Imatinib Mesylate (Page 2 of 10)

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, imatinib mesylate tablets 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 imatinib mesylate tablets 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), imatinib mesylate tablets 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 (starting dose 100 mg) ANC1 less than 1 x 109 /Land/orplatelets less than 50 x 109 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 109 /L and platelets greater than or equal to 75 x 109 /LResume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction)
HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1 x 109 /L and/orplatelets less than 50 x 109 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 109 /L and platelets greater than or equal to 75 x 109 /LResume treatment with imatinib mesylate tablets 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 dose 400 mg) ANC less than 1 x 109 /Land/orplatelets less than 50 x 109 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 109 /L and platelets greater than or equal to 75 x 109 /LResume treatment with imatinib mesylate tablets at the original starting dose of 400 mgIf recurrence of ANC less than 1 x 109 /L and/or platelets less than 50 x 109 /L, repeat step 1 and resume imatinib mesylate tablets 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 less than 0.5 x 109 /Land/orplatelets less than 10 x 109 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy)If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate tablets to 400 mgIf cytopenia persists 2 weeks, reduce further to 300 mgIf cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib mesylate tablets 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
DFSP (starting dose 800 mg) ANC less than 1 x 109 /Land/orplatelets less than 50 x 109 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 109 /L and platelets greater than or equal to 75 x 109 /L Resume treatment with imatinib mesylate tablets at 600 mgIn the event of recurrence of ANC less than 1 x 109 /L and/or platelets less than 50 x 109 /L, repeat step 1 and resume imatinib mesylate tablets at reduced dose of 400 mg.
Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m2) ANC less than 1 x 109 /Land/orplatelets less than 50 x 109 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 109 /L and platelets greater than or equal to 75 x 109 /LResume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction)In the event of recurrence of ANC less than 1 x 109 /L and/or platelets less than 50 x 109 /L, repeat step 1 and resume imatinib mesylate tablets 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

Yellow, circular, biconvex, film coated tablet debossed with “472” on one side and breakline on the other side.

400 mg film-coated tablets

Yellow, ovaloid shaped, biconvex, film coated tablet debossed with “475” on one side and breakline on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Fluid Retention and Edema

Imatinib mesylate 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 imatinib mesylate 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 mesylate tablets, and in 2% to 6% of other adult CML patients taking imatinib mesylate tablets. 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 mesylate tablets, and in 2% to 6% of other adult CML patients taking imatinib mesylate tablets. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib mesylate for GIST [see Adverse Reactions (6.1)]. In a randomized trial in patients with newly diagnosed Ph+CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate 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 mesylate 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 mesylate 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 imatinib mesylate tablets. 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 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 imatinib mesylate tablets 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 mesylate and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib mesylate 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.

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