Dasatinib

1 INDICATIONS AND USAGE Dasatinib tablets are indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Dasatinib tablets are indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase. newly diagnosed Ph+ ALL in combination with chemotherapy. Dasatinib tablets are a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. ( 1 , 14 ) adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. ( 1 , 14 ) adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. ( 1 , 14 ) pediatric patients 1 year of age and older with Ph+ CML in chronic phase. ( 1 , 14 ) pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL in combination with chemotherapy. ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION Chronic phase CML in adults: 100 mg once daily. ( 2 ) Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg once daily. ( 2 ) Chronic phase CML and ALL in pediatrics: starting dose based on body weight. ( 2 ) Administer orally, with or without a meal. Do not crush, cut, or chew tablets. ( 2 ) 2.1 Dosage of Dasatinib Tablets in Adult Patients The recommended starting dosage of dasatinib tablets for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of dasatinib tablets for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults is 140 mg administered orally once daily. Tablets should not be crushed, cut, or chewed; they should be swallowed whole. Dasatinib tablets can be taken with or without a meal, either in the morning or in the evening. 2.2 Dosage of Dasatinib Tablets in Pediatric Patients with CML or Ph+ ALL The recommended starting dosage for pediatrics is based on body weight as shown in Table 1. The recommended dose should be administered orally once daily with or without food. Recalculate the dose every 3 months based on changes in body weight, or more often if necessary. Do not crush, cut or chew tablets. Swallow tablets whole. There are additional administration considerations for pediatric patients who have difficulty swallowing tablets whole [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Table 1: Dosage of Dasatinib Tablets for Pediatric Patients a Body Weight (kg) b Daily Dose (mg) 10 to less than 20 40 mg 20 to less than 30 60 mg 30 to less than 45 70 mg at least 45 100 mg a For pediatric patients with Ph+ ALL, begin dasatinib tablets therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. b Tablet dosing is not recommended for patients weighing less than 10 kg. Refer to Section 2.4 for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. 2.3 Dose Modification Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers and St. John’s wort. If patients must be coadministered a strong CYP3A4 inducer, consider a dasatinib tablets dose increase. If the dose of dasatinib tablets is increased, monitor the patient carefully for toxicity [ see Drug Interactions (7.1) ] . Strong CYP3A4 Inhibitors Avoid the use of concomitant strong CYP3A4 inhibitors and grapefruit juice. Recommend selecting an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible. If dasatinib tablets must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: 40 mg daily for patients taking dasatinib tablets 140 mg daily. 20 mg daily for patients taking dasatinib tablets 100 mg daily. 20 mg daily for patients taking dasatinib tablets 70 mg daily. For patients taking dasatinib tablets 60 mg or 40 mg daily, consider interrupting dasatinib tablets until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib tablets. These reduced doses of dasatinib tablets are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If dasatinib tablets are not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib tablets until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib tablets dose is increased [ see Drug Interactions (7.1) ] . 2.4 Dose Escalation in Adults with CML and Ph+ ALL, and Pediatric Patients with CML For adult patients with CML and Ph+ ALL, consider dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ AL…

5 WARNINGS AND PRECAUTIONS Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt dasatinib tablets when indicated. ( 2.5 , 5.1 , 5.2 ) Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. ( 2.5 , 5.3 ) Cardiovascular Toxicity: Monitor patients for signs or symptoms and treat appropriately. ( 5.4 ) Pulmonary Arterial Hypertension (PAH): Dasatinib tablets may increase the risk of developing PAH which may be reversible on discontinuation. Consider baseline risk and evaluate patients for signs and symptoms of PAH during treatment. Stop dasatinib tablets if PAH is confirmed. ( 5.5 ) QT Prolongation: Use dasatinib tablets with caution in patients who have or may develop prolongation of the QT interval. ( 5.6 ) Severe Dermatologic Reactions: Individual cases of severe mucocutaneous dermatologic reactions have been reported. ( 5.7 ) Tumor Lysis Syndrome: Tumor lysis syndrome has been reported. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with dasatinib tablets. ( 5.8 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of potential risk to fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) Effects on Growth and Development in Pediatric Patients: epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia have been reported. Monitor bone growth and development in pediatric patients. ( 5.10 ) Hepatotoxicity: Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. ( 5.11 ) 5.1 Myelosuppression Treatment with dasatinib is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML [ see Adverse Reactions (6.1) ] . In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated. In pediatric patients with Ph+ ALL treated with dasatinib in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery. Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily and/or dose reduction [ see Dosage and Administration (2.5) ] . 5.2 Bleeding-Related Events Dasatinib can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving dasatinib. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal [ see Adverse Reactions (6.1) ] . Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro . Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage. 5.3 Fluid Retention Dasatinib may cause fluid retention [ see Adverse Reactions (6.1) ] . After 5 years of follow-up in the adult randomized newly diagnosed chronic phase …

4 CONTRAINDICATIONS None. None. (4)

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Dose reduction may be necessary. ( 2.3 , 7.1 ) Strong CYP3A4 Inducers: Dose increase may be necessary. ( 2.3 , 7.1 ) Antacids: Avoid simultaneous administration. ( 7.1 ) H 2 Antagonists and Proton Pump Inhibitors: Avoid coadministration. ( 7.1 ) 7.1 Effect of Other Drugs on Dasatinib Strong CYP3A4 Inhibitors The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations [ see Clinical Pharmacology (12.3) ] . Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a dasatinib dose reduction [ see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers The coadministration of dasatinib with strong CYP3A inducers may decrease dasatinib concentrations [ see Clinical Pharmacology (12.3) ] . Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a dasatinib dose increase. Gastric Acid Reducing Agents The coadministration of dasatinib with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy. Do not administer H 2 antagonists or proton pump inhibitors with dasatinib. Consider the use of antacids in place of H 2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Avoid simultaneous administration of dasatinib with antacids. 7.1 Effect of Other Drugs on Dasatinib Strong CYP3A4 Inhibitors The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations [ see Clinical Pharmacology (12.3) ] . Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a dasatinib dose reduction [ see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers The coadministration of dasatinib with strong CYP3A inducers may decrease dasatinib concentrations [ see Clinical Pharmacology (12.3) ] . Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a dasatinib dose increase. Gastric Acid Reducing Agents The coadministration of dasatinib with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy. Do not administer H 2 antagonists or proton pump inhibitors with dasatinib. Consider the use of antacids in place of H 2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Avoid simultaneous administration of dasatinib with antacids.

8.1 Pregnancy Risk Summary Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses. These findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses of dasatinib [see Data] . Advise a pregnant woman of the potential risk to a fetus. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal Adverse Reactions Transplacental transfer of dasatinib has been reported. Dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. Hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. These adverse pharmacologic effects on the fetus are similar to adverse reactions observed in adult patients and may result in fetal harm or neonatal death [see Warnings and Precautions ( 5.1 , 5.3 )] . Data Human Data Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy. Animal Data In nonclinical studies at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m 2 /day] and rabbit: 0.5 mg/kg/day [6 mg/m 2 /day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.5) and Warnings and Precautions (5.1) ] . • Bleeding-related events [see Warnings and Precautions (5.2) ] . • Fluid retention [see Warnings and Precautions (5.3) ] . • Cardiovascular toxicity [see Warnings and Precautions (5.4) ] . • Pulmonary arterial hypertension [see Warnings and Precautions (5.5) ] . • QT prolongation [see Warnings and Precautions (5.6) ] . • Severe dermatologic reactions [see Warnings and Precautions (5.7) ] . • Tumor lysis syndrome [see Warnings and Precautions (5.8) ] . • Effects on growth and development in pediatric patients [see Warnings and Precautions (5.10) ] . • Hepatotoxicity [see Warnings and Precautions (5.11) ] . Most common adverse reactions (≥15%) in patients receiving dasatinib tablets as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. ( 6 ) Most common adverse reactions (≥30%) in pediatric patients receiving dasatinib tablets in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc., at 1-866-924-6266 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 data described below reflect exposure to dasatinib administered as single-agent therapy at all doses tested in clinical studies (n=2809), including 324 adult patients with newly diagnosed chronic phase CML, 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML. The median duration of therapy in a total of 2712 adult patients was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months). In the overall population of 2712 adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation. In the randomized trial in adult patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of patients with a minimum of 60 months of follow-up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%. Among the 1618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1094 patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients. Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were report…