imatinib

High Alert

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 GI stromal tumors.
Adjuvant treatment following resection of Kit (CD117) positive GI stromal tumors.
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 associated with platelet-derived growth factor receptor gene rearrangements.
Aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
Hypereosinophilic syndrome and/or chronic eosinophilic leukemia.
Unresectable, recurrent, or metastatic dermatofibrosarcoma protuberans.

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, hypereosinophilic syndrome and/or chronic eosinophilic leukemia, and ALL and malignant cells in GI stromal tumor, myelodysplastic/myeloproliferative disease, aggressive systemic mastocytosis, and dermatofibrosarcoma protuberans.

Pharmacokinetics ⬆ ⬇

Absorption: Well absorbed (98%) following oral administration.

Distribution: Unknown.

Protein Binding: 95%.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme 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 ⬆ ⬇

(plasma concentrations of imatinib)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	2–4 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Hepatic impairment (dose ↓ recommended if bilirubin >3 x upper limit of normal (ULN) or AST/ALT >5 x ULN);
Cardiac disease (severe HF and left ventricular dysfunction may occur);
Renal impairment, diabetes, hypertension, HF (↑ risk of nephrotoxicity);
Rep: Women of reproductive potential;
Pedi: Children 1 yr (safety and effectiveness not established);
Geri: risk of edema in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

CV: edema, HF

Derm: petechiae, pruritus, rash, DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS)

EENT: epistaxis, nasopharyngitis, blurred vision

Endo: ↓growth (in children), hypothyroidism

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

GU: nephrotoxicity

Hemat: BLEEDING, NEUTROPENIA, THROMBOCYTOPENIA

Metab: ↑weight

MS: arthralgia, muscle cramps, myalgia, pain

Neuro: fatigue, headache, weakness, dizziness, somnolence

Resp: cough, dyspnea, pneumonia

Misc: fever, night sweats, TUMOR LYSIS SYNDROME

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inhibitors, including ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, nelfinavir, ritonavir, or voriconazole, may ↑ levels and risk of toxicity.
Strong CYP3A4 inducers, including dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, and phenobarbital, may ↓ levels and effectiveness; if used concurrently, ↑ imatinib dose by 50%.
May ↑ levels and risk of toxicity of benzodiazepines, simvastatin, and calcium channel blockers.

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage ⬆ ⬇

Chronic Myeloid Leukemia

PO (Adults ): Chronic phase: 400 mg once daily, may be ↑ to 600 mg once daily; Accelerated phase or blast crisis: 600 mg once daily; may be ↑ to 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 recurrence after failure of bone marrow transplant or resistance to interferon-alpha: 260 mg/m² once daily.

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Gastrointestinal Stromal Tumors

PO (Adults ): Metastatic or unresectable: 400 mg once daily; may be ↑ to 400 mg twice daily if well tolerated and response insufficient; Adjuvant treatment after resection: 400 mg once daily.

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Ph+ Acute Lymphoblastic Leukemia

PO (Adults ): 600 mg once daily.
PO (Children ): 340 mg/m² once daily (not to exceed 600 mg).

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Myelodysplastic/Myeloproliferative Diseases

PO (Adults ): 400 mg once daily.

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Aggressive Systemic Mastocytosis

PO (Adults ): 400 mg once daily. Patients with eosinophilia: 100 mg once daily; ↑ to 400 mg once daily if well tolerated and response insufficient.

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia

PO (Adults ): 400 mg once daily. For patients with FIP1L1–PDGFRa fusion kinase: 100 mg once daily; ↑ to 400 mg once daily if well tolerated and response insufficient.

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Dermatofibrosarcoma Protuberans

PO (Adults ): 400 mg twice daily.

Renal Impairment

PO (Adults ): CCr 40–59 mL/min: Do not exceed dose of 600 mg/day; CCr 20–39 mL/min:↓ initial dose by 50%; ↑ as tolerated.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by 25%.

Availability ⬆ ⬇

(Generic available)

Tablets: 100 mg; 400 mg

Assessment ⬆ ⬇

Monitor for fluid retention. Weigh regularly, and assess for signs of pleural effusion, pericardial effusion, pulmonary edema, ascites (dyspnea, periorbital edema, swelling in feet and ankles, weight gain). Evaluate unexpected weight gain. Edema is usually managed with diuretics. General fluid retention is usually dose related, more common in accelerated phase or blast crisis, and is more common in the elderly. Treatment usually involves diuretics, supportive therapy, and interruption of imatinib.
Monitor growth rate in children and adolescents; may cause decrease in growth.
Monitor vital signs; may cause fever.
Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and/or dehydration). Prevent by maintaining adequate hydration and correcting uric acid levels prior to starting imatinib.
Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, and/or facial swelling, associated with involvement of other organ systems (hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. May resemble an acute viral infection. Eosinophilia is often present. Discontinue therapy if signs occur.

Lab Test Considerations:

Monitor liver function before and monthly during treatment or when clinically indicated. May cause ↑ AST/ALT and bilirubin, which usually lasts 1 wk and may require dose reduction or interruption. If bilirubin is >3 x ULN or AST/ALT are >5 x ULN, withhold dose until bilirubin levels return to <1.5 x ULN and AST/ALT levels to <2.5 x ULN. Treatment may then be continued at reduced levels (patients on 400 mg/day should receive 300 mg/day and patients receiving 600 mg/day should receive 400 mg/day).
- Monitor CBC weekly for the 1st mo, biweekly for the 2nd mo, and periodically during therapy. May cause neutropenia and thrombocytopenia, usually lasting 2–3 wk or 3–4 wk, respectively, and anemia. Usually requires dose reduction, but may require discontinuation (see Implementation).
- Patients receiving chronic phase, myelodysplastic/myeloproliferative disease, aggressive systemic mastocytosis, and hypereosinophilic syndrome and/or chronic eosinophilic leukemia treatment who develop an absolute neutrophil count (ANC) <1.0 × 10⁹/L and/or platelets <50 × 10⁹/L should stop imatinib until ANC ≥1.5 × 10⁹/L and platelets are ≥75 × 10⁹/L. Then resume imatinib treatment at 400 mg or 600 mg/day.
- Patients receiving accelerated phase and blast crisis treatment or Ph+ ALL treatment who develop an ANC <0.5 × 10⁹/L and/or platelets <10 × 10⁹/L should determine if cytopenia is related to leukemia via marrow aspirate or biopsy. If cytopenia is unrelated to leukemia, reduce dose to 400 mg/day. If cytopenia persists for 2 wk, reduce dose to 300 mg/day. If cytopenia persists for 4 wk and is still unrelated to leukemia, stop imatinib until ANC ≥1 × 10⁹/L and platelets are ≥20 × 10⁹/L. Then resume imatinib treatment at 300 mg/day.
- Patients receiving aggressive systemic mastocytosis with eosinophilia or hypereosinophilic syndrome and/or chronic eosinophilic leukemia with FIP1L1–PDGFRa fusion kinase treatment who develop ANC <1.0 × 10⁹/L and platelets <50 × 10⁹/L should stop imatinib until ANC ≥1.5 × 10⁹/L and platelets ≥75 × 10⁹/L. Resume treatment at previous dose.
- May cause hypokalemia.
- Verify pregnancy status in females with reproductive potential before starting therapy.

Implementation ⬆ ⬇

Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order and dose calculations. Therapy should be initiated by physician experienced in the treatment of patients with chronic myeloid leukemia.
Patients requiring anticoagulation should receive low-molecular-weight or standard heparin, not warfarin.
- Treatment should be continued as long as patient continues to benefit.
PO: Administer with food and a full glass of water to minimize GI irritation.
- Tablets may be dispersed in water or apple juice (50 mL for the 100-mg and 100 mL for the 400-mg tablet) and stirred with a spoon for patients unable to swallow pills. Administer immediately after suspension.
- Doses for children may be given once daily or divided into two doses, one in morning and one in evening.
- Administer doses >800 mg/day as 400 mg twice daily to decrease exposure to iron.

Patient/Family Teaching ⬆ ⬇

Explain purpose of imatinib to patient. Instruct patient to take imatinib as directed. If a dose is missed, take next dose at regular scheduled time. Do not double doses.
Advise patient to avoid grapefruit and grapefruit juice during therapy.
May cause drowsiness or dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
Inform patient of possibility of edema and fluid retention. Advise patient to notify health care professional if unexpected rapid weight gain occurs.
Advise patient to notify health care professional if signs and symptoms of liver failure (jaundice, anorexia, bleeding or bruising) or DRESS occur.
Rep: Advise female patient of reproductive potential to use effective contraception during and for at least 14 days after last dose of imatinib. Advise patient to notify health care professional if pregnancy is planned or suspected; avoid breastfeeding for at least 1 mo after last dose of imatinib.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆