imatinib (i-mat-i-nib) Gleevec

 Indications

Newly diagnosed Philadelphia positive (Ph)

chronic myeloid leukemia (CML). CML in blast crisis,

accelerated phase, or in chronic phase after failure of

interferon-alpha treatment. Kit (CD117) positive

metastatic/unresectable malignant gastrointestinal stomal

tumors (GIST). Adjuvant treatment following resection

of Kit (CD117) positive GIST. Pediatric patients

with Ph CML after failure of bone marrow transplant

or resistance to interferon-alpha. Adult patients with

relapsed or refractory Ph acute lymphoblastic leukemia

(ALL). Newly diagnosed Ph ALL (in combination

with chemotherapy). Myelodysplastic/myeloproliferative

disease (MDS/MPD) associated with

platelet-derived growth factor receptor (PDGFR) gene

re-arrangements. Aggressive systemic mastocytosis

(ASM) without the D816V c-Kit mutation or with c-Kit

mutational status unknown. Hypereosinophilic syndrome

and/or chronic eosinophilic leukemia (HES/

CEL). Unresectable, recurrent, or metastatic dermatofibrosarcoma

protuberans (DFSP).

Action

Inhibits kinases which may be produced by malignant

cell lines. Therapeutic Effects: Inhibits production

of malignant cell lines with decreased proliferation of

leukemic cells in CML, HES/CEL, and ALL and malignant

cells in GIST, MDS/MPD, ASM, and DFSP.

Pharmacokinetics

Absorption: Well absorbed (98%) following oral

administration.

Distribution: Unknown.

Protein Binding: 95%.

Metabolism and Excretion: Mostly metabolized

by the CYP3A4 enzyme system to N-demethyl imatinib,

which is as active as imatinib. Excreted mostly in feces

as metabolites. 5% excreted unchanged in urine.

Half-life: Imatinib—18 hr; N-desmethyl imatinib—

40 hr.

TIME/ACTION PROFILE (blood levels of

imatinib)

ROUTE ONSET PEAK DURATION

PO unknown 2–4 hr 24 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity; OB: Potential

for fetal harm; Lactation: Potential for serious adverse

reactions in nursing infants; breast feeding should be

avoided.

Use Cautiously in: Hepatic impairment (dosep

recommended if bilirubin 3 times normal or liver

transaminases 5 times normal); Cardiac disease (severe

HF and left ventricular dysfunction may occur);

Rep: Women of reproductive potential; Pedi: Children

1 yr (safety not established); Geri:qrisk of edema.

Adverse Reactions/Side Effects

CNS: fatigue, headache, weakness, dizziness, somnolence.

CV: HF. EENT: epistaxis, nasopharyngitis,

blurred vision. Resp: cough, dyspnea, pneumonia.

GI: HEPATOTOXICITY, abdominal pain, anorexia, constipation, diarrhea, dyspepsia, nausea, vomiting. Derm:

DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS

(DRESS), petechiae, pruritus, skin rash. F and E:

edema (including pleural effusion, pericardial infusion,

pulmonary edema, and superficial edema), hypokalemia.

Endo:pgrowth (in children), hypothyroidism.

Hemat: BLEEDING, NEUTROPENIA, THROMBOCYTOPENIA.

Metab: weight gain. MS: arthralgia, muscle cramps,

musculoskeletal pain, myalgia. Misc: TUMOR LYSIS SYNDROME,

fever, night sweats.

Interactions

Drug-Drug: Blood levels and effects areqby concurrent

use of potent CYP3A4 inhibitors (e.g. ketoconazole,

itraconazole, clarithromycin, atazanavir,

indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,

or voriconazole). Blood levels and effects

may bepby potent CYP3A4 inducers (e.g., dexamethasone,

phenytoin, carbamazepine, rifampin, rifabutin,

and phenobarbital; if used concurrently,q

dose of imatinib by 50%.qblood levels of simvastatin.

Imatinib inhibits the following enzyme systems:

CYP2C9, CYP2D6, CYP3A4/5 and may be expected to alter

the effects of other drugs metabolized by these systems.

Drug-Food: Blood levels and effects areqby grapefruit

juice; concurrent use should be avoided.

Route/Dosage

Chronic Myeloid Leukemia

PO (Adults): Chronic phase—400 mg once daily,

may beqto 600 mg once daily; accelerated phase or

blast crisis—600 mg once daily; may beqto 800 mg/

day given as 400 mg twice daily based on response and

circumstances.

PO (Children): Newly diagnosed Ph CML—340

mg/m2 once daily (not to exceed 600 mg); CML recurrent

after failure of bone marrow transplant or resistance

to interferon-alpha—260 mg/m2 once daily.

Gastrointestinal Stromal Tumors

PO (Adults): Metastatic or unresectable—400 mg

once daily; may beqto 400 mg twice daily if well tolerated

and response insufficient; Adjuvant treatment after

resection—400 mg once daily.

Ph Acute Lymphoblastic Leukemia

PO (Adults): 600 mg once daily.

PO (Children): 340 mg/m2 once daily (not to exceed

600 mg).

Myelodysplastic/Myeloproliferative Diseases

PO (Adults): 400 mg once daily.

Aggressive Systemic Mastocytosis

PO (Adults): 400 mg once daily. For patients with

eosinophilia—100 mg once daily;qto 400 mg once

daily if well tolerated and response insufficient.

Hypereosinophilic Syndrome and/or

Chronic Eosinophilic Leukemia

PO (Adults): 400 mg once daily. For patients with

FIP1L1–PDGFRa fusion kinase 100 mg once daily;q

to 400 mg once daily if well tolerated and response insufficient.

Dermatofibrosarcoma Protuberans

PO (Adults): 400 mg twice daily.

Hepatic Impairment

PO (Adults):pdose by 25% in severe hepatic impairment.

Renal Impairment

PO (Adults): CCr 40–59 mL/min—Do not exceed

dose of 600 mg/day; CCr 20–39 mL/min—pinitial

dose by 50%;qas tolerated.

Availability (generic available)

Tablets: 100 mg, 400 mg.