Imatinib Mesylate (Page 2 of 9)

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 1.0 x 109 /L and/or

platelets less than 50 x 109 /L

  1. Stop imatinib mesylate 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 Imatinib mesylate tablet at previous dose (i.e., dose before severe adverse reaction)

HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg)

ANC less than

1.0 x 109 /L and/or

platelets less than 50 x 109 /L

  1. Stop imatinib mesylate 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 imatinib mesylate 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)

ANC less than 1.0 x 109 /L and/or

platelets less than 50 x109 /L

  1. Stop imatinib mesylate 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 imatinib mesylate at the original starting dose of 400 mg
  3. 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 imatinib mesylate 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 /L and/or

platelets less than 10 x109 /L

  1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
  2. If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate 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 imatinib mesylate 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 1.0 x 109 /L and/or

platelets less than 50 x109 /L

  1. Stop imatinib mesylate 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 imatinib mesylate 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 imatinib mesylate at reduced dose of 400 mg

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 x109 /L

  1. Stop imatinib mesylate 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 imatinib mesylate at previous dose (i.e., dose before severe adverse reaction)
  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 Imatinib mesylate tablet at reduced dose of 260 mg/m2

1 ANC=absolute neutrophil count

3 DOSAGE FORMS & STRENGTHS

100 mg film-coated tablets

Dark yellow to brownish orange colored, film-coated tablets, round, biconvex with bevelled edges debossed with ‘S’ and ’1′ on either side of break line on one side and plain on other side.

400 mg film-coated tablets

Dark yellow to brownish orange colored, film coated tablets, capsule shaped, biconvex with bevelled edges debossed with ‘S’ and ’2′ on either side of break line on one side and plain on 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, and in 2% — 6% of other adult CML patients taking imatinib mesylate. 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, and in 2%-6% of other adult CML patients taking imatinib mesylate. 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. 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 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 patient 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.

5.4 Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with imatinib mesylate [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 mesylate. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with imatinib mesylate interruption and/or dose reduction [see Dosage and Administration (2.13)]. When imatinib mesylate 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 mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate 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 imatinib mesylate 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.

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