Gleevec: Package Insert and Label Information

GLEEVEC — imatinib mesylate tablet
Physicians Total Care, Inc.

1 INDICATIONS AND USAGE

1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML )

Newly diagnosed adult and pediatric 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 Ph+ Acute Lymphoblastic Leukemia (ALL)

Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia.

1.4 M yelodysplastic/Myeloproliferative Diseases ( MDS/MPD )

Adult patients with myelodysplastic/ myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements.

1.5 Aggressive Systemic Mastocytosis (ASM)

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

1.6 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.

1.7 Dermatofibrosarcoma Protuberans (DFSP)

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

1.8 Kit+ Gastrointestinal Stromal Tumors (GIST)

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.9 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 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 CP

The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m2 /day (not to exceed 600 mg).

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 Metastatic 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.

2.9 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.

2. 10 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 Warnings and Precautions (5.3),Use in Specific Populations (8.7) ].

2. 11 Dose Adjustment for Hepatotoxicity and Non -Hematologic Adverse R eactions

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.

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. 12 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(starting dose 100 mg) ANC <1.0 x 109 /Land/orplatelets <50 x 109 /L
  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)
HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC <1.0 x 109 /Land/orplatelets <50 x 109 /L
  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)
Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg)GIST (starting dose400 mg) ANC <1.0 x 109 /L and/or platelets <50 x 109 /L
  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
  3. 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
Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg)Ph+ ALL (starting dose 600 mg) ANC <0.5 x 109 /L and/or platelets <10 x 109 /L
  1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
  2. If cytopenia is unrelated to leukemia, reduce dose of Gleevec to 400 mg
  3. If cytopenia persists 2 weeks, reduce further to 300 mg
  4. 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
DFSP(starting dose 800 mg) ANC <1.0 x 109 /Land/orplatelets <50 x 109 /L
  1. Stop Gleevec until ANC ≥1.5 x 109 /L and platelets ≥75 x 109 /L
  2. Resume treatment with Gleevec at 600 mg
  3. 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 400 mg
Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m2) ANC <1.0 x 109 /Land/orplatelets <50 x 109 /L
  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)
  3. 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

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 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. 12 ) ] .

5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction

Severe congestive heart failure and left ventricular dysfunction have 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 or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.

5.4 Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with Gleevec [ see Adverse Reactions (6.3) ] . 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. 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 Gleevec interruption and/or dose reduction [ see Dosage and Administration (2. 11 ) ].

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.

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