A-Z Drug Facts > Imatinib

Imatinib

Pronouncation: (im-A-ti-nib)
Class: Protein-tyrosine kinase inhibitor

Trade Names:
Gleevec
- Tablets 100 mg
- Tablets 400 mg

Pharmacology

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Imatinib inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Imatinib inhibits tumor growth of Bcr-Abl transfected murine myeloid cells and Bcr-Abl positive leukemia lines derived from CML patients in blast crisis. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.

Pharmacokinetics

Absorption

T _max is 2 to 4 h. Mean absolute bioavailability is 98%.

Distribution

Approximately 95% is protein bound.

Metabolism

In liver primarily via CYP-450 3A4 isoenzyme; minor: CYP-450 1A2, 2D6, 2C9, and 2C19. Major metabolite is N-desmethyl piperazine derivative (active).

Elimination

The t _½ is approximately 18 h (parent drug) and 40 h (major active metabolite); 68% is excreted in the feces and 13% in the urine, primarily as metabolites. Cl increases with body weight: 50ߙkg = 8 L/h and 100ߙkg = 14ߙL/h.

Indications and Usage

Newly diagnosed adults and children with Ph+ CML in chronic phase; patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy; children with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy; adults with relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL); adults with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGF receptor gene rearrangements; adults with aggressive systemic mastocytosis (ASM) without the D816 V c-kit mutation or with c-kit mutational status unknown; adults with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα 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-PDGFRα fusion kinase negative or unknown; adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP); patients with Kit (CD117) positive unresectable and/or metastatic malignant GI stromal tumors (GIST).

Contraindications

Standard considerations.

Dosage and Administration

Ph+ CML
Adults

PO 400 mg/day in chronic phase CML and 600 mg/day in accelerated phase or blast crisis. Dose increase from 400 to 600 mg (chronic phase) or 600 to 800 mg (accelerated phase or blast crisis) may be considered in adult patients in the absence of adverse reactions and severe nonleukemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression, failure to achieve hematologic response after 3 months of therapy, failure to achieve cytogenic response after 6 to 12 months of therapy, or loss of previously achieved hematologic or cytogenic response.

Children 2 yr of age and older

PO 340 mg/m ² /day (max, 600 mg) for children with newly diagnosed Ph+ CML. For children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon-alpha therapy, the recommended dose is 260 mg/m ² /day.

Ph+ ALL
Adults

PO 600 mg/day for patients with relapsed/refractory Ph+ ALL.

MDS/MPD
Adults

PO 400 mg/day.

ASM
Adults

PO 400 mg/day for patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, consider treating with 400 mg/day for patients not responding satisfactorily to other therapies. Start with 100 mg/day for patients with ASM-associated eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1–PDGFRα. Dose increase from 100 to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

HES/CEL
Adults

PO 400 mg/day. For HES/CEL patients with demonstrated FIP1L1–PDGFRα infusion kinase, start with 100 mg/day. Dose increase from 100 to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

DFSP
Adults

PO 800 mg/day.

GIST
Adults

PO 400 or 600 mg/day for patients with unresectable and/or metastatic malignant GIST.

Dose adjustment for hepatotoxicity or severe fluid retention
Adults and children

PO If a severe nonhematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), withhold imatinib until the reaction has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. If elevations in bilirubin are more than 3 times institutional upper limit of normal (IULN) or in liver transaminases more than 5 × IULN occur, withhold imatinib until bilirubin levels have returned to less than 1.5 × IULN and transaminases levels to less than 2.5 × IULN. In adults, treatment with imatinib may then be continued at a reduced daily dose (400 to 300 mg or 600 to 400 mg). In children, daily doses can be reduced under the same circumstances from 260 to 200 mg/m ² /day or from 340 to 260 mg/m ² /day, respectively.

Dose adjustment with concomitant medications
Adults and children

PO Increase dosage of imatinib at least 50% and carefully monitor clinical response in patients receiving imatinib and a potent CYP3A4 inducer (eg, phenytoin, rifampin).

Dose adjustment for neutropenia and thrombocytopenia in patients with chronic phase CML (starting dose, 400 mg/day) or MDS/MPD, ASM, and HES/CEL (starting dose, 400 mg/day) or GIST (starting dose, 400 or 600 mg/day)
Adults and children

PO If absolute neutrophil count (ANC) is less than 1 × 10 ⁹ /L and/or platelets less than 50 × 10 ⁹ /L, stop imatinib until ANC is at least 1.5 × 10 ⁹ /L and platelets are at least 75 × 10 ⁹ /L, then resume treatment at 400 or 600 mg. If recurrence of ANC less than 1 × 10 ⁹ /L and/or platelets less than 50 × 10 ⁹ /L, stop imatinib until ANC is at least 1.5 × 10 ⁹ /L and platelets are at least 75 × 10 ⁹ /L, then resume at a reduced dose of 300 mg (if starting dose was 400 mg) or 400 mg (if starting dose was 600 mg).

Dose adjustments for neutropenia and thrombocytopenia in newly diagnosed children with chronic phase CML (starting dose, 340 mg/m ² /day) or chronic phase recurring after transplant or resistant to interferon (starting dose, 260 mg/m ² /day)
Children 2 yr of age and older

PO If ANC is less than 1 × 10 ⁹ /L and/or platelets less than 50 × 10 ⁹ /L, stop imatinib until ANC is at least 1.5 × 10 ⁹ /L and platelets at least 75 × 10 ⁹ /L, then resume treatment with imatinib at the previous dose (ie, before severe adverse reaction). In the event of a recurrence of ANC less than 1 × 10 ⁹ /L and/or platelets less than 50 × 10 ⁹ /L, repeat the previous step and resume imatinib at reduced dose of 260 mg/m ² /day (if starting dose was 340 mg/m ² /day) or 200 mg/m ² /day (if starting dose was 260 mg/m ² /day).

Dose adjustments for neutropenia and thrombocytopenia in patients with accelerated phase CML and blast crisis or Ph+ ALL (starting dose, 600 mg)
Adults

PO If ANC is less than 0.5 × 10 ⁹ /L and/or platelets less than 10 × 10 ⁹ /L, check if cytopenia is related to leukemia by performing marrow aspirate or biopsy. If cytopenia is unrelated to leukemia, reduce dose to 400 mg. If cytopenia persists for 2 wk, reduce dose to 300 mg. If cytopenia persists 4 wk and still is unrelated to leukemia, stop imatinib until ANC is at least 1 × 10 ⁹ /L and platelets are at least 20 × 10 ⁹ /L, and then resume treatment at 300 mg.

Dose adjustments for neutropenia and thrombocytopenia in patients with ASM-associated eosinophilia or HES/CEL with FIP1L-PDGFRα fusion kinase (starting dose, 100 mg)
Adults

PO If ANC is less than 1 × 10 ⁹ /L and or platelets less than 50 × 10 ⁹ /L, stop imatinib until ANC is at least 1.5 × 10 ⁹ /L and platelets at least 75 × 10 ⁹ /L then resume treatment with imatinib at the previous dose (before severe adverse reaction).

Dose adjustment for neutropenia and thrombocytopenia in patients with DFSP (starting dose, 800 mg)
Adults

PO If ANC is less than 1 × 10 ⁹ /L and/or platelets less than 50 × 10 ⁹ /L stop imatinib until ANC is at least 1.5 × 10 ⁹ /L and platelets at least 75 × 10 ⁹ /L, then resume treatment with imatinib at 600 mg. In the event of a recurrence of ANC less than 1 × 10 ⁹ /L and/or platelets less than 50 × 10 ⁹ /L, repeat the previous step and resume imatinib at reduced dose of 400 mg.

General Advice

• Administer doses of 400 or 600 mg daily; administer dose of 800 mg as 400 mg twice daily. Use 400 mg tablets for daily doses of 800 mg and above to reduce exposure to iron.
• Start with 400 mg/day in patients with mild and moderate hepatic function impairment. In patients with severe hepatic function impairment, start treatment with 300 mg/day.
• Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
• Administer pediatric doses as a single dose once daily or split dose twice daily.
• Administer each dose with a meal and a large glass of water to reduce GI irritation.
• If patient is unable to swallow film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. Place required number of tablets in a glass with appropriate volume of beverage (eg, 50 mL for 100 mg tablet, 200 mL for 400 mg tablet) and stir with a spoon until the tablets have disintegrated. Immediately administer suspension after complete disintegration of the tablets.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Protect from moisture.

Drug Interactions

Acetaminophen

Increased risk of hepatotoxicity.

Drugs metabolized by CYP3A4 (eg, cyclosporine, dihydropyridine calcium channel blockers, pimozide, simvastatin, triazolobenzodiazepines)

Imatinib may reduce metabolism, resulting in increased concentrations and toxicity.

Drugs that induce CYP3A4 (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John's wort)

Decreased imatinib concentrations and antineoplastic efficacy.

Drugs that inhibit CYP3A4 (eg, clarithromycin, erythromycin, itraconazole, ketoconazole)

Increased imatinib concentrations and toxicity.

Thyroid hormones (eg, levothyroxine)

TSH levels may be elevated and symptoms of hypothyroidism may be evident. It may be necessary to adjust the thyroid hormone dose after starting or stopping imatinib.

Warfarin

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Fatigue (53%); headache (39%); asthenia (21%); insomnia (19%); anorexia (17%); dizziness (16%); depression (13%); anxiety (12%); CNS hemorrhage (9%); paresthesia (1% to 10%).

Dermatologic

Rash (53%); pruritus (14%); alopecia, dry skin (1% to 10%).

EENT

Eye edema (33%); nasopharyngitis (27%); lacrimation (25%); pharyngolaryngeal pain, rhinitis (17%); pharyngitis (15%); blurred vision, conjunctivitis (1% to 10%).

GI

Nausea (74%); diarrhea (70%); vomiting (58%); abdominal pain (40%); flatulence (34%); dyspepsia (27%); constipation (16%); taste disturbance (15%); loose stools (12%); GI hemorrhage (8%); abdominal distention, gastroesophageal reflux, mouth ulceration (1% to 10%).

Hepatic

Liver toxicity (12%).

Hematologic-Lymphatic

Hemorrhage (53%); neutropenia (48%); anemia (42%); thrombocytopenia (33%).

Lab Tests

Elevated creatinine (8%); elevated ALT (7%); elevated alkaline phosphatase (6%); albumin reduced, elevated AST, elevated bilirubin (4%).

Metabolic-Nutritional

Increased weight (32%); pleural effusion or ascites (15%); hypokalemia (13%).

Musculoskeletal

Muscle cramps (62%); musculoskeletal pain (49%); arthralgia (40%); joint pain (30%); myalgia (27%); back pain (26%); rigors (12%); joint swelling (1% to 10%).

Respiratory

Cough (27%); dyspnea (21%); upper respiratory tract infection (19%); exertional dyspnea (17%); pneumonia (13%); sinusitis (11%).

Miscellaneous

Fluid retention, superficial edema (81%); pyrexia (41%); periorbital edema, peripheral edema (33%); other fluid retention events (22%); face edema, night sweats (17%); chest pain, influenza (11%); tumor hemorrhage (4%).

Precautions

Monitor Carefully investigate unexpected rapid weight gain and provide appropriate treatment. Perform CBC and platelet counts weekly for first month, biweekly for second month, and periodically thereafter as clinically indicated. Monitor liver function (alkaline phosphatase, bilirubin, transaminases) prior to therapy, then monthly or as clinically indicated during treatment.

Pregnancy

Category D .

Lactation

Undetermined.

Children

The safety and efficacy of imatinib in children are not established, except in children with newly diagnosed Ph+ chronic phase CML and in children with Ph+ chronic phase CML whose disease recurred after stem cell transplantation or who are resistant to interferon-alpha therapy. No data are available in children younger than 2 yr of age.

Elderly

Higher frequency of edema.

Dermatologic toxicities

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported. May recur upon rechallenge but has been tolerated when reintroduced at lower dose and with concomitant treatment with corticosteroids or antihistamines.

Fluid retention

Risk of severe edema increases with imatinib dose and in patients older than 65 yr of age. Edema may manifest as rapid weight gain and should be managed promptly with dose reduction, interruption of therapy, diuretics, or supportive care as indicated.

GI disorders

Imatinib is associated with GI irritation, including rare reports of GI perforation.

Hematologic toxicity

Anemia, neutropenia, and thrombocytopenia can occur. Monitor CBC and platelet counts closely; be prepared to withhold therapy or change dose.

Hemorrhage

GI and intratumoral hemorrhage reported.

Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur. Interrupt therapy or reduce dose if abnormalities develop. Closely monitor patients with hepatic function impairment because exposure to imatinib may be increased.

Hypereosinophilic cardiac toxicity

In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock/left ventricular dysfunction has been associated with initiation of imatinib therapy.

Severe CHF and left ventricular dysfunction

Reported in patients taking imatinib, often in patients with comorbidity and risk factors, including advanced age and history of cardiac disease.

Toxicities from long-term therapy

Animal studies indicate potential for liver, kidney, and cardiac toxicities with long-term use of imatinib.

Overdosage

Symptoms

Ascites; elevated bilirubin, liver transaminase levels, and/or serum creatine; severe muscle cramps.

Patient Information

• Review dosing schedule with patient.
• Advise patient that dose may be changed, or medication temporarily stopped, based upon results of lab tests, development of adverse reactions, and response to therapy.
• Advise patient to take prescribed dose with food and large glass of water to minimize GI irritation.
• Advise patient if unable to swallow tablets that tablets may be dispersed in a glass of water or apple juice. Instruct patient to place required number of tablets in a glass with appropriate volume of beverage (eg, 2 oz for 100 mg tablet, 6 oz for 400 mg tablet) and stir with a spoon until the tablets have disintegrated. Instruct patient that suspension must be swallowed immediately after complete disintegration of the tablets.
• Caution patient to avoid grapefruit and grapefruit juice while taking imatinib.
• Advise patient that if a dose is missed to take it as soon as possible; however, if it is nearing time for the next dose, to skip the missed dose and take the next dose at the regularly scheduled time. Caution patient not to double the dose to catch up.
• Advise patient to immediately report any of the following to health care provider: skin rash; swelling of the feet, ankles, legs, or around the eyes; rapid weight gain; bloating; shortness of breath or difficulty breathing; fever, chills, or other signs of infection; sore throat; persistent nausea, vomiting, or appetite loss; bleeding; unusual bruising.
• Advise patient that drug may cause dizziness and to use caution while driving or performing other tasks requiring mental alertness and coordination until tolerance is determined.
• Caution women of childbearing potential to avoid becoming pregnant while being treated.

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