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Drugs reference index «Imatinib»

Imatinib


Imatinib

Pronunciation: (i-MA-tin-ib)Class: Protein-tyrosine kinase inhibitor

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

Pharmacology

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 CYP3A4 isoenzyme; minor: CYP1A2, 2D6, 2C9, and 2C19. Major metabolite is N-desmethyl piperazine derivative (active).

Elimination

The half-life 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: 50 kg = 8 L/h and 100 kg = 14 L/h.

Indications and Usage

Newly diagnosed adults 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 D816V 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); adjuvant treatment of adults following complete gross resection of Kit (CD117)–positive GIST.

Unlabeled Uses

Rectal administration.

Contraindications

Standard considerations.

Dosage and Administration

ASMAdults

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.

DFSPAdults

PO 800 mg/day.

Dose Adjustment for Hepatotoxicity or Nonhematologic Adverse ReactionsAdults and Children

PO If a severe nonhematologic adverse reaction develops (eg, severe hepatotoxicity, 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 ULN (IULN) or 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, 600 to 400 mg, or 800 to 600 mg). In children, daily dosages 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.

Dosage Adjustments for Hepatic Function ImpairmentAdults and Children

PO No dosage adjustment is needed in patients with mild or moderate hepatic function impairment. A 25% decrease in dose is recommended for patients with severe hepatic function impairment (total bilirubin more than 3 to 10 × ULN).

Dosage Adjustments for Renal Function ImpairmentAdults and Children

PO In patients with moderate renal function impairment (CrCl 20 to 39 mL/min), reduce the starting dose by 50%; increase as tolerated. Doses more than 400 mg are not recommended in patients with moderate renal function impairment. Doses more than 600 mg are not recommended in patients with mild renal function impairment (CrCl 40 to 59 mL/min). Use with caution in patients with severe renal function impairment (CrCl less than 20 mL/min).

Dose Adjustment With Concomitant Potent CYP3A4 InducersAdults and Children

PO If coadministration cannot be avoided, increase dosage of imatinib by 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 Dosage, 400 mg/day) or MDS/MPD, ASM, and HES/CEL (Starting Dosage, 400 mg/day), or GIST (Starting Dosage, 400 mg/day)Adults

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 mg. If recurrence of ANC is less than 1 × 10 9 /L and/or platelets are 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).

Dose Adjustments for Neutropenia and Thrombocytopenia in Newly Diagnosed Children With Chronic-Phase CML (Starting Dosage, 340 mg/m 2 /day) or Chronic-Phase Recurring After Transplant or Resistant to Interferon (Starting Dosage, 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 are 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, stop imatinib until ANC is at least 1.5 × 10 9 /L and platelets are at least 75 × 10 9 /L, then resume imatinib at reduced dosage of 260 mg/m 2 /day (if starting dosage was 340 mg/m 2 /day) or 200 mg/m 2 /day (if starting dosage was 260 mg/m 2 /day).

Dose Adjustments for Neutropenia and Thrombocytopenia in Patients With Accelerated-Phase and Blast Crisis Ph + CML 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 are 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 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 are at least 75 × 10 9 /L, then resume treatment with imatinib 600 mg. In the event of a recurrence of ANC less than 1 × 10 9 /L and/or platelets are 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 imatinib at reduced dose of 400 mg.

GISTAdults

PO 400 mg/day for patients with unresectable and/or metastatic malignant GIST. A dosage increase to 400 mg twice daily may be considered in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. 400 mg daily is recommended for the adjuvant treatment of adult patients following complete gross resection of GIST.

HES/CELAdults

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

MDS/MPDAdults

PO 400 mg/day.

Ph+ ALLAdults

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

Ph+ CMLAdults

PO 400 mg/day in chronic-phase CML and 600 mg/day in accelerated phase or blast crisis. Dosage 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 severe adverse reactions and severe nonleukemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression, failure to achieve hematologic response after 3 mo of therapy, failure to achieve cytogenic response after 6 to 12 mo 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+ CML in chronic-phase recurrent after stem cell transplant or who are resistant to interferon-alpha therapy, the recommended dosage is 260 mg/m 2 /day.

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 higher to reduce exposure to iron.
  • 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.

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

Decreased imatinib concentrations and antineoplastic efficacy.

CYP3A4 inhibitors (eg, atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Imatinib plasma concentrations may be elevated, increasing the pharmacologic effects and adverse reactions.

Drugs metabolized by CYP2D6 (eg, tolterodine)

Imatinib may increase exposure to these agents, increasing the risk of adverse reactions.

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

Imatinib may reduce metabolism, resulting in increased 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

Cardiovascular

Cardiac tamponade, pericarditis, thrombosis/embolism (postmarketing).

CNS

Asthenia, fatigue/lethargy, malaise (75%); headache (37%); dizziness (19%); depression, insomnia (15%); anxiety (12%); hypesthesia, paresthesia, weakness (1% to 10%); CNS hemorrhage (9%); cerebral edema (postmarketing).

Dermatologic

Rash/desquamation (50%); pruritus (19%); alopecia (15%); sweating (13%); dry skin, erythema, flushing, photosensitivity (1% to 10%); erythema multiforme, lichen planus, lichenoid keratosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

EENT

Eye edema (33%); nasopharyngitis (31%); increased lacrimation (25%); pharyngolaryngeal pain (18%); rhinitis (17%); pharyngitis (15%); blurred vision, conjunctival hemorrhage, conjunctivitis, dry eye, eyelid edema (1% to 10%); vitreous hemorrhage (postmarketing).

GI

Nausea (73%); diarrhea, vomiting (58%); abdominal pain (37%); anorexia (36%); dyspepsia (27%); constipation (16%); flatulence (10%); abdominal distention, dry mouth, gastritis, gastroesophageal reflux (1% to 10%); GI hemorrhage (8%); GI perforation, ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis (postmarketing).

Hematologic-Lymphatic

Hemorrhage (53%); neutropenia (48%); anemia (42%); thrombocytopenia (33%); leukopenia (20%); lymphopenia (10%); febrile neutropenia, pancytopenia (1% to 10%).

Hepatic

Liver toxicity (12%).

Hypersensitivity

Anaphylactic shock (postmarketing).

Lab Tests

Elevated creatinine (11%); elevated ALT, elevated AST (7%); elevated alkaline phosphatase (6%); reduced albumin (4%); elevated bilirubin (2%).

Metabolic-Nutritional

Increased weight (32%); hypokalemia (13%); decreased weight (1% to 10%).

Musculoskeletal

Muscle cramps (62%); musculoskeletal pain (49%); arthralgia (40%); myalgia (32%); joint pain (31%); rigors (12%); bone pain (11%); joint swelling (1% to 10%); avascular necrosis/hip osteonecrosis (postmarketing).

Respiratory

Cough (27%); dyspnea, upper respiratory tract infection (21%); exertional dyspnea (17%); pneumonia (13%); sinusitis (11%); epistaxis (1% to 10%); acute respiratory failure, interstitial lung disease (postmarketing).

Miscellaneous

Edema (86%); fluid retention (76%); superficial edema (74%); pyrexia (41%); periorbital edema, peripheral edema (33%); other fluid retention (22%); facial edema, infection, night sweats (17%); influenza (14%); chills (11%); chest pain (10%); anasarca (1% to 10%).

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. Monitor TSH levels in thyroidectomy patients receiving levothyroxine replacement therapy.

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.

Renal Function

Dosage adjustments are needed in patients with renal function impairment.

Hepatic Function

Dosage adjustments are needed in patients with severe hepatic function impairment.

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/or 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 HES and cardiac involvement, cardiogenic shock/left ventricular dysfunction has been associated with initiation of imatinib therapy.

Hypothyroidism

Has been reported in thyroidectomy patients undergoing levothyroxine replacement during imatinib treatment.

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 unable to swallow tablets that the 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: bleeding; bloating; fever, chills, or other signs of infection; persistent nausea, vomiting, or appetite loss; rapid weight gain; shortness of breath or difficulty breathing; skin rash; sore throat; swelling of the feet, ankles, legs, or around the eyes; 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.
  • Advise patients not to breast-feed while taking imatinib.

Copyright © 2009 Wolters Kluwer Health.

  • Imatinib MedFacts Consumer Leaflet (Wolters Kluwer)
  • imatinib Advanced Consumer (Micromedex) - Includes Dosage Information
  • Gleevec Prescribing Information (FDA)
  • Gleevec Consumer Overview

See Also...

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