Imatinib

What it is used for

Imatinib mesylate 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 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 Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown 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.

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. 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.

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. Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

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. Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia 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.

Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

Side effects, and when to stop

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

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Who should not take it

None.

Other medicines and interactions

Clinical Studies

Agents Inducing CYP3A Metabolism

Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate tablets, increased imatinib mesylate tablets oral-dose clearance by 3.8-fold, which significantly (p less than 0.05) decreased mean C max and AUC.

Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib mesylate tablets concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED.

Concomitant administration of imatinib mesylate tablets and St. John’s Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Imatinib mesylate tablets doses up to 1,200 mg/day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers.

Agents Inhibiting CYP3A Metabolism

There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when imatinib mesylate tablets were coadministered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided.

Interactions with Drugs Metabolized by CYP3A4

Imatinib mesylate tablets increase the mean C max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate tablets. Particular caution is recommended when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus).

Imatinib mesylate tablets will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

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

Interactions with Drugs Metabolized by CYP2D6

Imatinib mesylate tablets increased the mean C max and AUC of metoprolol by approximately 23% suggesting that imatinib mesylate tablets have a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window.

Interactions with Acetaminophen

Coadministration of imatinib mesylate tablets (400 mg/day for 8 days) with acetaminophen (1,000 mg single dose on Day 8) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Imatinib mesylate tablets pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of imatinib mesylate tablets at doses greater than 400 mg/day or the chronic use of concomitant acetaminophen and imatinib mesylate tablets.

In Vitro Studies

Cytochrome P450 (CYP450) Enzymes: Imatinib inhibits CYP2C9 and CYP2D6.

Transporter Systems: Imatinib is a substrate of BCRP, P-gp, OATP1A2, OATP1B3, and OCT1. Imatinib inhibits BCRP, BSEP, P-gp, MATE1, MATE2-K, OCT1, and OCT2.