------------------------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, 6.11)
`
`
`Cytopenias, particularly anemia, neutropenia, and thrombocytopenia,
`
`have occurred. Manage with dose reduction or dose interruption and in
`
`rare cases 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. Patients with cardiac disease or risk factors for cardiac failure
`
`should be monitored and treated (5.3)
`
`Severe hepatotoxicity 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 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).
`Consider potential toxicities, specifically, liver, kidney, and cardiac
`toxicity, and immunosuppression from long-term use (5.10)
`
`
`Fetal harm can occur when administered to a pregnant woman. Women
`
`should be apprised of the potential harm to the fetus (5.11, 8.1)
`
`
`•
`
`•
`
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS------------------------------
`The most frequently reported adverse reactions (>30%) were edema, nausea,
`
`
`vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and
`abdominal pain (6.1, 6.11)
`
`
`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 AUC (2.9, 7.1)
`
`•
`
`
`CYP3A4 inhibitors may increase Gleevec Cmax and AUC (7.2)
`•
`
`Gleevec is an inhibitor of CYP3A4 and may increase the Cmax and AUC
`•
`
`
`of other drugs ( 7.3)
`Patients who require anticoagulation should receive low-molecular
`
`weight or standard heparin and not warfarin (7.3)
`Systemic exposure to acetaminophen is expected to increase when co­
`
`administered with Gleevec (7.5)
`
`•
`
`
`•
`
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`• There is no experience in children less than 2 years of age (8.4)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`
`Revised: 05/2009
`
`
`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
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`--------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage Newly Diagnosed Ph+ CML (1.1)
`XX/2009
`
`Indications and Usage: GIST (1.9)
`09/2008
`
`
`Indications and Usage Adjuvant treatment of GIST (1.10)
`12/2008
`
`Dosage and Administration: GIST (2.8)
`09/2008
`
`
`Dosage and Administration Adjuvant treatment of GIST (2.8)
`12/2008
`09/2008
`Dose Modification Guidelines: Renal Impairment (2.9)
`Warnings and Precautions: Hepatotoxicity (5.4), Hemorrhage (5.5),
`
`
`
`09/2008
`Hypothyroidism (5.9)
`
`
`
`-------------------------INDICATIONS AND USAGE------------------------------
`Gleevec is a kinase inhibitor indicated for the treatment of:
`Newly diagnosed adult patients with Philadelphia chromosome positive
`•
`
`chronic myeloid leukemia (Ph+ CML) in chronic phase.
`
`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)
`
`Pediatric patients with Ph+ CML in chronic phase who are newly
`diagnosed or whose disease has recurred after stem cell transplant or
`
`who are resistant to interferon-alpha therapy. There are no controlled
`
`trials in pediatric patients demonstrating a clinical benefit, such as
`improvement in disease-related symptoms or increased survival (1.3)
`
`Adult patients with relapsed or refractory Philadelphia chromosome
`
`positive acute lymphoblastic leukemia (Ph+ ALL) (1.4)
`Adult patients with myelodysplastic/ myeloproliferative diseases
`(MDS/MPD) associated with PDGFR (platelet-derived growth factor
`receptor) 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 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---------------------
`
`Adults with Ph+ CML CP (2.1):
`400 mg/day
`
`
`•
`
`Adults with Ph+ CML AP or BC (2.1):
`600 mg/day
`
`
`
`•
`
`340 mg/m2/day or 260 mg/m2/day
`Pediatrics with Ph+ CML (2.2):
`
`
`
`•
`
`600 mg/day
`Adults with Ph+ ALL (2.3):
`
`
`
`•
`
`Adults with MDS/MPD (2.4):
`400 mg/day
`
`
`•
`
`100 mg/day or 400 mg/day
`Adults with ASM (2.5):
`
`
`•
`
`Adults with HES/CEL (2.6):
`100 mg/day or 400 mg/day
`
`
`
`•
`
`Adults with DFSP (2.7):
`800 mg/day
`
`
`•
`
`Adults with metastatic and/or unresectable GIST (2.8):
`400 mg/day
`
`
`•
`
` 400 mg/day
`Adjuvant treatment of adults with GIST (2.8):
`
`
`•
`
`Patients with mild to moderate hepatic impairment (2.9): 400 mg/day
`
`•
`
`300 mg/day
`Patients with severe hepatic impairment (2.9):
`
`
`•
`
`
`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.
`
`
`
`1
`
`AVENTIS EXHIBIT 2198
`Mylan v. Aventis IPR2016-00712
`
`

`
`
`6.6 Acute Lymphoblastic Leukemia
`
`
`6.7 Myelodysplastic/Myeloproliferative Diseases
`
`
`6.8 Aggressive Systemic Mastocytosis
`
`6.9 Hypereosinophilic Syndrome and Chronic Eosinophilic
`
`
`Leukemia
`
`
`6.10 Dermatofibrosarcoma Protuberans
`
`
`6.11 Gastrointestinal Stromal Tumors
`
`
`6.12 Additional Data from Multiple Clinical Trials
`
`
`
`6.13 Postmarketing Experience
`
`
`7 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
`
`
`7.5 Interaction with Acetaminophen
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`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
`
`
`14 CLINICAL STUDIES
`
`14.1 Chronic Myeloid Leukemia
`
`
`14.2 Pediatric CML
`
`
`14.3 Acute Lymphoblastic Leukemia
`
`
`14.4 Myelodysplastic/Myeloproliferative Diseases
`
`
`14.5 Aggressive Systemic Mastocytosis
`
`
`14.6 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia
`
`
`14.7 Dermatofibrosarcoma Protuberans
`
`
`14.8 Gastrointestinal Stromal Tumors
`
`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Dosing and Administration
`
`
`17.2 Pregnancy and Breast-Feeding
`
`
`17.3 Adverse Reactions
`
`
`17.4 Drug Interactions
`
`* Sections or subsections omitted from the full prescribing
`
`information are not listed
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid
`
`
`Leukemia (Ph+ CML)
`
`1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or
`
`
`Chronic Phase (CP) After Interferon-alpha (IFN) Therapy
`
`
`1.3 Pediatric Patients with Ph+ CML in Chronic Phase
`
`
`1.4 Ph+ Acute Lymphoblastic Leukemia (ALL)
`
`
`1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)
`
`
`1.6 Aggressive Systemic Mastocytosis (ASM)
`
`1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic
`
`
`Leukemia (CEL)
`
`
`1.8 Dermatofibrosarcoma Protuberans (DFSP)
`
`
`1.9 Kit+ Gastrointestinal Stromal Tumors (GIST)
`
`
`1.10 Adjuvant Treatment of GIST
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Adult Patients with Ph+ CML CP, AP and BC
`
`
`2.2 Pediatric Patients with Ph+ CML
`
`
`2.3 Ph+ ALL
`
`
`2.4 MDS/MPD
`
`
`2.5 ASM
`
`
`2.6 HES/CEL
`
`2.7 DFSP
`
`2.8 GIST
`
`
`2.9 Dose Modification Guidelines
`
`2.10 Dose Adjustment for Hepatotoxicity and Non-Hematologic
`
`
`Adverse Reactions
`
`
`2.11 Dose Adjustment for Hematologic Adverse Reactions
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Fluid Retention and Edema
`
`
`5.2 Hematologic Toxicity
`
`5.3 Severe 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 Toxicities from Long-Term Use
`
`
`
`5.11 Use in Pregnancy
`
`
`6 ADVERSE REACTIONS
`
`6.1 Chronic Myeloid Leukemia
`
`
`6.2 Hematologic Toxicity
`
`
`6.3 Hepatotoxicity
`
`
`6.4 Adverse Reactions in Pediatric Population
`
`
`6.5 Adverse Reactions in Other Subpopulations
`
`
`
`
`2
`
`

`
`
`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML)
`Newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia 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 Pediatric Patients with Ph+ CML in Chronic Phase
`Pediatric patients with Ph+ CML in chronic phase who are newly diagnosed or whose disease has recurred after
`stem cell transplant or who are resistant to interferon-alpha therapy. There are no controlled trials in pediatric
`patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased
`survival.
`1.4 Ph+ Acute Lymphoblastic Leukemia (ALL)
`Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia.
`1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)
`Adult patients with myelodysplastic/ myeloproliferative diseases associated with PDGFR (platelet-derived
`growth factor receptor) 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 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
`Therapy should be initiated by a physician experienced in the treatment of patients with hematological
`malignancies or malignant sarcomas, as appropriate. 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.
`In children, Gleevec treatment can be given as a once-daily dose or alternatively the daily dose may be split into
`
`two - once in the morning and once in the evening. There is no experience with Gleevec treatment in children
`under 2 years of age.
`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
`
`3
`
`

`
`
` 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.
`2.1 Adult Patients with Ph+ CML CP, AP and BC
`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 6-12 months of
`treatment, or loss of a previously achieved hematologic or cytogenetic response.
`2.2 Pediatric Patients with Ph+ CML
`The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to
`exceed 600 mg). The recommended Gleevec dose is 260 mg/m2/day for children with Ph+ chronic phase CML
`recurrent after stem cell transplant or who are resistant to interferon-alpha therapy.
`2.3 Ph+ ALL
`The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
`2.4 MDS/MPD
`The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.
`2.5 ASM
`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.
`2.6 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.
`2.7 DFSP
`The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.
`2.8 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.
`
`4
`
`

`
`
`The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following
`complete gross resection of GIST. In the clinical study, Gleevec was administered for one year. The optimal
`treatment duration with Gleevec is not known.
`2.9 Dose Modification Guidelines
`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 co-administered 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 (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 Use in Specific Populations (8.7)]
`2.10 Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions
`If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN
`occur, Gleevec should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels
`to <2.5 x 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 or from 260 mg/m2/day to 200 mg/m2/day, respectively.
`
`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.
`2.11 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
`ANC <1.0 x 109/L
`
` ASM associated with eosinophilia
`1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets
`
`
`(starting dose 100 mg)
`and/or
`≥75 x 109/L
`platelets <50 x 109/L
`
`2. Resume treatment with Gleevec at previous dose
`
`
`(i.e., dose before severe adverse reaction)
`ANC <1.0 x 109/L
`1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets
`
`
`and/or
`≥75 x 109/L
`platelets <50 x 109/L
`
`2. Resume treatment with Gleevec at previous dose
`
`(i.e., dose before severe adverse reaction)
`1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets
`
`
`≥75 x 109/L
`2. Resume treatment with Gleevec at the original
`
`starting dose of 400 mg
`
`If recurrence of ANC <1.0 x 109/L and/or platelets
`
`<50 x 109/L, repeat step 1 and resume Gleevec at a
`reduced dose of 300 mg
`
`
`
`
`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)
`Ph+ CML : Accelerated Phase and
`Blast Crisis (starting dose 600 mg)
`
`3.
`
`
`ANC <1.0 x 109/L
`and/or
`
`platelets <50 x 109/L
`
`
`
`ANC <0.5 x 109/L
`and/or
`
`
`1. Check if cytopenia is related to leukemia (marrow
`
`aspirate or biopsy)
`
`
`5
`
`

`
`2.
`
`
`3.
`
`
`4.
`
`
`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 ≥1 x 109/L
`and platelets ≥20 x 109/L and then resume
`
`treatment at 300 mg
`
`1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets
`
`
`≥75 x 109/L
`2. Resume treatment with Gleevec at 600 mg
`
`
`In the event of recurrence of ANC <1.0 x 109/L
`3.
`
`and/or platelets <50 x 109/L, repeat step 1 and
`resume Gleevec at reduced dose of 400 mg
`
`
`1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets
`
`
`≥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 <1.0 x 109/L
`and/or platelets <50 x 109/L, repeat step 1 and
`resume Gleevec at reduced dose of 260 mg/m2
`
`
`1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets
`
`
`≥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 <1.0 x 109/L
`and/or platelets <50 x 109/L, repeat step 1 and
`resume Gleevec at reduced dose of 200 mg/m2
`
`
`
`3.
`
`
`3.
`
`
`platelets <10 x 109/L
`
`
`
`ANC <1.0 x 109/L
`and/or
`platelets <50 x 109/L
`
`
`
`ANC <1.0 x 109/L
`and/or
`platelets <50 x 109/L
`
`ANC <1.0 x 109/L
`and/or
`platelets <50 x 109/L
`
`
`
`
` Ph+ ALL
`
`(starting dose 600 mg)
`
`
`
`
`DFSP
`(starting dose 800 mg)
`
`
`
`Pediatric newly diagnosed chronic
`phase CML
`(starting dose 340 mg/m2)
`
`
`
`Pediatric patients with chronic phase
`CML recurring after transplant or
`resistant to Interferon (starting dose
`260 mg/m2)
`
`
`
`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
`“400” on one side with score on the other side, and “SL” on each side of the score
`4 CONTRAINDICATIONS
`None
`5 WARNINGS AND PRECAUTIONS
`5.1 Fluid Retention and Edema
`
`Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1)].
`Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected
`rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema
`was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was
`reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-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%-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 (6.11)].
`5.2 Hematologic Toxicity
`Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts
`should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as
`
`6
`
`

`
`
`clinically indicated (for example, every 2-3 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 (2.11)].
`
`5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction
`
`Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients
`taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk
`factors, including advanced age and previous medical history of cardiac disease. In an international randomized
`phase 3 study in 1,106 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. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and
`any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
`5.4 Hepatotoxicity
`Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Liver function
`(transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and
`monthly, or as clinically indicated. Laboratory abnormalities should be managed with interruption and/or dose
`reduction of the treatment with Gleevec [see Dosage and Administration (2.10)].
`
`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 the newly diagnosed CML trial, 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.
`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 gastrointestinal
`
`perforation.
`5.7 Hypereosinophilic Cardiac Toxicity
`In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left
`ventricular dysfunction have been associated with 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. Performance of an echocardiogram and determination of serum troponin should
`therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with
`high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to
`two weeks concomitantly with Gleevec should be considered at the initiation of therapy.
`5.8 Dermatologic Toxicities
` Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been
`reported with use of Gleevec.
`5.9 Hypothyroidism
`Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine
`replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.
`
`7
`
`

`
`
`5.10 Toxicities from Long-Term Use
`It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and
`cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with
`elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was
`observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular
`nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of
`opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a
`39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial
`infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term
`
`toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on
`study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland
`papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study
`which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine
`organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of
`
`cardiac insufficiency in some animals.
`5.11 Use in Pregnancy
`Pregnancy Category D
`Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec. Sexually
`active female patients taking Gleevec should use adequate contraception. 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.. 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 body
`surface area. [ see Use in Specific Populations (8.1)]
`
`
`6 ADVERSE REACTIONS
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed
`cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical
`practice.
`6.1 Chronic Myeloid Leukemia
`The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of
`mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly
`diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated
`phase and 5% 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 for newly diagnosed CML, Table 3 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 Gleevec. [see Dosage and Administration (2.10)]. 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