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Imatinib Mesylate

Pronunciation

Pronunciation: im-AT-in-ib MES-i-late
Class: Protein-tyrosine kinase inhibitor

Trade Names

Gleevec
- Tablets, oral 100 mg
- Tablets, oral 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 tyrosine kinase receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events.

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Pharmacokinetics

Absorption

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

Distribution

Approximately 95% is protein bound.

Metabolism

In the liver, primarily via CYP3A4 isoenzyme, but also via CYP1A2, 2D6, 2C9, and 2C19. Major metabolite is N-demethylated 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.

Special Populations

Renal Function Impairment

AUC increased 1.5- to 2-fold in patients with mild and moderate renal impairment compared with patients with healthy renal function. Patients with severe renal impairment dosed at 100 mg/d had exposure similar to patients with healthy renal function receiving 400 mg/d.

Hepatic Function Impairment

Patients with severe hepatic impairment have higher exposure to imatinib and its metabolite.

Children

Pharmacokinetics were similar to those of adults.

Body weight

Cl increases with body weight are 8 L/h for 50 kg and 14 L/h for 100 kg.

Indications and Usage

Newly diagnosed adults and children with Ph+ CML in chronic phase; adults with Ph+ CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy; adults with relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL); adults with myelodysplastic/myeloproliferative diseases associated with PDGF-receptor gene rearrangements; adults with aggressive systemic mastocytosis without the D816V c-kit mutation or with c-kit mutational status unknown; adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFR alpha fusion kinase (mutational analysis or fluorescent in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who are FIP1L1-PDGFR alpha fusion kinase negative or unknown; adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans; patients with Kit (CD117)–positive unresectable and/or metastatic malignant GI stromal tumors; adjuvant treatment of adults following complete gross resection of Kit (CD117)–positive GI stromal tumors.

Unlabeled Uses

Rectal administration.

Contraindications

None well documented.

Dosage and Administration

Aggressive Systemic Mastocytosis
Adults

PO 400 mg/d for patients without the D816V c-kit mutation. If c-kit mutational status is not known or is unavailable, consider treating with 400 mg/d for patients not responding satisfactorily to other therapies. Start with 100 mg/d for patients with aggressive systemic mastocytosis associated with eosinophilia. 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.

Dermatofibrosarcoma Protuberans
Adults

PO 800 mg/d.

GI Stromal Tumors
Adults

PO 400 mg/d for patients with unresectable and/or metastatic malignant GI stromal tumors. 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 patients following complete gross resection of GI stromal tumors.

Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia
Adults

PO 400 mg/d. For patients with demonstrated FIP1L1-PDGFR alpha fusion kinase, start with 100 mg/d. 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.

Myelodysplastic/Myeloproliferative Diseases
Adults

PO 400 mg/d.

Ph+ ALL
Adults

PO 600 mg/d.

Ph+ CML
Adults

PO 400 mg/d in chronic phase CML and 600 mg/d 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 severe adverse reactions and severe non–leukemia-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 y and older

PO 340 mg/m 2 /d (max, 600 mg).

Dosage Adjustment Hepatic impairment

PO A 25% decrease in dose is recommended for patients with severe hepatic impairment (total bilirubin more than 3 to 10 × ULN).

Renal impairment

PO Doses more than 600 mg are not recommended in patients with mild renal impairment (CrCl 40 to 59 mL/min). In patients with moderate renal impairment (CrCl 20 to 39 mL/min), reduce the starting dose by 50%; increase as tolerated. Doses more than 400 mg are not recommended. Use with caution in patients with severe renal impairment (CrCl less than 20 mL/min). A dosage of 100 mg/d was tolerated in 2 patients with severe renal impairment.

Concomitant potent CYP3A4 inducers

PO If coadministration cannot be avoided, increase dosage of imatinib by at least 50% and carefully monitor the clinical response in patients receiving imatinib and a potent CYP3A4 inducer (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin).

Hepatotoxicity or nonhematologic adverse reactions Adults 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 340 to 260 mg/m 2 /d.

Neutropenia and thrombocytopenia in patients with chronic phase CML, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome and/or chronic eosinophilic leukemia, or GI stromal tumors (starting dosage 400 mg/d) Adults

PO If absolute neutrophil count (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 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.

Neutropenia and thrombocytopenia in newly diagnosed chronic phase CML (starting dosage 340 mg/m 2 /d) Children 2 y and older

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 (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 /d.

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 are 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.

Neutropenia and thrombocytopenia in patients with aggressive systemic mastocytosis associated with eosinophilia or hypereosinophilic syndrome and/or chronic eosinophilic leukemia with FIP1L-PDGFR alpha 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).

Neutropenia and thrombocytopenia in patients with dermatofibrosarcoma protuberans (starting dose 800 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 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, 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.

General Advice

  • Administer doses of 400 or 600 mg once 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 (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.
  • Do not crush imatinib tablets. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If contact occurs, wash thoroughly. Personnel should avoid exposure to crushed tablets.

Storage/Stability

Store tablets between 59° and 86°F. Protect from moisture.

Drug Interactions

Acetaminophen

Increased risk of hepatotoxicity. Coadminister with caution.

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

Decreased imatinib concentrations and antineoplastic efficacy. If coadministration cannot be avoided, increase the dosage of imatinib by at least 50% and carefully monitor the clinical response.

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. Coadminister with caution and close clinical monitoring.

Drugs metabolized by CYP2D6 (eg, metoprolol, tolterodine)

Imatinib may increase exposure to these agents, increasing the risk of adverse reactions. Coadminister with caution, especially with substrates that have a narrow therapeutic window.

Drugs metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydropyridine calcium channel blockers, ergotamine, pimozide, quinidine, simvastatin, sirolimus, tacrolimus, triazolobenzodiazepines [eg, midazolam, triazolam])

Imatinib may reduce metabolism, resulting in increased concentrations and toxicity. Particular caution and close clinical monitoring are warranted when administering imatinib with CYP3A4 substrates that have a narrow therapeutic window.

Ginseng

The risk of hepatotoxicity may be increased. Avoid coadministration.

Thyroid hormones (eg, levothyroxine)

TSH levels may be elevated and symptoms of hypothyroidism may be evident. Monitor thyroid function. 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 instead of heparin.

Adverse Reactions

Cardiovascular

Flushing (1% to 10%); palpitations (5%); cardiac tamponade, pericarditis, thrombosis/embolism (postmarketing).

CNS

Asthenia, fatigue/lethargy, malaise (75%); headache (37%); dizziness (19%); depression, insomnia (15%); anxiety, paresthesia (12%); light-headedness (11%); hypesthesia, weakness (1% to 10%); CNS hemorrhage (9%); cerebral edema (postmarketing).

Dermatologic

Rash/desquamation (50%); dermatitis (39%); exfoliative rash, pruritis (26%); alopecia (15%); sweating (13%); dry skin, erythema, photosensitivity (1% to 10%); lichen planus, lichenoid keratosis, palmar-plantar erythrodysesthesia syndrome, TEN (postmarketing).

EENT

Periorbital edema (74%); eye edema (33%); nasopharyngitis (31%); increased lacrimation (25%); pharyngolaryngeal pain (18%); rhinitis (17%); pharyngitis (15%); blurred vision (11%); conjunctival hemorrhage, conjunctivitis, dry eye, eyelid edema (1% to 10%); vitreous hemorrhage (postmarketing).

GI

Nausea (73%); diarrhea (59%); vomiting (58%); abdominal pain/cramping (57%); anorexia (36%); dyspepsia (27%); flatulence (25%); abdominal distention (19%); constipation (16%); dysgeusia (13%); stomatitis (10%); dry mouth, gastritis, gastroesophageal reflux (1% to 10%); GI hemorrhage (8%); diverticulitis, 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

Decreased Hgb (80%); elevated LDH (60%); decreased WBC (47%); elevated creatinine (44%); elevated AST (38%); elevated ALT (34%); decreased neutrophil count (33%); elevated alkaline phosphatase (17%); decreased platelet count (14%); elevated bilirubin (13%); reduced albumin (4%).

Metabolic-Nutritional

Hypoproteinemia, increased weight (32%); hypoalbuminemia (21%); hypokalemia (13%); decreased appetite, decreased weight (10%); hypocalcemia (6%).

Musculoskeletal

Muscle cramps (62%); muscle spasms, musculoskeletal pain (49%); arthralgia (40%); myalgia (32%); joint pain (31%); rigors (12%); bone pain (11%); joint swelling (1% to 10%); avascular necrosis/hip osteonecrosis, growth retardation (children), myopathy, rhabdomyolysis (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%); pain (46%); peripheral edema, pyrexia (41%); infection (28%); other fluid retention (22%); facial edema, night sweats (17%); influenza (14%); chest pain, chills (11%); anasarca (1% to 10%); pain in extremity (7%); hemorrhagic corpus luteum/hemorrhagic ovarian cyst (postmarketing).

Precautions

Monitor

Monitor patients for GI symptoms at the start of therapy. Weigh and monitor patients regularly for signs and symptoms of fluid retention. Carefully investigate unexpected rapid weight gain and provide appropriate treatment. Perform CBC 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. Closely monitor the growth of children under treatment. Carefully monitor patients with cardiac disease, risk factors for cardiac failure, or a history of renal failure, and evaluate and treat any patient with signs and symptoms consistent with cardiac failure. Perform an echocardiogram and determine serum troponin levels in patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia and in patients with myelodysplastic/myeloproliferative diseases or aggressive systemic mastocytosis associated with high eosinophil levels. Closely monitor patients at risk for tumor lysis syndrome (eg, patients with tumors having a high proliferative rate or a high tumor burden prior to treatment).


Pregnancy

Category D . There have been postmarketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib.

Lactation

Excreted in breast milk. Discontinue breast-feeding or the drug because of potential toxicity in the infant.

Children

Safety and efficacy have been established in children 2 y and older for the treatment of newly diagnosed Ph+ chronic phase CML.

Elderly

Higher frequency of edema in patients older than 65 y in CML and GI stromal tumor studies.

Renal Function

Use with caution in patients with severe renal impairment. Dosage adjustments are needed in patients with renal impairment.

Hepatic Function

Dosage adjustments are needed in patients with severe hepatic impairment.

Hazardous Tasks

Reports of motor vehicle accidents have been received in patients receiving imatinib. Patients may experience blurred vision, dizziness, or somnolence, and should use caution when driving a car or operating machinery.

Cardiac effects

Severe CHF and left ventricular dysfunction has been reported, mostly in patients with comorbidity and risk factors, including advanced age and history of cardiac disease.

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/edema

Risk of severe edema increases with imatinib dose and in patients older than 65 y. 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 effects

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

Hematologic toxicity

Anemia, neutropenia, and thrombocytopenia can occur. Be prepared to withhold therapy or change the dose.

Hemorrhage

GI and/or intratumoral hemorrhage have been reported.

Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported. Interrupt therapy or reduce dose if abnormalities develop. Closely monitor patients with hepatic 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.

Hypothyroidism

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

Tumor lysis syndrome

Has been reported, including fatal cases. Patients at risk include those with tumors having a high proliferative rate or high tumor burden prior to treatment. Correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib.

Overdosage

Symptoms

Abdominal pain; anorexia; ascites; decreased appetite; decreased neutrophil count; decreased WBC; diarrhea; edema; elevated bilirubin, CPK, liver transaminase levels, and/or serum creatinine; facial swelling; fatigue; GI pain; headache; muscle spasms; myalgia; nausea; pancytopenia; pyrexia; rash erythema; severe muscle cramps; swelling; thrombocytopenia; vomiting; weakness.

Patient Information

  • Review dosing schedule with patients.
  • Advise patients that the dose may be changed, or medication temporarily stopped, based on results of lab tests, development of adverse reactions, and response to therapy.
  • Advise patients to take the prescribed dose with food and large glass of water to minimize GI irritation.
  • Advise patients not to crush imatinib, and to avoid direct contact of crushed tablets with the skin or mucous membranes. If such contact occurs, advise patients to wash thoroughly.
  • Advise patients unable to swallow tablets that the tablets may be dispersed in a glass of water or apple juice. Instruct patients to place required number of tablets in a glass with appropriate volume of beverage (50 mL for 100 mg tablet, 200 mL for 400 mg tablet) and stir with a spoon until the tablets have disintegrated. Instruct patients that suspension must be swallowed immediately after complete disintegration of the tablets.
  • Caution patients to avoid grapefruit and grapefruit juice while taking imatinib.
  • Advise patients 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 patients not to double the dose to catch up.
  • Advise patients 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 patients that the drug may cause dizziness, blurred vision, or somnolence, and to use caution while driving or performing other tasks requiring mental alertness and coordination until tolerance is determined.
  • Inform patients that growth retardation has been reported in children and preadolescents during therapy and that growth should be monitored closely during treatment.
  • Caution women of childbearing potential to avoid becoming pregnant while being treated. Instruct sexually active women to use highly effective contraception.
  • Advise women not to breast-feed while taking imatinib.

Copyright © 2009 Wolters Kluwer Health.

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