PHYRAGO

RECENT MAJOR CHANGES Indications and Usage ( 1 ) 8/2025 Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 ) 8/2025 Warnings and Precautions ( 5.1 , 5.3 ) 8/2025

1. INDICATIONS AND USAGE PHYRAGO is 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. PHYRAGO is 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. PHYRAGO TM is 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 orally once daily. ( 2 ) Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg orally once daily. ( 2 ) Chronic phase CML and ALL in pediatrics: starting dose based on body weight. ( 2 ) Administer with or without a meal. Do not crush, cut, or chew tablets. ( 2 ) 2.1 Recommended Dosage in Adult Patients The recommended starting dosage of PHYRAGO for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of PHYRAGO for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults is 140 mg administered orally once daily. Swallow PHYRAGO whole. Do not crush, cut, or chew the tablets. PHYRAGO can be taken with or without a meal, either in the morning or in the evening. 2.2 Recommended Dosage 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 )]. Table 1: Dosage of PHYRAGO for Pediatric Patients* Body Weight (kg) † 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 * For pediatric patients with Ph+ ALL, begin PHYRAGO therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. † Tablet dosing is not recommended for patients weighing less than 10 kg. See Dosage and Administration 2.4 below for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. 2.3 Dosage Modifications for Drug Interactions Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers. If patients must be coadministered a strong CYP3A4 inducer, consider a PHYRAGO dose increase. If the dose of PHYRAGO 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 PHYRAGO must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: 40 mg daily for patients taking PHYRAGO 140 mg daily. 20 mg daily for patients taking PHYRAGO 100 mg daily. 20 mg daily for patients taking PHYRAGO 70 mg daily. For patients taking PHYRAGO 60 mg or 40 mg daily, consider interrupting PHYRAGO until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating PHYRAGO. These reduced doses of PHYRAGO 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 PHYRAGO is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt PHYRAGO until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the PHYRAGO dose is increased [see Drug Interactions ( 7.1 )] . Antacids Avoid concomitant use of PHYRAGO with antacids. If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO [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 C …

3. DOSAGE FORMS AND STRENGTHS PHYRAGO is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg white to light yellow, biconvex, immediate release tablets. 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 ) Most common adverse reactions (≥30%) in pediatric patients receiving dasatinib 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 Cycle Pharmaceuticals Ltd at 1-844-784-1807 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 and 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 reported in 1 pat …

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 concomitant use. ( 2.3 , 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 dose reduction [see Dosage and Administration ( 2.3 )] . Strong CYP3A4 Inducers The coadministration of PHYRAGO 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 dose increase [see Dosage and Administration ( 2.3 )] . Antacids Avoid concomitant use of PHYRAGO with antacids. If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO [see Dosage and Administration ( 2.3 )] . Concomitant use with antacids decreases dasatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce PHYRAGO efficacy.

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 dose reduction [see Dosage and Administration ( 2.3 )] . Strong CYP3A4 Inducers The coadministration of PHYRAGO 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 dose increase [see Dosage and Administration ( 2.3 )] . Antacids Avoid concomitant use of PHYRAGO with antacids. If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO [see Dosage and Administration ( 2.3 )] . Concomitant use with antacids decreases dasatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce PHYRAGO efficacy.

8. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on limited human data, PHYRAGO 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. 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, breastfeeding is not recommended during treatment with PHYRAGO and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential PHYRAGO 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 PHYRAGO and for 30 days after the last dose. Infertility Based on animal data, PHYRAGO 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 monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase CM …

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 PHYRAGO (dasatinib) is a kinase inhibitor. The chemical name for dasatinib (anhydrous) is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide. The molecular formula is C 22 H 26 ClN 7 O 2 S, which corresponds to a formula weight of 488.01. Dasatinib (anhydrous) has the following chemical structure: Dasatinib (anhydrous) is a white to light yellow powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. PHYRAGO is supplied as white to light yellow, biconvex, immediate release tablets for oral use containing dasatinib (anhydrous), with the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, microcrystalline cellulose, propyl gallate, and silica dimethyl silylate. structure

10. OVERDOSAGE Experience with overdose of dasatinib 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 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 PHYRAGO (dasatinib) tablets are available in bottles with a child-resistant closure and desiccant container(s) as described in Table 21. The desiccant container(s) should remain within the bottle after opening and should not be swallowed or eaten. Table 21: PHYRAGO Trade Presentations NDC Number Strength Description Tablets per Bottle 70709-151-20 20 mg white to light-yellow, biconvex, round shaped tablet with “NC 2” debossed on one side and plain on the other side 60 70709-152-50 50 mg white to light-yellow, biconvex, oval shaped tablet with “NC 5” debossed on one side and plain on the other side 60 70709-153-70 70 mg white to light-yellow, biconvex, round shaped tablet with “NC 7” debossed on one side and plain on the other side 60 70709-154-80 80 mg white to light-yellow, biconvex, triangular shaped tablet with “NC 8” debossed on one side and plain on the other side 30 70709-155-10 100 mg white to light-yellow, biconvex, oval shaped tablet with “NC 10” debossed on one side and plain on the other side 30 70709-156-14 140 mg white to light-yellow, biconvex, round shaped tablet with “NC 14” debossed on one side and plain on the other side 30 Storage PHYRAGO should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Handling and Disposal PHYRAGO is a hazardous drug. Follow special handling and disposal procedures. Personnel who are pregnant should avoid exposure to tablets. To prevent exposure of healthcare professionals to the active substance, the use of latex or nitrile gloves for appropriate disposal when handling tablets is recommended, to minimize the risk of dermal exposure.