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Imatinib; Uses, Dosage, Side Effects, Drug Interactions

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

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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.

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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

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

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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.