Revised 1 Feb 2007
SYNONYM(S): STI-571, imatinib mesylate
COMMON TRADE NAME(S): GLEEVEC®, GLIVEC®
CLASSIFICATION: tyrosine kinase inhibitor, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION:
Imatinib inhibits BCR-ABL tyrosine kinase, the fusion protein created by the Philadelphia chromosome abnormality that characterizes chronic myeloid leukemia. Competitive inhibition at the enzyme's ATP-binding site leads to inhibition of tyrosine phosphorylation of proteins involved in BCR-ABL signal transduction.1 Inhibition is not completely selective as imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor and c-Kit, a stem cell factor.2 Cells that express BCR-ABL undergo growth inhibition or apoptosis but normal cells are not affected.1,2
PHARMACOKINETICS:
|
Interpatient variability |
40% for clearance |
|
Oral Absorption |
98% mean absolute bioavailability; not affected by fatty food3 |
|
time to peak plasma concentration |
2-4 h |
|
Distribution |
extensively bound to plasma protein |
|
cross blood brain barrier? |
animal studies showed poor penetration4 |
|
volume of distribution |
~ 295 L5 |
|
plasma protein binding |
95%, mostly to albumin and a1-acid glycoprotein |
|
Metabolism |
75%, primarily oxidative6 via CYP3A4/5. The main active metabolite is equipotent to imatinib. Other CYP450 enzymes (1A2, 2D6, 2C9, 2C19) have a minor role. |
|
active metabolite(s) |
N-desmethyl derivative (CGP 74588)6 |
|
inactive metabolite(s) |
none known |
|
Excretion |
fecal and urinary excretion |
|
urine |
13% over 7 days |
|
feces |
68% over 7 days |
|
terminal half life |
imatinib: 18 h
CGP 74588: 40 h |
|
clearance |
13-17 L/h5 |
|
Gender |
no clinically significant difference7 |
|
Elderly |
small effect of age on the volume of distribution (12% increase in patients > 65 years old); not clinically significant7 |
|
Children |
no clinically significant difference |
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Ethnicity |
no information found |
Adapted from reference 2 unless specified otherwise.
USES:
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Primary uses: |
Other uses: |
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*leukemia, chronic myeloid (CML)2,8 |
leukemia, acute (Ph+)9-12 |
|
*sarcoma, gastrointestinal stromal tumour (GIST)13 |
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*Health Canada Therapeutic Products Programme approved indication
SPECIAL PRECAUTIONS:
Contraindicated in patients who have a history of hypersensitivity reaction to imatinib.2
Carcinogenicity: carcinoma was seen at doses of 30-60 mg/kg/day in an animal carcinogenicity study. No significant increase in second malignancies was seen in clinical trials.14
Mutagenicity: Imatinib was not mutagenic in the Ames test and mammalian in vitro mutation test. Two intermediates of the manufacturing process, which are present in the final product, are mutagenic in the Ames test. Imatinib is clastogenic in mammalian in vitro tests.2
Fertility: Studies in animals have shown decreased fertility.2
Pregnancy: FDA Pregnancy Category D.2 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding is not recommended because an amount equivalent to 30% of the maternal dose per unit body weight has been found in breast milk in animal studies.2
SIDE EFFECTS:
ORGAN SITE |
SIDE EFFECT |
|
Clinically important side effects are in bold, italics |
|
blood/bone marrow
febrile neutropenia |
anemia
newly diagnosed CML and GIST: severe 3-4%
CML accelerated phase and blast crisis: severe 40-50% |
|
anemia, hemolytic (rare)15,16; generally occurs within 1-4 weeks16 |
|
bone marrow necrosis (< 1%); generally occurs within 1-4 weeks17 |
|
myelodysplasia (< 1%); generally occurs after more than 3 months18,19 |
|
neutropenia
newly diagnosed CML and GIST: severe 8-13%
CML accelerated phase and blast crisis: severe 58-63%
median duration 2-3 weeks |
|
splenic rupture (< 1%); generally occurs after more than 1-3 months20 |
|
thrombocytopenia (severe 17-58%)
newly diagnosed CML and GIST: severe 0.7-7%
CML accelerated phase and blast crisis: severe 40-50%
median duration 3-4 weeks |
|
cardiovascular (general) |
cardiac tamponade (< 1%); generally occurs after more than 3 months21 |
|
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congestive heart failure (<1%); generally occurs after 7 months22 |
|
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edema, more common in > 65 years old (52-68%, severe 2-10%) |
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constitutional symptoms |
fatigue (24-33%, severe 0.2-3%) |
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fever (14-38%, severe 1-7%) |
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night sweats (8-10%, severe <1%) |
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weakness (5-10%, severe 0.2-3%) |
|
weight gain (1-4%, severe 0.4-2%) |
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dermatology/skin |
cutaneous reactions, severe (< 1%)16,23-41 |
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photosensitivity (0.1-1%)24 |
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pruritus (6-10%, severe <1%) |
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rash (32-39%, severe 3-4%) |
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gastrointestinal |
emetogenic potential: low moderate |
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anorexia (3-14%, severe 0-2%) |
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constipation (4-13%, severe <1%) |
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diarrhea (33-39%, severe 3-4%) |
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diverticulitis (< 1%)14 |
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gastrointestinal perforation (< 1%)14 |
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nausea (55-68%, severe 2-5%) |
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vomiting (28-49%, severe 0.9-3%) |
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endocrine |
gynecomastia (0.1-1%)24; generally occurs after more than 3 months42 |
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hemorrhage |
bleeding episode (13-48%, severe 8-16%) |
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CNS bleeding (0.4-4%, severe 0.4-2%) |
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epistaxis (3-12%, severe 0-3%) |
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gastrointestinal bleeding (0.2-5%, severe <3%) |
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petechiae (0.9-10%, severe <1%) |
|
hepatic |
elevated bilirubin (severe 0.4-3.5%) |
|
elevated ALT, AST, alkaline phosphatase (severe 1.1-5.5%) |
|
|
hepatic necrosis, early to delayed (< 1%); generally occurs after more than 1-3 months43,44 |
|
infection |
pneumonia (1-10%, 0-5%) |
|
|
varicella-zoster virus infection (2%); generally occurs after 1-3 months45 |
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metabolic/laboratory |
hypokalemia (2-12%, severe 0-3%) |
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musculoskeletal |
arthralgia (21-26%, severe 0.8-5%) |
|
avascular necrosis/hip necrosis (< 1%)14 |
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muscle cramps (25-46%, severe <1%) |
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myalgia (7-18%, severe 0-2%) |
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ocular/visual |
periorbital edema2 (70%, rarely severe)46-48; generally occurs after more than 1-3 months47,48 |
|
|
watery eye (12%)46 |
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pain |
abdominal pain (20-23%, severe 0.2-5%) |
|
headache (24-28%, severe 0.2-4%) |
|
|
pain (27-39%, severe 1-8%) |
|
pulmonary |
cough (9-22%, severe <1%) |
|
dyspnea (5-12%, severe 0.2-5%) |
|
pneumonitis (< 1%)24,49-51; generally occurs within 1-3 months50,51 |
|
pleural effusions (< 1%)24,52 |
|
pulmonary alveolar proteinosis (< 1%); generally occurs after more than 1-3 months53 |
|
nasopharyngitis (5-10%, severe 0.2%) |
|
renal/genitourinary |
elevated creatinine (severe <1.2%) |
|
|
renal failure, acute (< 1%)54,55; may occur after one week54 to two months55 |
|
syndromes |
tumour lysis syndrome (< 1%) ; generally occurs within 4-5 days56,57 |
Adapted from reference 2 unless specified otherwise.
Bone marrow suppression, especially neutropenia and thrombocytopenia, is more common at higher doses (>750 mg/day) and in blast crisis or accelerated phase compared to chronic phase when treating chronic myeloid leukemia. Management is dose reduction, interruption or (rarely) discontinuation of imatinib.2 Filgrastim at a dose of 300-480 mcg two to three times weekly58,59 or daily60 has also been used.
Edema is usually mild to moderate and most frequently periorbital or in lower limbs but may include pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema.2 Serious or life threatening edema has rarely been reported, including periorbital edema,47,48 intramuscular edema,61 and cerebral edema.62 It appears to be dose related (especially > 600 mg /day) and is more common in the elderly and female patients.2 Edema may be due to inhibition of platelet-derived growth factor receptor which regulates interstitial fluid pressure. Onset varies from weeks to months.47,48,61,62 Management is largely symptomatic with diuretics, other supportive measures or imatinib dose reduction.2
Hepatotoxicity with severe elevations of transaminases or bilirubin may be life threatening. Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored before initiation of treatment and monthly or as clinically indicated. Management of hepatotoxicity is dose reduction, interruption (median duration one week) or discontinuation (<0.5%) of imatinib.2
Severe skin reactions are rare and varied in presentations,23,24 including exanthematous (erythematous) reactions,24-28 erythroderma and exfoliative dermatitis,16,24,28,29 eruptions,24,30-33 pigmentation reactions,24,34-37 photosensitisation,24,36 hemorrhagic blisters,38,39 and inflammation of subcutaneous fat tissue40 and blood vessels.28 The onset is variable and may be early,26,28,41 delayed34-37 or late.34-37 The median onset was about 1-2 months26,28,41 but may be more delayed with pigmentation changes34,35,37 and photosensitisation.36 Skin biopsies tended to show infiltration of inflammatory cells 23,28,35,41 and reactions seemed to be dose-related.23,28,35,41,63 Management is largely symptomatic, including discontinuation or reduction of dose,oral and/or topical corticosteroids, antihistamines and immunosuppressants.23,26,28,35,41,60,63
INTERACTIONS:
AGENT |
EFFECT |
MECHANISM |
MANAGEMENT |
|
grapefruit or grapefruit juice64 |
may increase plasma level of imatinib |
may inhibit CYP3A4 metabolism of imatinib in the intestinal wall |
avoid grapefruit and grapefruit juice |
|
ketoconazole64 |
increases plasma level of imatinib |
inhibits CYP 3A4 metabolism of imatinib |
use with caution |
|
levothyroxine65 |
imatinib may increase thyroid-stimulating hormone level and symptoms of hypothyroidism |
imatinib may increase hepatic clearance of levothyroxine |
closely monitor thyroid function during concurrent use and adjust levothyroxine dose as needed |
|
rifampin |
decreases plasma level of imatinib |
induces CYP3A4 metabolism of imatinib |
avoid concurrent use |
|
simvastatin |
increases plasma level of simvastatin |
inhibits CYP3A4 metabolism of simvastatin |
avoid concurrent use |
|
warfarin |
prolongs bleeding time |
possibly inhibits CYP2C9 and CYP3A4 metabolism of warfarin |
closely monitor bleeding parameters during concurrent use and adjust warfarin dose as needed, or consider other alternatives (eg, low-molecular weight or standard heparin) |
Adapted from reference 2 unless specified otherwise.
Imatinib may increase plasma concentrations of other CYP3A4 metabolised drugs (eg, triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors).24
CYP3A4 inhibitors may decrease metabolism and increase imatinib plasma concentrations. Concurrent administration of drugs that inhibit CYP3A4 (eg, clarithromycin, erythromycin, grapefruit juice, itraconazole) may significantly increase exposure of imatinib.24 Drugs that have high oral bioavailability (eg. >0.7) are less likely to be affected by grapefruit juice.
CYP3A4 inducers may increase metabolism and decrease imatinib plasma concentrations. Concurrent administration of drugs that induce CYP3A4 (eg, carbamazepine, dexamethasone, phenytoin, phenobarbital, St. John’s Wort) may significantly reduce exposure of imatinib.24
Imatinib may increase systemic exposure to acetaminophen, at therapeutic doses, through inhibition of acetaminophen O-glucuronidation. Human studies have not been performed, but caution is recommended when using imatinib and acetaminophen concurrently.66
SUPPLY AND STORAGE:
Tablets: 100 mg, 400 mg; store at room temperature.14
DOSAGE GUIDELINES:
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults:
|
|
|
BCCA usual dose noted in bold, italics |
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Oral: |
400-600 mg (range 400-800mg) PO once daily.
Administer with food.2 800 mg dose should be administered in two divided doses.24
|
|
Dosage in myelosuppression24: |
CML chronic phase or GIST |
|
|
If ANC < 1 x109/L or platelet < 50 x109/L, hold until ANC > 1.5 and platelets > 75:
- CML: if 1st episode, restart at 400 mg daily; if 2nd episode, restart at 300 mg daily (dosages < 300 mg/day not recommended as they were found to be ineffective in early studies)
- GIST: if 1st episode, restart at 600 mg daily; if 2nd episode, restart at 400 mg daily
|
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CML accelerated phase or blast crisis |
|
|
If ANC < 0.5 x109/L or platelet < 10 x109/L and
- cytopenia unrelated to disease: reduce from 600 mg to 400 mg daily
- cytopenia persists for 2 weeks: reduce further to 300 mg daily
- cytopenia persists for 4 weeks: hold until ANC > 1 and platelets > 20 and then restart 300 mg daily
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|
|
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Dosage in renal failure: |
no adjustment required |
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Dosage in hepatic failure24,67: |
If bilirubin > 3 x ULN or ALT/AST > 5 x ULN:
- hold until bilirubin < 1.5 x ULN and ALT/AST < 2.5 x ULN
- restart at 300 mg (reduced from 400 mg) or 400 mg (reduced from 600 mg)
- full dose had been used in four patients with severe jaundice68,69
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Dosage in dialysis: |
no information found |
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Children:
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Oral: |
260 mg/m2 once daily or split daily into two (once in the morning and once in the evening)24
Administer with food.24 |
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Dosage in myelosuppression24: |
CML chronic phase |
|
|
If ANC < 1 x109/L or platelet < 50 x109/L, hold until ANC > 1.5 and platelets > 75:
- If 1st episode, restart at 260 mg/m2 daily.
- If 2nd episode, restart at 200 mg/m2 daily.
|
|
|
|
|
Dosage in hepatic failure24,67: |
If bilirubin > 3 x ULN or ALT/AST > 5 x ULN:
- hold until bilirubin < 1.5 x ULN and ALT/AST < 2.5 x ULN
- restart at 200 mg/m2 daily (reduced from 260 mg/m2 daily) or 260 mg/m2 daily (reduced from 340 mg/m2 daily)
|
References:
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3. Reckmann AH, Fischer T, Peng B, et al. Effect of food on STI571 Glivec pharmacokinetics and bioavailability. Proc Am Soc Clin Oncol 2001;20(Part 1 of 2):(abstract 1223).
4. Senior K. Gleevec does not cross blood-brain barrier. Lancet Oncol 2003;4(4):198.
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6. Ford JM. STI571 (formerly CGP 57 148 B) investigators brochure. Basel: Novartis Pharma AG; 23 June 2000. p. 77.
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8. Druker BJ. STI571 (Gleevec/Glivec, imatinib) versus interferon (IFN) + cytarabine as initial therapy for patients with CML: results of a randomized study. Proc Am Soc Clin Oncol 2002;21 (Part 1 of 2):1a (abstract ).
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10. Wassmann B, Scheuring U, Pfeifer H, et al. Efficacy and safety of imatinib mesylate (Glivec) in combination with interferon-alpha (IFN-alpha) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Leukemia 2003;17(10):1919-24.
11. Wassmann B, Pfeifer H, Scheuring U, et al. Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Leukemia 2002;16(12):2358-65.
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13. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344(14):1052-6.
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33. Schaich M, Schakel K, Illmer T, et al. Severe epidermal necrolysis after treatment with imatinib and consecutive allogeneic hematopoietic stem cell transplantation. Ann Hematol 2003;82(5):303-4.
34. Raanani P, Goldman JM, Ben-Bassat I. Challenges in oncology. Case 3. Depigmentation in a chronic myeloid leukemia patient treated with STI-571. J Clin Oncol 2002;20(3):869-70.
35. Tsao AS, Kantarjian H, Cortes J, et al. Imatinib mesylate causes hypopigmentation in the skin. Cancer 2003;98(11):2483-7.
36. Rousselot P, Larghero J, Raffoux E, et al. Photosensitization in chronic myelogenous leukaemia patients treated with imatinib mesylate. Br J Haematol 2003;120(6):1091-2.
37. Etienne G, Cony-Makhoul P, Mahon FX. Imatinib mesylate and gray hair.[comment]. N Engl J Med 2002;347(6):446.
38. Breccia M, Latagliata R, Carmosino I, et al. Reactivation of porphyria cutanea tarda as a possible side effect of Imatinib at high dosage in chronic myeloid leukemia. Leukemia 2004;18(1):182.
39. Ho AY, Deacon A, Osborne G, et al. Precipitation of porphyria cutanea tarda by imatinib mesylate? Br J Haematol 2003;121(2):375.
40. Ugurel S, Lahaye T, Hildenbrand R, et al. Panniculitis in a patient with chronic myelogenous leukaemia treated with imatinib. Br J Dermatol 2003;149(3):678-9.
41. Stone R, Galinsky I, Haynes H, et al. Skin reactions to imatinib mesylate (STI-571) in patients with chronic myeloid leukemia (CML): clinical features and histopathology. Blood 2001;98(11):141a (abstract 592).
42. Gambacorti-Passerini C, Tornaghi L, Cavagnini F, et al. Gynaecomastia in men with chronic myeloid leukaemia after imatinib. Lancet 2003;361(9373):1954-6.
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44. Lin NU, Sarantopoulos S, Stone JR, et al. Fatal hepatic necrosis following imatinib mesylate therapy. Blood 2003;102(9):3455-6.
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54. Kitiyakara C, Atichartakarn V. Renal failure associated with a specific inhibitor of BCR-ABL tyrosine kinase, STI 571. Nephrol Dial Transplant 2002;17(4):685-7.
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56. Dann EJ, Fineman R, Rowe JM. Tumor lysis syndrome after STI571 in Philadelphia chromosome-positive acute lymphoblastic leukemia. J Clin Oncol 2002;20(1):354-5.
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59. Marin D, Marktel S, Foot N, et al. Granulocyte colony-stimulating factor reverses cytopenia and may permit cytogenetic responses in patients with chronic myeloid leukemia treated with imatinib mesylate. Haematologica 2003;88(2):227-9.
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62. Ebnoether M, Stentoft J, Ford J, et al. Cerebral oedema as a possible complication of treatment with imatinib. Lancet 2002;359(9319):1751-2.
63. Rule SA, O'Brien SG, Crossman LC. Managing cutaneous reactions to imatinib therapy.[see comment]. Blood 2002;100(9):3434-5.
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65. de Groot JW, Zonnenberg BA, Plukker JT, et al. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 2005;78(4):433-8.
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67. Novartis Pharmaceuticals Canada Inc. Gleevec product monograph. Dorval, QC; 2003.
68. Bauer S, Hagen V, Pielken HJ, et al. Imatinib mesylate therapy in patients with gastrointestinal stromal tumors and impaired liver function. Anticancer Drugs 2002;13(8):847-9.
69. De Pas T, Danesi R, Catania C, et al. Imatinib administration in two patients with liver metastases from GIST and severe jaundice. Br J Cancer 2003;89(8):1403-4.