Imatinib

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.

Oral solution: 80 mg/mL imatinib as 140 mL of a clear yellow to brownish yellow colored solution with a strawberry flavor. Oral solution: 80 mg/mL of imatinib ( 3 )

None. None. ( 4 )

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 1.3% of newly diagnosed CML patients taking imatinib, and in 2% to 6% of other adult CML patients taking imatinib. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib for GIST [see Adverse Reactions (6.1) ] . In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the imatinib arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.

5.2 Hematologic Toxicity Treatment with imatinib can cause anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.14) ].

5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Imkeldi [see Adverse Reactions (6.1) ]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with Imkeldi interruption and/or dose reduction [see Dosage and Administration (2.13) ]. When imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

5.5 Hemorrhage In a trial of imatinib versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. […]

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 = 551 (%) IFN+Ara-C N = 533 (%) Fluid retention 61.7 11.1 2.5 0.9 – Superficial edema 59.9 9.6 1.5 0.4 – Other fluid retention reactions Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. 6.9 1.9 1.3

0.6 Nausea 49.5 61.5 1.3

5.1 Muscle cramps 49.2 11.8 2.2

0.2 Musculoskeletal pain 47.0 44.8 5.4

8.6 Diarrhea 45.4 43.3 3.3

3.2 Rash and related terms 40.1 26.1 2.9

2.4 Fatigue 38.8 67.0 1.8

25.1 Headache 37.0 43.3 0.5

3.8 Joint pain 31.4 38.1 2.5

7.7 Abdominal pain 36.5 25.9 4.2

3.9 Nasopharyngitis 30.5 8.8 0

0.4 Hemorrhage 28.9 21.2 1.8 1.7 – GI hemorrhage 1.6 1.1 0.5 0.2 – CNS hemorrhage 0.2 0.4 0

0.4 Myalgia 24.1 38.8 1.5

8.3 Vomiting 22.5 27.8 2.0

3.4 Dyspepsia 18.9 8.3 0

0.8 Cough 20.0 23.1 0.2

0.6 Pharyngolaryngeal pain 18.1 11.4 0.2 0 Upper respiratory tract infection 21.2 8.4 0.2

0.4 Dizziness 19.4 24.4 0.9

3.8 Pyrexia 17.8 42.6 0.9

3.0 Weight increased 15.6 2.6 2.0

0.4 Insomnia 14.7 18.6 0

2.3 Depression 14.9 35.8 0.5

13.1 Influenza 13.8 6.2 0.2

0.2 Bone pain 11.3 15.6 1.6

3.4 Constipation 11.4 14.4 0.7

0.2 Sinusitis 11.4 6.0 0.2

0.2 Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. Table 3: Most Frequently Reported Non-Hematologic Adverse Reactions (regardless of relationship to study drug) in Patients With Newly Diagnosed Ph+ CML-CP in the Imatinib Versus Nilotinib Study (Greater Than or Equal to 10% in Imatinib 400 mg Once Daily or Nilotinib 300 mg Twice Daily Groups) 60-Month Analysis Excluding laboratory abnormalities. Patients with newly diagnosed Ph+ CML-CP Imatinib 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 Imatinib 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 Body system and preferred term All Grades (%) CTC Grades NCI Common Terminology Criteria for Adverse Events, version 3.0. 3/4 (%) Skin and subcutaneous tissue disorders Rash > 19 38 2 < 1 Pruritus 7 21 0 < 1 Alopecia 7 13 0 0 Dry skin 6 12 0 0 Gastrointestinal disorders Nausea 41 22 2 2 Constipation 8 20 0 < 1 Diarrhea 46 19 4 1 Vomiting 27 15 < 1 < 1 Abdominal pain upper 14 18 < 1 1 Abdominal pain 12 15 0 2 Dyspepsia 12 10 0 0 Nervous system disorders Headache 23 32 < 1 3 Dizziness 11 12 < 1 < 1 General disorders and administration-site conditions Fatigue 20 23 1 1 Pyrexia 13 14 0 < 1 Asthenia 12 14 0 < 1 Peripheral edema 20 9 0 < 1 Face edema 14 < 1 < 1 0 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 17 22 < 1 < 1 Muscle spasms 34 12 1 0 Pain in extremity 16 15 < 1 < 1 Back pain 17 19 1 1 Respiratory, thoracic and mediastinal disorders Cough 13 17 0 0 Oropharyngeal pain 6 12 0 0 Dyspnea 6 11 < 1 2 Infections and infestations Nasopharyngitis 21 27 0 0 Upper respiratory tract infection 14 17 0 < 1 Influenza 9 13 0 0 Gastroenteritis 10 7 < 1 0 Eye disorders Eyelid edema 19 1 < 1 0 Periorbital edema 15 < 1 0 0 Psychiatric disorders Insomnia 9 11 0 0 Vascular disorder Hypertension 4 10 < 1 1 Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. Table 4: Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (Greater Than or Equal to 10% of All Patients in Any Trial) All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment. Myeloid blast Crisis (n = 260) Accelerated phase (n = 235) Chronic phase, IFN failure (n = 532) % % % Preferred term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Fluid retention 72 11 76 6 69 4 -Superficial edema 66 6 74 3 67 2 -Other fluid retention reactions Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. […]

• 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.

Lactation: Advise not to breastfeed.( 8.2 )

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.

8.2 Lactation Risk Summary Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed children from Imkeldi, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose. Human Data Based on data from 3 breastfeeding women taking imatinib, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed child could receive up to 10% of the maternal therapeutic dose based on body weight.

8.3 Females and Males of Reproductive Potential Based on human postmarketing reports and animal studies, Imkeldi can cause fetal harm [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females with reproductive potential prior to the initiation of treatment with Imkeldi. Contraception Females Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Imkeldi during treatment and for fourteen days after stopping treatment with Imkeldi [see Use in Specific Populations (8.1) ]. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [see Nonclinical Toxicology (13) ].

8.4 Pediatric Use The safety and effectiveness of Imkeldi have been established in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2 , 14.4) ] . There are no data in pediatric patients under 1 year of age. The safety and efficacy of Imkeldi have not been established in pediatric patients for all other indications [see Indications and Usage (1) ].

8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1) ] . The efficacy of imatinib was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of imatinib was similar in patients older than 65 years and younger patients.

8.6 Hepatic Impairment Reduce the dose by 25% for patients with severe hepatic impairment [see Dosage and Administration (2.12) ] . Patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) do not require a dose adjustment. The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Mild hepatic impairment (total bilirubin ≤ ULN and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃1.5 to 3 times ULN and any value for AST) do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, (total bilirubin ˃ 3 to 10 times ULN and any value for AST), the imatinib C max and area under curve (AUC) increased by 63% and 45% and the CGP74588 C max and AUC increased by 56% and 55%, relative to patients with normal hepatic function [see Clinical Pharmacology (12.3) ] .

8.7 Renal Impairment Dose reductions are necessary for patients with moderate and severe renal impairment [see Dosage and Administration (2.12) ] . The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild (CLcr = 40-59 mL/min) and moderate renal impairment (CLcr = 20-39 mL/min) increased 1.5- to 2-fold compared to patients with normal renal function. […]

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.