Trade Names:Gleevec- Tablets 100 mg- Tablets 400 mg
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.
T max is 2 to 4 h. Mean absolute bioavailability is 98%.
Approximately 95% is protein bound.
In liver, primarily via CYP3A4 isoenzyme; minor: CYP1A2, 2D6, 2C9, and 2C19. Major metabolite is N-desmethyl piperazine derivative (active).
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.
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.
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.
Store tablets at controlled room temperature (59° to 86°F). Protect from moisture.
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.
None well documented.
Cardiac tamponade, pericarditis, thrombosis/embolism (postmarketing).
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).
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).
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).
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).
Hemorrhage (53%); neutropenia (48%); anemia (42%); thrombocytopenia (33%); leukopenia (20%); lymphopenia (10%); febrile neutropenia, pancytopenia (1% to 10%).
Liver toxicity (12%).
Anaphylactic shock (postmarketing).
Elevated creatinine (11%); elevated ALT, elevated AST (7%); elevated alkaline phosphatase (6%); reduced albumin (4%); elevated bilirubin (2%).
Increased weight (32%); hypokalemia (13%); decreased weight (1% to 10%).
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).
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).
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%).
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.
Category D .
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.
Higher frequency of edema.
Dosage adjustments are needed in patients with renal function impairment.
Dosage adjustments are needed in patients with severe hepatic function impairment.
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.
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.
Imatinib is associated with GI irritation, including rare reports of GI perforation.
Anemia, neutropenia, and thrombocytopenia can occur. Monitor CBC and platelet counts closely; be prepared to withhold therapy or change dose.
GI and/or intratumoral hemorrhage reported.
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.
In patients with HES and cardiac involvement, cardiogenic shock/left ventricular dysfunction has been associated with initiation of imatinib therapy.
Has been reported in thyroidectomy patients undergoing levothyroxine replacement during imatinib treatment.
Reported in patients taking imatinib, often in patients with comorbidity and risk factors, including advanced age and history of cardiac disease.
Animal studies indicate potential for liver, kidney, and cardiac toxicities with long-term use of imatinib.
Ascites; elevated bilirubin, liver transaminase levels, and/or serum creatine; severe muscle cramps.
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