HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`GLEEVEC safely and effectively. See full prescribing information for
`GLEEVEC.
`GLEEVEC® (imatinib mesylate) tablets, for oral use
`Initial U.S. Approval: 2001
`---------------------------INDICATIONS AND USAGE----------------------------
`Gleevec 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)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`400 mg/day
` Adults with Ph+ CML CP (2.2):
` Adults with Ph+ CML AP or BC (2.2):
`600 mg/day
` Pediatrics with Ph+ CML CP (2.3):
`340 mg/m2/day
` Adults with Ph+ ALL (2.4):
`600 mg/day
` Pediatrics with Ph+ ALL (2.5):
`340 mg/m2/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 Gleevec 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. Gleevec can be
`dissolved in water or apple juice for patients having difficulty swallowing.
`Daily dosing of 800 mg and above should be accomplished using the 400-mg
`tablet to reduce exposure to iron.
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets (scored): 100 mg and 400 mg (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None. (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
` 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)
` 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)
` 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)
` 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)
` 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 (GI) perforations, some fatal, have been reported. (5.6)
` Cardiogenic shock/left ventricular dysfunction has been associated with the
`initiation of Gleevec in patients with conditions associated with high
`eosinophil levels (e.g., HES, MDS/MPD, and ASM). (5.7)
` Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-
`Johnson syndrome) have been reported with the use of Gleevec. (5.8)
` Hypothyroidism has been reported in thyroidectomy patients undergoing
`levothyroxine replacement. Closely monitor TSH levels in such patients.
`(5.9)
` Fetal harm can occur when administered to a pregnant woman. Apprise
`women of the potential harm to the fetus, and to avoid pregnancy when
`taking Gleevec. (5.10, 8.1)
` Growth retardation occurring in children and pre-adolescents receiving
`Gleevec has been reported. Close monitoring of growth in children under
`Gleevec treatment is recommended. (5.11, 6.2)
` Tumor Lysis Syndrome. Close monitoring is recommended. (5.12)
` Reports of motor vehicle accidents have been received in patients receiving
`Gleevec. Caution patients about driving a car or operating machinery.
`(5.13)
` Renal Toxicity. A decline in renal function may occur in patients receiving
`Gleevec. Evaluate renal function at baseline and during therapy, with
`attention to risk factors for renal dysfunction. (5.14)
`-------------------------------ADVERSE REACTIONS------------------------------
`The most frequently reported adverse reactions (greater than or equal to 30%)
`were edema, nausea, vomiting, muscle cramps, musculoskeletal pain,
`diarrhea, rash, fatigue, and abdominal pain. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS------------------------------
` CYP3A4 inducers may decrease Gleevec Cmax and area under curve (AUC).
`(2.12, 7.1, 12.3)
` CYP3A4 inhibitors may increase Gleevec Cmax and AUC. (7.2, 12.3)
` Gleevec is an inhibitor of CYP3A4 and CYP2D6 which may increase the
`Cmax and AUC of other drugs. (7.3, 7.4, 12.3)
` Patients who require anticoagulation should receive low-molecular weight
`or standard heparin and not warfarin. (7.3)
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 3/2022
`
`Rigel Exhibit 1053
`Page 1 of 42
`
`

`

`2
`
`1.2
`
`1.3
`1.4
`
`1.5
`1.6
`1.7
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1
`Newly Diagnosed Philadelphia Positive Chronic Myeloid
`Leukemia (Ph+ CML)
`Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or
`Chronic Phase (CP) After Interferon-alpha (IFN) Therapy
`Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)
`Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia
`(ALL)
`Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)
`Aggressive Systemic Mastocytosis (ASM)
`Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic
`Leukemia (CEL)
`Dermatofibrosarcoma Protuberans (DFSP)
`1.8
`Kit+ Gastrointestinal Stromal Tumors (GIST)
`1.9
`1.10 Adjuvant Treatment of GIST
`DOSAGE AND ADMINISTRATION
`2.1
`Drug Administration
`2.2
`Adult Patients With Ph+ CML CP, AP, or BC
`2.3
`Pediatric Patients With Ph+ CML CP
`2.4
`Adult Patients With Ph+ ALL
`2.5
`Pediatric Patients With Ph+ ALL
`2.6
`Adult Patients With MDS/MPD
`2.7
`Adult Patients With ASM
`2.8
`Adult Patients With HES/CEL
`2.9
`Adult Patients With DFSP
`2.10 Adult Patients With Metastatic and/or Unresectable GIST
`2.11 Adult Patients With Adjuvant GIST
`2.12 Dose Modification Guidelines
`2.13 Dose Adjustment for Hepatotoxicity and Non-Hematologic
`Adverse Reactions
`2.14 Dose Adjustment for Hematologic Adverse Reactions
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Fluid Retention and Edema
`5.2
`Hematologic Toxicity
`5.3
`Congestive Heart Failure and Left Ventricular Dysfunction
`5.4
`Hepatotoxicity
`5.5
`Hemorrhage
`5.6
`Gastrointestinal Disorders
`5.7
`Hypereosinophilic Cardiac Toxicity
`5.8
`Dermatologic Toxicities
`5.9
`Hypothyroidism
`5.10
`Embryo-Fetal Toxicity
`
`8
`
`6
`
`7
`
`5.11 Growth Retardation in Children and Adolescents
`5.12
`Tumor Lysis Syndrome
`5.13
`Impairments Related to Driving and Using Machinery
`5.14
`Renal Toxicity
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Agents Inducing CYP3A Metabolism
`7.2
`Agents Inhibiting CYP3A Metabolism
`7.3
`Interactions With Drugs Metabolized by CYP3A4
`7.4
`Interactions With Drugs Metabolized by CYP2D6
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`8.7
`Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1
`Chronic Myeloid Leukemia
`14.2
`Pediatric CML
`14.3 Acute Lymphoblastic Leukemia
`14.4
`Pediatric ALL
`14.5 Myelodysplastic/Myeloproliferative Diseases
`14.6 Aggressive Systemic Mastocytosis
`14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia
`14.8 Dermatofibrosarcoma Protuberans
`14.9 Gastrointestinal Stromal Tumors
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Rigel Exhibit 1053
`Page 2 of 42
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML)
`1.1
`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
`2.1
`Drug Administration
`The prescribed dose should be administered orally, 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.
`For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The
`required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100-mg
`tablet, and 200 mL for a 400-mg tablet) and stirred with a spoon. The suspension should be administered immediately
`after complete disintegration of the tablet(s).
`For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.
`Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
`
`Rigel Exhibit 1053
`Page 3 of 42
`
`

`

`Adult Patients With Ph+ CML CP, AP, or BC
`2.2
`The recommended dose of Gleevec 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 dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600
`mg). Gleevec treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the
`morning and one portion in the evening. There is no experience with Gleevec treatment in children under 1 year of age.
`2.4
`Adult Patients With Ph+ ALL
`The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
`2.5
`Pediatric Patients With Ph+ ALL
`The recommended dose of Gleevec to be given in combination with chemotherapy to children with newly diagnosed Ph+
`ALL is 340 mg/m2/day (not to exceed 600 mg). Gleevec treatment can be given as a once daily dose.
`2.6
`Adult Patients With MDS/MPD
`Determine PDGFRb gene rearrangements status prior to initiating treatment.
`The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.
`2.7
`Adult Patients With ASM
`Determine D816V c-Kit mutation status prior to initiating treatment.
`The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-
`Kit mutational status is not known or unavailable, treatment with Gleevec 400 mg/day may be considered for patients with
`ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal
`hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose
`increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if
`assessments demonstrate an insufficient response to therapy.
`2.8
`Adult Patients With HES/CEL
`The recommended dose of Gleevec is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with
`demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg
`to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an
`insufficient response to therapy.
`2.9
`Adult Patients With DFSP
`The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.
`2.10
`Adult Patients With Metastatic and/or Unresectable GIST
`The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.
`A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients
`showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug
`reactions.
`2.11
`Adult Patients With Adjuvant GIST
`The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross
`resection of GIST. In clinical trials, one year of Gleevec and three years of Gleevec were studied. In the patient population
`defined in Study 2, three years of Gleevec is recommended [see Clinical Studies (14.8)]. The optimal treatment duration
`with Gleevec is not known.
`
`Rigel Exhibit 1053
`Page 4 of 42
`
`

`

`Dose Modification Guidelines
`2.12
`Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g.,
`dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be
`coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Gleevec should be increased
`by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1)].
`Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be
`treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe
`hepatic impairment [see Use in Specific Populations (8.6)].
`Renal Impairment: Patients with moderate renal impairment (creatinine clearance [CrCL] = 20-39 mL/min) should receive
`a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600
`mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate
`renal impairment doses greater than 400 mg are not recommended.
`Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two
`patients with severe renal impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.7)].
`2.13
`Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions
`If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases
`greater than 5 times the IULN occur, Gleevec should be withheld until bilirubin levels have returned to a less than 1.5
`times the IULN and transaminase levels to less than 2.5 times the IULN. In adults, treatment with Gleevec may then be
`continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg). In children, daily
`doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day.
`If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Gleevec
`should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the
`initial severity of the event.
`2.14
`Dose Adjustment for Hematologic Adverse Reactions
`Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in
`Table 1.
`Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia
`ASM associated with eosinophilia
`ANC less than 1.0 x 109/L
`1. Stop Gleevec until ANC greater than or equal to
`(starting dose 100 mg)
`and/or
`1.5 x 109/L and platelets greater than or equal to
`platelets less than 50 x 109/L
`75 x 109/L
`2. Resume treatment with Gleevec at previous dose
`(i.e., dose before severe adverse reaction)
`1. Stop Gleevec until ANC greater than or equal to
`1.5 x 109/L and platelets greater than or equal to
`75 x 109/L
`2. Resume treatment with Gleevec at previous dose
`(i.e., dose before severe adverse reaction)
`1. Stop Gleevec until ANC greater than or equal to
`1.5 x 109/L and platelets greater than or equal to
`75 x 109/L
`2. Resume treatment with Gleevec at the original
`starting dose of 400 mg
`If recurrence of ANC less than 1.0 x 109/L and/or
`platelets less than 50 x 109/L, repeat step 1 and
`resume Gleevec at a reduced dose of 300 mg
`
`ANC less than 1.0 x 109/L
`and/or
`platelets less than 50 x 109/L
`
`ANC less than 1.0 x 109/L
`and/or
`platelets less than 50 x 109/L
`
`3.
`
`HES/CEL with FIP1L1-PDGFRα
`fusion kinase (starting dose 100 mg)
`
`Chronic Phase CML (starting dose
`400 mg)
`
`MDS/MPD, ASM and HES/CEL
`(starting dose 400 mg)
`
`GIST (starting dose 400 mg)
`
`Rigel Exhibit 1053
`Page 5 of 42
`
`

`

`ANC less than 0.5 x 109/L
`and/or
`platelets less than 10 x 109/L
`
`DFSP
`(starting dose 800 mg)
`
`ANC less than 1.0 x 109/L
`and/or
`platelets less than 50 x 109/L
`
`Pediatric newly diagnosed chronic
`phase CML
`(starting dose 340 mg/m2)
`
`ANC less than 1.0 x 109/L
`and/or
`platelets less than 50 x 109/L
`
`2.
`
`3.
`
`4.
`
`3.
`
`Ph+ CML: Accelerated Phase and
`Blast Crisis (starting dose 600 mg)
`Ph+ ALL
`(starting dose 600 mg)
`
`1. Check if cytopenia is related to leukemia (marrow
`aspirate or biopsy)
`If cytopenia is unrelated to leukemia, reduce dose
`of Gleevec to 400 mg
`If cytopenia persists 2 weeks, reduce further to
`300 mg
`If cytopenia persists 4 weeks and is still unrelated
`to leukemia, stop Gleevec until ANC greater than
`or equal to 1 x 109/L and platelets greater than or
`equal to 20 x 109/L and then resume treatment at
`300 mg
`1. Stop Gleevec until ANC greater than or equal to
`1.5 x 109/L and platelets greater than or equal to
`75 x 109/L
`2. Resume treatment with Gleevec at 600 mg
`3.
`In the event of recurrence of ANC less than 1.0 x
`109/L and/or platelets less than 50 x 109/L, repeat
`step 1 and resume Gleevec at reduced dose of 400
`mg
`1. Stop Gleevec until ANC greater than or equal to
`1.5 x 109/L and platelets greater than or equal to
`75 x 109/L
`2. Resume treatment with Gleevec at previous dose
`(i.e., dose before severe adverse reaction)
`In the event of recurrence of ANC less than 1.0 x
`109/L and/or platelets less than 50 x 109/L, repeat
`step 1 and resume Gleevec at reduced dose of 260
`mg/m2
`Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia;
`CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD,
`myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia
`chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.
`3
`DOSAGE FORMS AND STRENGTHS
`100 mg film coated tablets
`
`Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on
`one side, and “SA” with score on the other side
`400 mg film coated tablets
`
`Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with
`“gleevec” on one side and score on the other side.
`4
`CONTRAINDICATIONS
`None.
`WARNINGS AND PRECAUTIONS
`5
`Fluid Retention and Edema
`5.1
`Gleevec is often associated with 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 Gleevec 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
`Gleevec, and in 2% to 6% of other adult CML patients taking Gleevec. 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 Gleevec, and in 2% to 6% of other adult CML patients taking Gleevec. Severe fluid retention was
`reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.1)]. In a randomized trial in
`patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, severe (Grade 3 or 4) fluid
`retention occurred in 2.5% of patients receiving Gleevec 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
`
`Rigel Exhibit 1053
`Page 6 of 42
`
`

`

`were Grade 3 or 4) of patients in the Gleevec 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 Gleevec is associated with 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 Gleevec. 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 Gleevec 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 Gleevec and nilotinib, cardiac failure was observed in 1.1% of patients in the Gleevec 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 Gleevec [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 Gleevec.
`Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or
`as clinically indicated. Manage laboratory abnormalities with Gleevec interruption and/or dose reduction [see Dosage and
`Administration (2.13)]. When Gleevec 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 Gleevec 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. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic
`phase comparing Gleevec and nilotinib, GI hemorrhage occurred in 1.4% of patients in the Gleevec arm, and in 2.9% of
`patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the Gleevec arm; 0.7% were
`Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in
`postmarketing experience.
`5.6
`Gastrointestinal Disorders
`Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to
`minimize this problem. There have been rare reports, including fatalities, of GI perforation.
`5.7
`Hypereosinophilic Cardiac Toxicity
`In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of
`cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of
`Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory
`support measures and temporarily withholding Gleevec.
`Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels.
`Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with
`MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic
`steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec at the initiation of therapy.
`
`Rigel Exhibit 1053
`Page 7 of 42
`
`

`

`Dermatologic Toxicities
`5.8
`Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with
`use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson
`syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge.
`Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of Gleevec
`therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower
`than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or
`antihistamines.
`5.9
`Hypothyroidism
`Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement
`during treatment with Gleevec. Monitor TSH levels in such patients.
`5.10
`Embryo-Fetal Toxicity
`Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when
`administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on
`body surface area (BSA). Significant post-implantation loss was seen in female rats administered imatinib mesylate at
`doses approximately one-half the maximum human dose of 800 mg/day based on BSA. Advise sexually active female
`patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates)
`when using Gleevec and for 14 days after stopping Gleevec. If this drug is used during pregnancy or if the patient
`becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific
`Populations (8.1)].
`5.11 Growth Retardation in Children and Adolescents
`Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long-term effects of
`prolonged treatment with Gleevec on growth in children are unknown. Therefore, monitor growth in children under
`Gleevec treatment [see Adverse Reactions (6.1)].
`5.12
`Tumor Lysis Syndrome
`Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and
`eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate
`or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible
`occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of Gleevec.
`5.13
`Impairments Related to Driving and Using Machinery
`Motor vehicle accidents have been reported in patients receiving Gleevec. Advise patients that they may experience side
`effects, such as dizziness, blurred vision, or somnolence during treatment with Gleevec. Recommend caution when
`driving a car or operating machinery.
`5.14
`Renal Toxicity
`A decline in renal function may occur i