Imatinib is an antineoplastic agent that inhibits the Bcr-Abl fusion protein tyrosine kinase, an abnormal enzyme produced by chronic myeloid leukemia cells that contain the Philadelphia chromosome. Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF)/c-kit; the SCF/c-kit receptor tyrosine kinase is activated in the gastrointestinal stromal tumor (GIST). This agent inhibits proliferation and induces apoptosis in cells that overexpress these oncoproteins.

Imatinib is a medication used to treat cancer. Specifically, it is used for chronic myelogenous leukemia and acute lymphocytic leukemia that are Philadelphia chromosome-positive (Ph⁺) and certain types of gastrointestinal stromal tumors, systemic mastocytosis, and myelodysplastic syndrome chronic, myelogenous leukemia a number of other malignancies. It is taken by mouth. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.

Mechanism of Action of Imatinib

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF) – called c-kit. Imatinib was identified in the late 1990s by Dr. Brian J. Druker. Its development is an excellent example of rational drug design. Soon after identification of the bar-abl target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.

Indications of Imatinib

• Chordomas
• Chronic myelogenous leukemia
• Gastrointestinal stromal tumor
• Acute lymphoblastic leukemia
• Chronic eosinophilic leukemia
• Dermatofibrosarcoma protuberans
• Hypereosinophilic syndrome
• Myelodysplastic diseases
• Myeloproliferative disorders
• Systemic mastocytosis
• Chronic eosinophilic leukemia
• Chronic myeloid leukemia
• Desmoid tumors
• FIP1L1-PDGFRα fusion kinase status unknown chronic eosinophilic leukemia
• FIP1L1-PDGFRα fusion kinase status unknown hypereosinophilic syndrome
• Hypereosinophilic syndromes
• Metastatic gastrointestinal stromal tumor
• Metastatic melanoma
• Myelodysplastic Syndromes
• Myeloproliferative disorders
• Refractory acute lymphoblastic leukemia
• CKit mutational status unknown aggressive systemic mastocytosis
• Metastatic dermatofibrosarcoma protuberans
• Newly diagnosed, chronic phase chronic myeloid leukemia
• Newly diagnosed acute lymphoblastic leukemia
• Recurrent dermatofibrosarcoma protuberans
• Refractory, accelerated phase chronic myeloid leukemia
• Refractory, blast crisis chronic myeloid leukemia
• Refractory, chronic phase chronic myeloid leukemia
• Systemic mastocytosis with associated hematological neoplasm
• Unresectable gastrointestinal stromal tumor.

Contra-Indications of Imatinib

• Diabetes
• Overweight
• Anemia
• Decreased blood platelets
• Decreased neutrophils a type of white blood cell
• Fluid accumulation in the brain
• High blood pressure
• Coronary artery disease
• Fluid in the covering of the heart or pericardium
• Heart valve disease
• Chronic heart failure
• Failure of the left ventricle of the heart
• Inflammation of the middle tissue heart muscle
• Bleeding
• Escape of fluid into the lungs
• Fluid in the lungs
• Liver problems
• Severe liver disease
• Bleeding of the stomach or intestines
• Kidney disease with a reduction in kidney function
• Heart disease present at birth
• Visible water retention
• Blood circulation failure due to a Serious heart condition

Dosage of Imatinib

Strengths: 100 mg  ;400 mg;

Chronic Myelogenous Leukemia

• Chronic phase: 400 mg orally once a day
• Accelerated phase or blast crisis: 600 mg orally once a dayDisease progression chronic phase: 600 mg orally once a day
• Disease progression accelerated phase or blast crisis: 400 mg orally 2 times a day

Acute Lymphoblastic Leukemia

• 600 mg orally daily
• Duration of therapy: Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Myeloproliferative Disorder

• 400 mg orally once a day
• Duration of therapy: Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Myelodysplastic Disease

• 400 mg orally once a day
• Duration of therapy: Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Systemic Mastocytosis

• For patients with ASM without the D816V c-Kit mutation: 400 mg orally daily
• If the c-Kit mutational status is not known or unavailable: 400 mg orally daily may be considered for patients with ASM not responding satisfactorily to other therapies
• For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR alpha, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
• For patients with ASM associated with eosinophilia (a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR alpha: 100 mg orally daily; a dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy
• Duration of therapy: Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Hypereosinophilic Syndrome

• For patients with HES/CEL: 400 mg orally daily
• For patients with HES/CEL with demonstrated FIP1L1-PDGFR alpha fusion kinase: 100 mg orally daily; dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy
• Duration of therapy: Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Chronic Eosinophilic Leukemia

• For patients with HES/CEL: 400 mg orally daily
• For patients with HES/CEL with demonstrated FIP1L1-PDGFR alpha fusion kinase: 100 mg orally daily; dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy
• Duration of therapy: Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Acute Lymphoblastic Leukemia

1 year and older

• 340 mg/m2 orally once a day
• Maximum Dose: 600 mg once a day
• Duration of therapy: Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Side Effects of Imatinib

The most common

• chest pain
• headache
• joint painPain
• dizziness
• nausea and vomiting
• Severe stomach ache
• epigastric pain,
• diarrhoea,
• anorexia,
• flatulence,
• headache,
• dizziness,
•  fainting, fast or pounding heartbeats.

More common

• Fast or irregular heartbeat
• appetite loss
• changes in nails
• constipation
• fatigue
• fever
• Back pain
• dizziness
• headache
• increased cough
• Acid or sour stomach
• decreased appetite
• Agitation
• chest congestion
• chest pain
• cold sweats
• confusion
• decreased sexual ability or desire
• stomach or abdominal cramps, gas, or pain
• trouble sleeping

Less common

• bleeding gums
• blood in the urine or stools
• chest pain
• diarrhea
• Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
• difficulty in moving
• muscle stiffness
• redness of the face, neck, arms and occasionally, upper chest
• lack or loss of strength
• muscle spasm
• difficult or labored breathing
• dry mouth
• headache
• irritability
• lack or loss of strength
• loose stools
• loss of interest or pleasure
• muscle stiffness
• night sweats
• passing gas
• stomach discomfort, upset, or pain
• swollen joints
• trouble concentrating
• increased blood pressure

Drug Interactions of Imatinib

Imatinib may interact with following drugs, supplements & may decrease the efficacy of drugs

• antipsychotic medications (e.g., chlorpromazine, haloperidol, olanzapine, quetiapine, risperidone)
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
• beta-blockers (e.g., carvedilol, metoprolol, propranolol)
• bupropion
• captopril
• celecoxib
• clopidogrel
• abatacept
• bisphosphonates (e.g., alendronate, risedronate)
• canakinumab
• clozapine
• diabetes medications (e.g., chlorpropamide, glipizide, glyburide, insulin, metformin,nateglinide, rosiglitazone)
• domperidone
• glucosamine
• heparin
• ketoconazole
• losartan
• low molecular weight heparins (e.g., dalteparin, enoxaparin, tinzaparin)
• macrolide antibiotics (e.g., clarithromycin, erythromycin)
• MAO inhibitors (e.g., linezolid, moclobemide, phenelzine, selegiline, tranylcypromine)
• mirabegron
• multivitamins/minerals
• muscle relaxants (e.g., baclofen, cyclobenzaprine, methocarbamol, orphenadrine, tizanidine)
• nonsteroidal anti-inflammatory medications (NSAIDs; diclofenac, ibuprofen, naproxen)
• omega-3 fatty acids
• estrogens and progestins (such as those found in birth control pills and hormone replacement therapies)
• tocilizumab
• trastuzumab
• pentoxifylline
• quinolone antibiotics (e.g., levofloxacin, moxifloxacin)
• seizure medications (e.g., carbamazepine, clobazam,  felbamate, levetiracetam, phenobarbital, phenytoin, primidone, topiramate, valproic acid, zonisamide)
• serotonin/norepinephrine reuptake inhibitors (SNRIs e.g., desvenlafaxine, duloxetine, venlafaxine)
• other selective serotonin reuptake inhibitors (SSRIs;e.g., citalopram, fluoxetine, sertraline)
• 5-HT3 antagonists (e.g., granisetron, ondansetron)
• tamsulosin
• tapentadol
• thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
• tramadol
• tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, desipramine)
• tyrosine kinase inhibitors (e.g., imatinib, lapatinib, pazopanib, sunitinib)
• vitamin E
• warfarin

Pregnancy & Lactation

FDA Pregnancy Category D 

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. Women of childbearing age who are taking imatinib should use an effective method of birth control during treatment.

Lactation

This medication passes into breast milk. If you are a breastfeeding mother and are taking imatinib, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.

References