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Gleevec (Imatinib Mesylate) - Indications and Dosage

 
 



1 INDICATIONS AND USAGE

1.1 Newly D iagnosed Philadelphia P ositive 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) A fter Interferon-alpha (IFN) T herapy

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 P atients 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 M yelodysplastic/ M yeloproliferative D iseases ( 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 S yndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL)

Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRalpha fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRalpha 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 800mg 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 100mg tablet, and 200 mL for a 400mg 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 400mg 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 400mg/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-PDGFRalpha, 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-PDGFRalpha fusion kinase, a starting dose of 100mg/day is recommended. Dose increase from 100mg to 400mg 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.

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 [ s ee 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 260mg/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 1Dose Adjustments for Neutropenia and Thrombocytopenia
ASM associated with eosinophilia (starting dose 100 mg)

ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
  • Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
  • Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction)
HES/CEL with FIP1L1-PDGFRalpha fusion kinase (starting dose 100mg) ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
  • Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
  • 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 dose
400 mg)
ANC <1.0 x 109/L
and/or
platelets <50 x 109/L




  • Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
  • 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 doseof 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






  • Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
  • 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
DFSP
(starting dose 800 mg)



ANC <1.0 x 109/L
and/or
platelets <50 x 109/L


  • Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
  • Resume treatment with Gleevec at 600 mg
  • 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/L
and/or
platelets <50 x 109/L
  • Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
  • 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
Pediatric patients with chronic phase CML recurring after transplant or resistant to Interferon (starting dose 260 mg/m2)


ANC <1.0 x 109/L
and/or
platelets <50 x 109/L



  • Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
  • 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 DOSAGE FORMS AND STRENGTHS

100mg 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

400mg 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

16 HOW SUPPLIED/STORAGE AND HANDLING

Each film-coated tablet contains 100 mg or 400 mg of imatinib free base.

100mg 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.

Bottles of 90 tablets'……………………………….NDC 0078-0401-34

400mg 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.

Bottles of 30 tablets'………………………………...NDC 0078-0438-15

Storage and Handling

Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight container, USP.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4

Gleevec tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets. [see Nonclinical Toxicology].

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