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Imatinib Mesylate

FDA Drug Information • Also known as: Gleevec, Imatinib Mesylate, Imatinib Mesylate 400 Mg

Brand Names
Gleevec, Imatinib Mesylate, Imatinib Mesylate 400 Mg
Dosage Form
POWDER
Product Type
BULK INGREDIENT

Description

11 DESCRIPTION Imatinib is a small molecule kinase inhibitor. Imatinib mesylate film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration. Each 100 mg tablet contains 119.50 mg of imatinib mesylate equivalent to 100 mg of imatinib free base. Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white colored powder. Its molecular formula is C 29 H 31 N 7 O

  • CH 3 SO 3 H and its molecular weight is 589.7 g/mol. Imatinib mesylate is freely soluble in water. Inactive Ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate and microcrystalline cellulose. Tablet coating: hypromellose, polyethylene glycol, talc and titanium dioxide. imatinibstructure

    • What Is Imatinib Mesylate Used For?

    1 INDICATIONS AND USAGE Imatinib mesylate tablet is a kinase inhibitor indicated for the treatment of:

  • Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. (1.1)
  • Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy. (1.2)
  • Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). (1.3)
  • Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. (1.4)
  • Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. (1.5)
  • Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. (1.6)
  • Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence 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. (1.7)
  • Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). (1.8)
  • Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). (1.9)
  • Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. (1.10) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7...

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Adults with Ph+ CML CP ( 2.2 ): 400 mg/day
  • Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day
  • Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day
  • Adults with Ph+ ALL ( 2.4 ): 600 mg/day
  • Pediatrics with Ph+ ALL (2.5): 340 mg/m 2 /day
  • Adults with MDS/MPD ( 2.6 ): 400 mg/day
  • Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day
  • Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day
  • Adults with DFSP ( 2.9 ): 800 mg/day
  • Adults with metastatic and/or unresectable GIST (2.10): 400 mg/day
  • Adjuvant treatment of adults with GIST ( 2.11): 400 mg/day
  • Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day
  • Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of imatinib mesylate tablets should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400 mg tablet to reduce exposure to iron. 2.1 Drug Administration The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s). For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dose of imatinib mesylate tablets...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:

  • Fluid Retention and Edema [see Warnings and Precautions ( 5.1 )]
  • Hematologic Toxicity [see Warnings and Precautions ( 5.2 )]
  • Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions ( 5.3 )]
  • Hepatotoxicity [see Warnings and Precautions ( 5.4 )]
  • Hemorrhage [see Warnings and Precautions ( 5.5 )]
  • Gastrointestinal Disorders [see Warnings and Precautions ( 5.6 )]
  • Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions ( 5.7 )]
  • Dermatologic Toxicities [see Warnings and Precautions ( 5.8 )]
  • Hypothyroidism [see Warnings and Precautions ( 5.9 )]
  • Growth Retardation in Children and Adolescents [see Warnings and Precautions ( 5.11 )]
  • Tumor Lysis Syndrome [see Warnings and Precautions ( 5.12 )]
  • Impairments Related to Driving and Using Machinery [see Warnings and Precautions ( 5.13 )]
  • Renal Toxicity [see Warnings and Precautions ( 5.14 )] The most frequently reported adverse reactions (greater than or equal to 30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Myeloid Leukemia The majority of imatinib mesylate-treated patients experienced adverse reactions at some time. Imatinib mesylate was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate versus IFN+Ara-C, and in 12.5% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib. Imatinib mesylate was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate [see Dosage and Administration (2.13) ] . The frequency of severe superficial edema was 1.5% to 6%. A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib mesylate treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib mesylate-treated patients are shown in Tables 2, 3, and 4. Table 2: Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Imatinib Mesylate Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib Mesylate-Treated Patients) (1) All Grades CTC Grades * 3/4 Preferred term I matinib Mesylate IFN+Ara−C I matinib Mesylate IFN+Ara−C N = 551 (%) N = 533 (%) N = 551...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • CYP3A4 inducers may decrease imatinib mesylate C max and area under curve (AUC). ( 2.12 , 7.1 , 12.3 )
  • CYP3A4 inhibitors may increase imatinib mesylate C max and AUC. ( 7.2 , 12.3 )
  • Imatinib mesylate is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max and AUC of other drugs. ( 7.3 , 7.4 , 12.3 )
  • Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin. ( 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of imatinib mesylate and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3) ]. 7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of imatinib mesylate and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology (12.3)] . 7.3 Interactions With Drugs Metabolized by CYP3A4 Imatinib mesylate will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering imatinib mesylate with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation [see Clinical Pharmacology (12.3)] . 7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering imatinib mesylate with CYP2D6 substrates that have a narrow therapeutic window.

    • Contraindications

    4 CONTRAINDICATIONS None. None. ( 4 )

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Imatinib mesylate can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were...

    Overdosage

    10 OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of imatinib mesylate overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and GI pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib mesylate tablets daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate tablets daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of imatinib mesylate tablets on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Imatinib mesylate tablets are supplied as 100 mg and 400 mg tablets for oral administration. Each 100 mg tablet contains 119.50 mg of imatinib mesylate equivalent to 100 mg of imatinib free base. Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base. Imatinib mesylate tablets, 100 mg are white to off white colored, round, biconvex scored, bevel edged, film coated tablets, debossed with 'H' on one side and '7' on the other side with score line. Bottle of 90 tablets NDC 31722-296-90 Imatinib mesylate tablets, 400 mg are white to off white colored, oval, biconvex scored, bevel edged, film coated tablets, debossed with 'H' on one side and '4' on the other side with score line. Bottle of 30 tablets NDC 31722-297-30 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP. Do not crush imatinib mesylate tablets. Avoid direct contact of crushed tablets with the skin or mucous membranes. If such contact occurs, wash thoroughly as outlined in the references. Avoid exposure to crushed tablets.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.