Imitab

Approved Indications:

• Chronic Myeloid Leukemia (CML):
• Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase CML in adults and children.
• Ph+ CML in chronic, accelerated, or blast crisis phase after failure of interferon-alpha therapy.
• Acute Lymphoblastic Leukemia (ALL):
• Philadelphia chromosome-positive (Ph+) ALL in adults and pediatric patients.
• Gastrointestinal Stromal Tumors (GIST):
• Unresectable and/or metastatic KIT-positive GIST.
• Adjuvant treatment following complete gross resection of KIT-positive GIST.
• Myelodysplastic/Myeloproliferative Diseases (MDS/MPD):
• Associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.
• Aggressive Systemic Mastocytosis (ASM):
• Without the D816V c-KIT mutation or when mutation status is unknown.
• Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL):
• Including patients with FIP1L1-PDGFRα fusion kinase.
• Dermatofibrosarcoma Protuberans (DFSP):
• Unresectable, recurrent, or metastatic disease.

Clinically Accepted Off-Label Uses:

• Desmoid tumors (aggressive fibromatosis)
• Systemic sclerosis (under investigational protocols)
• Chronic eosinophilic pneumonia (rare and case-specific)

Adult Dosage:

• CML:
• Chronic phase: 400 mg orally once daily.
• Accelerated or blast crisis: 600 mg once daily.
• Maximum: Up to 800 mg/day in divided doses if needed.
• Ph+ ALL: 600 mg orally once daily.
• GIST:
• Metastatic/unresectable: 400 mg once daily (can increase to 600–800 mg if no response).
• Adjuvant setting: 400 mg once daily for 3 years post-surgery.
• MDS/MPD, HES/CEL, ASM: 400 mg once daily.
• DFSP: 800 mg once daily.

Pediatric Dosage:

• CML or Ph+ ALL: 340 mg/m² orally once daily (maximum 600 mg/day).

Special Populations:

• Hepatic Impairment: Use with caution. Reduce initial dose if moderate to severe impairment is present.
• Renal Impairment: No adjustment for mild/moderate impairment. Severe impairment: initiate with 300 mg/day.
• Elderly: No specific adjustment, but increased monitoring is advised.

Administration Notes:

• Must be taken with food and a large glass of water to minimize gastrointestinal irritation.
• Do not crush or chew tablets. Swallow whole.
• Take doses at the same time each day.

Imatinib Mesylate is a selective tyrosine kinase inhibitor (TKI) that acts by inhibiting the ATP-binding site of several key abnormal tyrosine kinases including BCR-ABL, c-KIT, and PDGFRα/β. In Ph+ CML and ALL, it targets the BCR-ABL fusion protein, which is responsible for unregulated cell proliferation. In GIST, it inhibits c-KIT (CD117), a receptor tyrosine kinase essential for tumor growth. By blocking these pathways, Imatinib suppresses abnormal cellular proliferation and induces apoptosis in cancerous cells.

• Absorption: Oral bioavailability ~98%; food does not significantly affect absorption.
• Peak Plasma Time: 2–4 hours post-dose.
• Distribution: Large volume of distribution; ~95% plasma protein bound.
• Metabolism: Primarily hepatic, via CYP3A4; minor contributions from CYP1A2, CYP2D6, and CYP2C9.
• Active Metabolite: CGP74588 (similar activity as the parent compound).
• Half-life:
• Parent drug: ~18 hours.
• Active metabolite: ~40 hours.
• Excretion:
• Feces: ~81% (mainly as metabolites).
• Urine: ~13% (minimal unchanged drug).

Pregnancy:

• FDA Category D (prior classification): Positive evidence of human fetal risk.
• Not recommended during pregnancy unless the potential benefits justify the risk.
• Teratogenic and embryotoxic effects observed in animal studies.
• Fetal anomalies reported in human use.

Lactation:

• Excreted into human breast milk.
• Serious adverse effects may occur in breastfed infants.
• Breastfeeding is contraindicated during treatment and for at least 1 week after discontinuation.

• Primary Class: Antineoplastic Agent
• Subclass: Tyrosine Kinase Inhibitor (TKI)
• Generation: First-generation BCR-ABL inhibitor

• Hypersensitivity to Imatinib or any inactive components.
• Concurrent use with strong CYP3A4 inducers in uncontrolled disease.
• Use in pregnancy unless absolutely necessary.
• Severe hepatic impairment (relative contraindication).

• Hepatotoxicity: Liver enzyme elevations and liver failure have been reported; monitor LFTs.
• Fluid Retention & Edema: Can lead to pleural/pericardial effusion, pulmonary edema, or heart failure.
• Myelosuppression: Frequent complete blood counts (CBC) needed due to risk of anemia, neutropenia, thrombocytopenia.
• Cardiotoxicity: Rare reports of congestive heart failure; monitor in patients with cardiac history.
• Growth Retardation in Children: Long-term use may impair growth; regular monitoring is necessary.
• Skin Reactions: Severe reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) have occurred.
• Tumor Lysis Syndrome (TLS): Risk in patients with high tumor burden; monitor electrolytes and renal function.

Very Common (≥10%):

• Edema (especially periorbital)
• Nausea and vomiting
• Diarrhea
• Muscle cramps
• Rash
• Fatigue
• Myelosuppression (neutropenia, thrombocytopenia, anemia)

Common (1–10%):

• Headache
• Abdominal pain
• Weight gain
• Arthralgia
• Increased liver enzymes
• Dyspepsia

Serious/Rare:

• Hepatic failure
• Cardiac tamponade
• Pulmonary edema
• SJS/TEN
• Pancreatitis
• Acute renal failure
• GI perforation

Onset & Severity:

• Most side effects occur within the first 2–4 weeks.
• Hematologic and hepatic toxicities may be dose-related and cumulative.

CYP Enzyme Involvement:

• Major substrate of CYP3A4
• Minor: CYP2C9, CYP2D6, CYP1A2

CYP3A4 Inhibitors:

• Ketoconazole, itraconazole, clarithromycin, grapefruit juice → Increase plasma levels → Toxicity risk.

CYP3A4 Inducers:

• Rifampin, carbamazepine, phenytoin, St. John’s Wort → Decrease plasma levels → Reduced efficacy.

Other Interactions:

• Warfarin: Monitor INR closely due to bleeding risk.
• Paracetamol (Acetaminophen): Risk of hepatotoxicity at high doses.
• Alcohol: Increases hepatotoxicity risk; should be limited or avoided.
• Live Vaccines: Avoid due to immunosuppressive effects.

• GIST Adjuvant Therapy: NCCN and ESMO now recommend 3 years of adjuvant therapy for high-risk patients (previously 1 year).
• Pediatric Monitoring: Regular assessment of height, weight, and bone development in children is now recommended.
• Hepatotoxicity: Updated label warnings regarding liver monitoring frequency and thresholds for dose adjustment.
• EMA and FDA Alerts: Emphasize enhanced vigilance for fluid retention, hepatotoxicity, and serious skin reactions.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Excursion Limits: Allowable between 15°C to 30°C (59°F to 86°F).
• Humidity: Store in a dry place; avoid exposure to moisture.
• Light Protection: Keep in original container; protect from direct light.
• Handling: Do not crush or split tablets. Wear gloves when handling broken tablets.
• Refrigeration/Reconstitution: Not required.
• Child Safety: Store out of reach of children.