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) a For pediatric patients with Ph+ ALL, begin Dasatinib tablet 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. 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 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 tablet 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+ ALL) i …

3 DOSAGE FORMS AND STRENGTHS Dasatinib Tablets, 20 mg are white to off-white, round, film-coated tablets, debossed with '1741' on one side and plain on the other side Dasatinib Tablets, 50 mg are white to off-white, oval, film-coated tablets, debossed with '1742' on one side and plain on the other side. Dasatinib Tablets, 70 mg are white to off-white, round, film-coated tablets, debossed with '1743' on one side and plain on the other side. Dasatinib Tablets, 80 mg are white to off-white, oblong, film-coated tablets, debossed with '1744' on one side and plain on the other side Dasatinib Tablets, 100 mg are white to off-white, oval, film-coated tablets, debossed with '1745' on one side and plain on the other side Dasatinib Tablets, 140 mg are white to off-white, round, film-coated tablets, debossed with '1746' on one side and plain on the other side. Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea and musculoskeletal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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=2,809), including 324 adult patients with newly diagnosed chronic phase CML, 2,388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL. The median duration of therapy in a total of 2,712 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 1,618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). In the overall population of 2,712 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 1,618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1,094 patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients. Adverse reactions reported in ≥ 10% of adult patients and other adverse reactions of interest, in a randomized trial in patients with newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 6. Adverse reactions reported in ≥ 10% of adult patients treated at the recommended dose of 100 mg once daily (n=165) and other adverse reactions of interest, in a randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy at a median follow-up of approximately 84 months are presented in Table 8. Drug-related serious adverse reactions (SARs) were reported for 16.7% of adult patients in the randomized trial of patients with newly diagnosed chronic phase CML. Serious adverse reactions reported in ≥ 5% of patients included pleural effusion (5%). Drug-related SARs were reported for 26.1% of patien …

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 tablet dose reduction [see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers The coadministration of Dasatinib tablets 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 tablet dose increase. Gastric Acid Reducing Agents The coadministration of Dasatinib tablets 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 tablets. 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 tablets. Avoid simultaneous administration of Dasatinib tablets 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 tablet dose reduction [see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers The coadministration of Dasatinib tablets 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 tablet dose increase. Gastric Acid Reducing Agents The coadministration of Dasatinib tablets 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 tablets. 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 tablets. Avoid simultaneous administration of Dasatinib tablets with antacids.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on limited human data, dasatinib tablets 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 tablets. 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. 8.2 Lactation Risk Summary No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing children from dasatinib tablets, breastfeeding is not recommended during treatment with dasatinib tablets and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Dasatinib tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Contraception Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with dasatinib tablets and for 30 days after the last dose. Infertility Based on animal data, dasatinib may result in damage to female and male reproductive tissues [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Ph+ CML in Chronic Phase The safety and effectiveness of dasatinib tablets monotherapy have been demons …

12.1 Mechanism of Action Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro , dasatinib was active in leukemic cell lines representing variants of imatinib mesylate-sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib could overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

11 DESCRIPTION Dasatinib is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C 22 H 26 ClN 7 O 2 S • H 2 O, which corresponds to a molecular weight of 506.02 g/mol (monohydrate). The anhydrous free base has a molecular weight of 488.01 g/mol. Dasatinib has the following chemical structure: Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. Each dasatinib tablet intended for oral administration contains 20 mg, 50 mg, 70 mg, 80 mg, 100 mg or 140 mg of dasatinib. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, glyceryl monocaprylocaprate type 1, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-partially hydrolyzed, sodium lauryl sulfate, talc and titanium dioxide. Image

10 OVERDOSAGE Experience with overdose of dasatinib tablets in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since dasatinib tablets is associated with severe myelosuppression [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] , monitor patients who ingest more than the recommended dosage closely for myelosuppression and give appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m 2 ) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m 2 ).

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Dasatinib Tablets, 20 mg are white to off-white, biconvex, round, film-coated tablet with “D” debossed on one side and “20” on the other side and are supplied as follows: Bottles of 60 NDC 59651-542-60 Cartons of 15 (1 x 15) Unit-dose Tablets NDC 59651-542-15 Dasatinib Tablets, 50 mg are white to off-white, biconvex, oval, film-coated tablet with “D” debossed on one side and “50” on the other side and are supplied as follows: Bottles of 60 NDC 59651-543-60 Cartons of 15 (1 x 15) Unit-dose Tablets NDC 59651-543-15 Dasatinib Tablets, 70 mg are white to off-white, biconvex, round, film-coated tablet with “D” debossed on one side and “70” on the other side and are supplied as follows: Bottles of 60 NDC 59651-544-60 Cartons of 15 (1 x 15) Unit-dose Tablets NDC 59651-544-15 Dasatinib Tablets, 80 mg are white to off-white, biconvex, triangle, film-coated tablet with “D” debossed on one side and “80” on the other side and are supplied as follows: Bottles of 30 NDC 59651-545-30 Cartons of 15 (1 x 15) Unit-dose Tablets NDC 59651-545-15 Dasatinib Tablets, 100 mg are white to off-white, biconvex, oval, film-coated tablet with “D” debossed on one side and “100” on the other side and are supplied as follows: Bottles of 30 NDC 59651-546-30 Cartons of 15 (1 x 15) Unit-dose Tablets NDC 59651-546-15 Dasatinib Tablets, 140 mg are white to off-white, biconvex, round, film-coated tablet with “D” debossed on one side and “140” on the other side and are supplied as follows: Bottles of 30 NDC 59651-547-30 Cartons of 15 (1 x 15) Unit-dose Tablets NDC 59651-547-15 Storage Dasatinib tablets should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Handling and Disposal Dasatinib is an antineoplastic product. Follow special handling and disposal procedures. 1 Personnel who are pregnant should avoid exposure to crushed or broken tablets. Dasatinib tablets consist of a core tablet, surrounded by a film coating to prevent exposure of healthcare professionals to the active substance. The use of latex or nitrile gloves for appropriate disposal when handling tablets that are inadvertently crushed or broken is recommended, to minimize the risk of dermal exposure.