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Imatinib

Imatinib

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Imatinib mesylate, a specific inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent that is structurally and pharmacologically distinct from other currently available antineoplastic agents.
The Philadelphia chromosome, characteristic of chronic myelogenous leukemia (CML), is created by a reciprocal translocation. Translocation between chromosomes results in production of an abnormal protein (Bcr-Abl tyrosine kinase) that exhibits enhanced tyrosine kinase activity.
Imatinib competitively inhibits Bcr-Abl tyrosine kinase, The drug has been shown to inhibit proliferation and induce apoptosis of Bcr-Abl positive cells as well as fresh leukemic cells from Philadelphia chromosome positive CML.

lmatinib also appears to inhibit receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and PDGF mediated and SCF-media cellular events. Data from in vitro studies shows that imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells.




DOSAGE AND ADMINISTRATION

  • Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML): Oral:

Chronic phase: 400 mg once daily; may be increased to 600 mg daily, if tolerated, for disease progression, lack of hematologic response after 3 months, lack of cytogenetic response after 6 to 12 months, or loss of previous hematologic or cytogenetic response. An increase to 800 mg daily has been used

  • Accelerated phase or blast crisis: 600 mg once daily; may be increased to 800 mg daily (400 mg twice daily), if tolerated, for disease progression, lack of hematologic response after 3 months, lack of cytogenetic response after 6 to 12 months, or loss of previous hematologic or cytogenetic response
  • Ph+ acute lymphoblastic leukemia (ALL) (relapsed or refractory): Oral: 600 mg once daily
  • Gastrointestinal stromal tumors (GIST) (adjuvant treatment following complete resection): Oral: 400 mg once daily; recommended treatment duration: 3 years
  • GIST (unresectable and/or metastatic malignant): Oral: 400 mg once daily; may be increased up to 800 mg daily (400 mg twice daily), if tolerated, for disease progression. Note: Significant improvement (progression-free survival, objective response rate) was demonstrated in patients with KIT exon 9 mutation with 800 mg (versus 400 mg), although overall survival (OS) was not impacted. The higher dose did not demonstrate a difference in time to progression or OS patients with Kit exon 11 mutation or wild-type status
  • Aggressive systemic mastocytosis (ASM) associated with eosinophilia: Oral: Initiate at 100 mg once daily; if assessments demonstrate insufficient response, increase from 100 mg to 400 mg/day in the absence of adverse reactions.
  • ASM without D816V c-Kit mutation or c-Kit mutation status unknown: Oral: 400 mg once daily

Dermatofibrosarcoma protuberans (DFSP): Oral: 400 mg twice daily

  • Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL): Oral: 400 mg once daily
  • HES/CEL with FIP1L1-PDGFRα fusion kinase: Oral: Initiate at 100 mg once daily; if assessments demonstrate insufficient response, increase from 100 mg to 400 mg/day in the absence of adverse reactions.
  • Myelodysplastic/myeloproliferative disease (MDS/MPD) with PDGF receptor gene rearrangements: Oral: 400 mg once daily
  • Chordoma, progressive, advanced, or metastatic expressing PDGFRB and/or PDGFB (off-label use): Oral: 400 mg twice daily
  • Desmoid tumors, unresectable and/or progressive (off-label use): Oral: 300 mg twice daily (BSA ≥1.5 m2), 200 mg twice daily (BSA 1 to 1.49 m2), 100 mg twice daily (BSA <1 m2) (Chugh 2010) or 400 mg once daily; may increase to 400 mg twice daily if progressive disease on 400 mg daily (Penel 2011)

Melanoma, advanced or metastatic with C-KIT mutation (off-label use): Oral: 400 mg twice daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

  • Note: Imatinib is associated with a moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting
  • Acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive (Ph+); newly diagnosed: Children and Adolescents: Oral: 340 mg/m2/day administered once daily; in combination with intensive chemotherapy (Schultz 2014); maximum daily dose: 600 mg/day; treatment may be continued until disease progression or unacceptable toxicity
  • Chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph+); chronic phase, newly diagnosed: Children and Adolescents: Oral: 340 mg/m2/day administered once daily or in 2 divided doses; maximum daily dose: 600 mg/day. Treatment may be continued until disease progression or unacceptable toxicity. The optimal duration of therapy for CML in complete remission is not yet determined. Discontinuing CML treatment is not recommended unless part of a clinical trial
  • Dosing adjustment with concomitant strong CYP3A4 inducers: Children and Adolescents: Avoid concomitant use of strong CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin); if concomitant use cannot be avoided, increase imatinib dose by at least 50% with careful monitoring.
  • Dosing adjustment for nonhematologic adverse reactions: Children and Adolescents: Withhold treatment until toxicity resolves; may resume if appropriate (depending on initial severity of adverse event)
  • Dosing adjustment for hematologic adverse reactions: Children and Adolescents:

ALL Ph+ (newly diagnosed): Hematologic toxicity requiring dosage adjustments was not observed in the study. No major toxicities were observed with imatinib at 340 mg/m2/day in combination with intensive chemotherapy

  • CML Ph+ (chronic phase): If ANC <1 x 109/L and/or platelets <50 x 109/L: Withhold until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L; resume treatment at previous dose. For recurrent neutropenia and/or thrombocytopenia, withhold until recovery and reinstitute treatment at a reduced dose as follows: If initial dose 340 mg/m2/day, reduce dose to 260 mg/m2/day.
INDICATIONS
  • Acute lymphoblastic leukemia: Treatment of relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in adults
  • Treatment of newly diagnosed Ph+ ALL in children (in combination with chemotherapy)
  • Aggressive systemic mastocytosis: Treatment of aggressive systemic mastocytosis in adults without D816V c-Kit mutation (as determined by an approved test) or with c-Kit mutational status unknown.

Chronic myeloid leukemia:

  • Treatment of Ph+ chronic myeloid leukemia (CML) in chronic phase (newly diagnosed) in adults and children
  • Treatment of Ph+ CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alfa therapy
  • Dermatofibrosarcoma protuberans: Treatment of unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP) in adults
  • Gastrointestinal stromal tumors: Treatment of Kit (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST)
  • Adjuvant treatment of Kit (CD117)–positive GIST following complete gross resection
  • Hypereosinophilic syndrome and/or chronic eosinophilic leukemia: Treatment of hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) in adult patients who have the FIP1L1–platelet-derived growth factor (PDGF) receptor alpha fusion kinase (mutational analysis or fluorescent in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGF receptor alpha fusion kinase negative or unknown
  • Myelodysplastic/Myeloproliferative diseases: Treatment of myelodysplastic syndrome/myeloproliferative diseases (MDS/MPD) associated with PDGF receptor gene rearrangements as determined by an approved test in adults

WARNINGS AND PRECAUTIONS

Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus

 Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics

 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

 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

 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

 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

 Gastrointestinal perforations, some fatal, have been reported

 Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Imatinib in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD and ASM)

 Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been   reported with the use of Imatinib

 Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients

 Consider potential toxicities, specifically, liver, kidney, and cardiac toxicity, and immunosuppression from long-term use


DRUG INTERACTIONS

CYP3A4 inducers may decrease Imatinib Cmax and AUC

 CYP3A4 inhibitors may increase Imatinib Cmax and AUC

 • Imatinib is an inhibitor of CYP3A4 and may increase the Cmax and AUC of other drugs

 Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin

 Systemic exposure to acetaminophen is expected to increase when co-administered with Gleevec


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