IMKELDI

1 INDICATIONS AND USAGE Imkeldi is a kinase inhibitor indicated for the treatment of: Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ( 1.1 ) Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy. ( 1.2 ) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ( 1.3 ) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. ( 1.4 ) Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. ( 1.5 ) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. ( 1.6 ) Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. ( 1.7 ) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). ( 1.8 ) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). ( 1.9 ) Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. ( 1.10 ) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. 1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

2 DOSAGE AND ADMINISTRATION Adults with Ph+ CML CP ( 2.2 ): 400 mg/day Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day Adults with Ph+ ALL ( 2.4 ): 600 mg/day Pediatrics with Ph+ ALL ( 2.5 ): 340 mg/m 2 /day Adults with MDS/MPD ( 2.6 ): 400 mg/day Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day Adults with DFSP ( 2.9 ): 800 mg/day Adults with metastatic and/or unresectable GIST ( 2.10 ): 400 mg/day Adjuvant treatment of adults with GIST ( 2.11 ): 400 mg/day Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device. A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose. ( 2.1 , 5.15 ) 2.1 Important Administration Instructions All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, and a dose of 800 mg should be administered as 400 mg twice a day. If a dose is missed, the patient should wait until the next scheduled dose and not take two doses at the same time. Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device [see Warnings and Precautions (5.15) , Instructions for Use ]. A household teaspoon is not an accurate measuring device. A pharmacist can provide a press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose. Recommendations for Dose Rounding Round each dose to the nearest measurable graduation mark on the oral syringe, if necessary [see Instructions for Use ] . Continue treatment until disease progression or unacceptable toxicity. Imkeldi is a hazardous drug. Follow applicable special handling and disposal procedures 1 . 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dosage of Imkeldi is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dosage of Imkeldi for pediatric patients with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose or the daily dose may be split into two–one portion doses in the morning and one portion in the evening. There is no experience with Imkeldi treatment in children under 1 year of age. Follow recommendations for dose rounding [see Dosage and Administration (2.1) ]. 2.4 Adult Patients With Ph+ ALL The recommended dosage of Imkeldi is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dosage of Imkeldi to be given in combination with chemotherapy to pediatric patients with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg). Imkeldi treatment c…

5 WARNINGS AND PRECAUTIONS Fluid Retention and Edema: Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics. ( 5.1 , 6.1 ) Hematologic Toxicity: Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter. ( 5.2 ) Congestive Heart Failure and Left Ventricular Dysfunction: Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure. ( 5.3 ) Hepatotoxicity: Severe hepatotoxicity, including fatalities may occur. 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. ( 5.4 ) Hemorrhage: Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST. ( 5.5 ) Gastrointestinal Disorders: Gastrointestinal (GI) perforations, some fatal, have been reported. ( 5.6 ) Hypereosinophilic Cardiac Toxicity: Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Imkeldi in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM). ( 5.7 ) Dermatologic Toxicities: Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Imkeldi. ( 5.8 ) Hypothyroidism: Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients. ( 5.9 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to use effective contraception. ( 5.10 , 8.1 ) Growth Retardation in Children and Adolescents: Growth retardation occurring in children and pre-adolescents receiving Imkeldi has been reported. Close monitoring of growth in children under Imkeldi treatment is recommended. ( 5.11 , 6.2 ) Tumor Lysis Syndrome: Close monitoring is recommended. ( 5.12 ) Impairments Related to Driving and Using Machinery: Motor vehicle accidents have been reported in patients receiving imatinib. Caution patients about driving a car or operating machinery. ( 5.13 ) Renal Toxicity: A decline in renal function may occur in patients receiving Imkeldi. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction. ( 5.14 ) Measuring Device: Advise patients to measure IMKELDI with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions. Advise patients to ask their pharmacist to recommend an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring the correct dose. ( 5.15 ) 5.1 Fluid Retention and Edema Imatinib can cause edema and occasionally serious fluid retention [see Adverse Reactions (6.1) ] . Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib, and in 2% to 6% of other adult CML patients taking imatinib. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS • CYP3A4 inducers: Avoid or increase imatinib dosage if unavoidable. ( 7.1 ) • CYP3A4 inhibitors: Use caution. Avoid grapefruit juice. ( 7.2 ) • CYP3A4 substrates: Use caution. Patients who require anticoagulation should receive other anticoagulants instead of warfarin. ( 7.3 ) • CYP2D6 substrates: Use caution. ( 7.4 ) 7.1 Agents Inducing CYP3A Metabolism Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other strong CYP3A4 inducers are indicated for concomitant use with Imkeldi. The dosage of Imkeldi should be increased if concomitant use with a strong CYP3A4 inducer is required [see Dosage and Administration (2.12) ] . Imatinib is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases imatinib exposure [see Clinical Pharmacology (12.3) ], which may reduce imatinib efficacy . 7.2 Agents Inhibiting CYP3A Metabolism Caution is recommended when administering Imkeldi with strong CYP3A4 inhibitors. Grapefruit juice should be avoided. Imatinib is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor increases imatinib exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of Imkeldi adverse reactions. 7.3 Interactions With Drugs Metabolized by CYP3A4 Use caution when administering Imkeldi with CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions. Because warfarin is metabolized by both CYP2C9 and CYP3A4, use other anti-coagulants instead of warfarin in patients receiving Imkeldi who require anticoagulation. Imatinib is a CYP3A inhibitor. Imatinib increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. 7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering Imkeldi with CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions. Imatinib is a CYP2D6 inhibitor. Imatinib increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

8.1 Pregnancy Risk Summary Imkeldi can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Imkeldi in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes. In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Fluid Retention and Edema [see Warnings and Precautions (5.1) ] Hematologic Toxicity [see Warnings and Precautions (5.2) ] Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hemorrhage [see Warnings and Precautions (5.5) ] Gastrointestinal Disorders [see Warnings and Precautions (5.6) ] Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7) ] Dermatologic Toxicities [see Warnings and Precautions (5.8) ] Hypothyroidism [see Warnings and Precautions (5.9) ] Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.12) ] Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13) ] Renal Toxicity [see Warnings and Precautions (5.14) ] The most frequently reported adverse reactions (≥30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shorla Oncology at 844-9-SHORLA 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. Chronic Myeloid Leukemia The majority of imatinib-treated patients experienced adverse reactions at some time. Imatinib was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib versus IFN+Ara-C, and in 12.5% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib and nilotinib. Imatinib was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of imatinib [see Dosage and Administration (2.13) ] . The frequency of severe superficial edema was 1.5%-6%. A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib-treated patients are shown in Tables 2, 3, and 4. Table 2: Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Imatinib Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib-Treated Patients) All adverse reactions occurring in greater than or equal to 10% of imatinib-treated patients are listed regardless of suspected relationship to treatment. All Grades CTC Grades NCI Common Terminology Criteria for Adverse Events, version 3.0. 3/4 Preferred term Imatinib N = 551 (%) IFN+Ara-C N = 533 (%) Imatinib N = …