11/88 (13%) in the newly diagnosed population and 14/56 (25%) in the population previously treated with imatinib. Other adverse reactions observed in the nilotinib re-treatment phase were similar to those observed during nilotinib 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 G reater than 48 Weeks Ph+ CML- CP patients N Median follow- up in Patients with musculoskeletal symptoms N Year prior to nilotinib discontinuation 1st year after nilotinib discontinuation 2nd year after nilotinib discontinuation TFR 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% Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive ;TFR, treatment-free remission. Additional Data from Clinical Trials The following adverse drug reactions were reported in adult patients in the nilotinib 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, facial paralysis. 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 In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse reactions were hyperbilirubinemia, headache, alanine aminotransferase increased, rash, pyrexia, nausea, aspartate aminotransferase increased, pain in extremity, upper respiratory tract infection, vomiting, diarrhea, and nasopharyngitis. The most common (greater than 5%) Grade 3/4 non-hematologic adverse reactions were hyperbilirubinemia, rash, alanine aminotransferase increased, and neutropenia. Laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), were reported at a higher frequency than in adult patients. The most common hematological laboratory abnormalities (greater than or equal to 30% of patients, of all Grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (44%), hemoglobin (38%), and absolute lymphocytes (36%). Discontinuation of study treatment due to adverse reactions occurred in 15 patients (22%). The most frequent adverse reactions leading to discontinuation were hyperbilirubinemia (9%) and rash (6%). Increase in QTcF greater than 30 msec from baseline was observed in 19 patients (28%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline. Growth Retardation in Pediatric Population Close monitoring of growth in pediatric patients under nilotinib treatment is recommended [see Warnings and Precautions ( 5.14 )]. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna ® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of nilotinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : thrombotic microangiopathy Nervous System Disorders : facial paralysis Musculoskeletal and Connective Tissue Disorders : osteonecrosis

• Strong CYP3A Inhibitors : Avoid concomitant use with DANZITEN or reduce DANZITEN dose if concomitant use cannot be avoided. ( 7.1 )
• Strong CYP3A Inducers : Avoid concomitant use with DANZITEN. ( 7.1 )
• Proton Pump Inhibitors : Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. ( 7.1 ) 7.1 Effect of Other Drugs on DANZITEN Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors with DANZITEN. If concomitant use cannot be avoided, reduce DANZITEN dose [see Dosage and Administration ( 2.9 )] . Nilotinib is a CYP3A substrate [see Clinical Pharmacology ( 12.3 )]. Concomitant use with a strong CYP3A inhibitor increases nilotinib exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of DANZITEN adverse reactions. Strong CYP3A Inducers Avoid concomitant use of strong CYP3A inducers with DANZITEN. Nilotinib is a CYP3A substrate [see Clinical Pharmacology ( 12.3 )] . Concomitant use with a strong CYP3A inducer decreases nilotinib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce DANZITEN efficacy. Proton Pump Inhibitors Avoid concomitant use of PPI with DANZITEN. As an alternative to PPIs, use H 2 blockers approximately 10 hours before or approximately 2 hours after the dose of DANZITEN, or use antacids approximately 2 hours before or approximately 2 hours after the dose of DANZITEN. Nilotinib displays pH-dependent aqueous solubility [see Description ( 11 )] . Concomitant use with a proton pump inhibitor (PPI) decreases nilotinib concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce DANZITEN efficacy. 7.2 Drugs that Prolong the QT Interval Avoid coadministration of DANZITEN with agents that may prolong the QT interval, such as anti-arrhythmic drugs [see Boxed Warning, Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )]. Nilotinib is associated with a clinically significant concentration-dependent QT prolongation [see Clinical Pharmacology ( 12.2 )].

Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, DANZITEN can cause fetal harm when administered to a pregnant woman. 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.

Pediatric Use 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: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), which were reported at a higher frequency in pediatric patients than in adults . For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with nilotinib. The safety and effectiveness of nilotinib in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase and accelerated phase, have not been established. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna ® (nilotinib) capsules.

However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. DANZITEN is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

Overdose with nilotinib has been reported, where an unspecified number of nilotinib were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, observe the patient and provide appropriate supportive treatment.