Imatib

Uses

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 in blast crisis, accelerated phase, or in chronic phase 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 or myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements as determined with an FDA-approved test

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA approved test

Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISHdemonstration 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.

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

Imatib is also used to associated treatment for these conditions: Chordomas, Chronic Eosinophilic Leukemia (CEL), Chronic Myeloid Leukemia (CML), 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 (MDS), Myeloproliferative Disorders, Refractory Acute Lymphoblastic Leukemia, CKit mutational status unknown Aggressive systemic mastocytosis, Metastatic Dermatofibrosarcoma protuberans, Newly diagnosed Acute Lymphoblastic Leukaemia, Newly diagnosed, chronic phase Chronic myeloid 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

How Imatib works

Imatib 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. Imatib also inhibits the receptor tyrosine kinases for platelet derived growth factor (PDGF) and stem cell factor (SCF) - called c-kit. Imatib 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 bcr-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.

Dosage

Imatib dosage

Oral (Adult)-

• Dermatofibrosarcoma protuberans: 400 mg bid.
• Chronic myeloid leukaemia: Chronic phase: 400 mg daily, increased to 600 mg daily or 400 mg bid. Blast crisis or accelerated phase: 600 mg daily, increased to 400 mg bid as required.
• Mastocytosis: 400 mg daily. Start with 100 mg daily if there is associated eosinophilia, may increase to 400 mg if response is insufficient.
• Unresectable, metastatic malignant gastrointestinal stromal tumours: 400 mg daily, may increase up to 400 mg bid.
• Myelodysplastic disease: 400 mg daily.
• Acute lymphoblastic leukaemia, Monotherapy in relapsed or refractory acute lymphoblastic leukaemia: 600 mg daily with induction, consolidation or maintenance chemotherapy.
• Hypereosinophilic syndrome: 400 mg daily. Start with 100 mg daily in patients with FIP1L1-PDGF receptor-α fusion kinase, may increase to 400 mg if response is inadequate.

Oral (Child)-

• Chronic myeloid leukaemia: 340 mg/m2 daily. Max: 800 mg. May be given once daily or divided into morning and evening doses. May be increased to 570 mg/m2 daily in childn w/ disease progression, unsatisfactory haematological response at least 3 mth of treatment, failed to achieve cytogenic response after 12 mth of treatment or loss a previously achieved haematological or cytogenic response.
• Acute lymphoblastic leukaemia, Monotherapy in relapsed or refractory acute lymphoblastic leukaemia:340 mg/m2 daily. Max: 600 mg.

Should be taken with food.

Side Effects

GI disturbances and bleeding, myelosuppression, superficial oedema, myalgia, arthralgia, muscle cramps, fatigue, rhabdomyolysis, rashes, pruritus, headache, dizziness, taste disturbances, anorexia, paraesthesia, insomnia, eye disorders or visual disturbances, epistaxis, cough, dyspnoea, dry skin, alopecia, night sweats, pyrexia, weakness, rigors, haemorrhages, growth retardation in childn, CHF, palpitations, tachycardia, arrhythmias, angina pectoris and MI. Rarely, serious and severe skin disorders (e.g. erythema multiforme, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, exfoliative dermatitis and bullous eruptions); aseptic necrosis of bone, ulceration.

Toxicity

The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.

Precaution

Patient with cardiac disease or increased risk for CHF. Renal and hepatic impairment. Pregnancy.

Interaction

Increased serum levels with CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics). Reduced serum levels with CYP3A4 inducers (e.g. carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampicin). May increase serum levels of substrates of CYP3A4 (e.g. ciclosporin, pimozide, triazolo-benzodiazepines, dihydropyridine Ca channel blockers, certain statins), CYP2C9 (e.g. warfarin) and CYP2D6.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which can increase serum levels of imatinib.
• Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of imatinib.
• Take with a full glass of water. Taking imatinib with water may reduce gastric irritation.
• Take with food. Food reduces gastric irritation.

[Moderate] GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice.

If coadministration is unavoidable, monitor for prolonged and

Imatib Drug Interaction

Moderate: metoprolol, metoprolol, metoprolol, metoprolol, acetaminophen, acetaminophen, levothyroxine, levothyroxine, ondansetron, ondansetronUnknown: aspirin, aspirin, diphenhydramine, diphenhydramine, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Imatib Disease Interaction

Moderate: cardiovascular disease, fluid retention, bone marrow suppression, gastrointestinal disorders, hepatic impairment, hypothyroidism, renal impairment

Elimination Route

The pharmacokinetics in CML and GIST patients are similar. Imatib is well absorbed with mean absolute bioavailability is 98% and maximum plasma levels achieved within 2-4 hours of dosing

Half Life

Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588) are approximately 18 and 40 hours, respectively.

Clearance

• 8 L/h [50-year-old CML and GIST patient weighing 50 kg]
• 14 L/h [50-year-old CML and GIST patient weighing 100 kg]

Elimination Route

Imatib elimination is predominately in the feces, mostly as metabolites. 81% of the dose is eliminated within 7 days, in feces (68% of the dose) and urine (13% of the dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faces), the remainder being metabolites.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Hypersensitivity. Lactation.

Special Warning

Patients on potent CYP3A4 inducers: Increase dose by 50% and carefully monitor clinical response.

Severe Hepatic Impairment: Reduce dose by 25%.

Acute Overdose

Symptoms: Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, headache, pyrexia, decreased appetite, weakness, myalgia, GI pain, decreased neutrophil count, increased creatine phosphokinase, bilirubin and transaminases.

Management: Supportive and symptomatic treatment.

Storage Condition

Store below 30° C. Protect from moisture.

Innovators Monograph

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