Imatero-400

Imatero-400

imatinib

Manufacturer:

Camber

Distributor:

Camber
Full Prescribing Info
Contents
Imatinib mesylate.
Description
Each film coated tablet contains Imatinib Mesylate equivalent to Imatinib 400 mg.
Action
Pharmacology: Pharmacodynamics: Imatinib 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 CML. It inhibits proliferation and induces apoptosis in Bcr-Abl-positive cell lines, as well as fresh leukemic cells from Ph+ CML. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from patients with CML.
In vivo, it inhibits tumor growth of Bcr-Abl-transfected murine myeloid cells, as well as Bcr-Abl-positive leukemia lines derived from patients with CML in blast crisis.
Imatinib also is an inhibitor of the receptor tyrosine kinases for PDGF and stem-cell factor, c-kit, and inhibits PDGF- and stem-cell factor-mediated cellular events. In-vitro, imatinib inhibits proliferation and induces apoptosis in GI stromal tumor cells, which express an activating c-kit mutation.
Pharmacokinetics: Absorption/Distribution: Imatinib is well absorbed after oral administration, with maximal drug concentration (Cmax) achieved within 2 to 4 hours postdose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 to 1000 mg. There is no significant change in the pharmacokinetics of imatinib upon repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when imatinib is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and alpha-1 acid glycoprotein.
Metabolism: CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other CYP enzymes, such as 1A2, 2D6, 2C9, and play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is approximately 15% of the AUC for imatinib. The plasma-protein binding of the N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that imatinib is a potent competitive inhibitor of CYP2C9, 2D6, and 3A4/5, with Ki values of 27, 7.5 and 8 mcM, respectively.
Excretion: Elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces); the remainder was metabolites.
Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), were approximately 18 and 40 hours, respectively.
Indications/Uses
Acute lymphoblastic leukemia: Adults with relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Aggressive systemic mastocytosis: Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
Dermatofibrosarcoma protuberans: Adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
GI stromal tumors: Patients with Kit (CD117)-positive unresectable and/or metastatic malignant GI stromal tumors; adjuvant treatment of adults following complete gross resection of Kit (CD117)-positive GI stromal tumors.
Hypereosinophilic syndrome and/or chronic eosinophilic leukemia: Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-platelet-derived growth factor (PDGF) receptor alpha fusion kinase (mutational analysis or fluorescent in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who are FIP1L1-PDGF receptor alpha fusion kinase negative or unknown.
Myelodysplastic/Myeloproliferative diseases: Adults with myelodysplastic/ myeloproliferative diseases associated with PDGF receptor gene rearrangements.
Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia: Newly diagnosed adults and pediatric patients with Ph+ chronic myeloid leukemia (CML) in chronic phase.
Philadelphia chromosome-positive chronic myeloid leukemia in blast crisis, accelerated phase, or chronic phase after interferon-alpha therapy: Patients with Ph+ chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
Dosage/Direction for Use
General dosing considerations: If a severe nonhematologic adverse reaction develops (eg, severe hepatotoxicity, severe fluid retention); imatinib should be withheld until the reaction has resolved. Thereafter, treatment can be resumed as appropriate, depending on the initial severity of the event.
Dose reduction or treatment interruptions for revere neutropenia and thrombocytopenia are recommended.
Adults: Acute lymphoblastic leukemia: 600 mg/day.
Aggressive systemic mastocytosis: 400 mg/day without D816V c-Kit mutation.
If c-Kit mutational status is not known or unavailable, treatment with imatinib 400 mg/day may be considered for patients with aggressive systemic mastocytosis not responding satisfactorily to other therapies.
Aggressive systemic mastocytosis associated with eosinophilia: Initial dosage: 100 mg/day.
Dosage adjustment: A dose increase from 100 to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Chronic eosinophilic leukemia: 400 mg/day.
Chronic eosinophilic leukemia with demonstrated FIP1L1-PDGF receptor alpha fusion kinase: Initial dosage: 100 mg/day.
Dosage adjustment: A dose increase from 100 to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Chronic myeloid leukemia: Accelerated phase or blast crisis: Usual dosage: 600 mg/day.
Dosage adjustment: A dose increase from 600 to 800 mg (given as 400 mg twice daily) may be considered in the absence of severe adverse drug reactions and severe non-leukemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, and loss of a previously achieved hematologic or cytogenetic response.
Chronic phase: Usual dosage: 400 mg/day.
Dosage adjustment: A dose increase from 400 to 600 mg may be considered in the absence of severe adverse drug reactions and severe non- leukemia- related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, and loss of a previously achieved hematologic or cytogenetic response.
Dermatofibrosarcoma protuberans: 800 mg/day.
GI stromal tumors: Adjuvant treatment of GI stromal tumors: Usual dosage: 400 mg/day.
Duration of therapy: In the clinical study, imatinib was administered for 1 year and 3 years. In the patient population defined in study 2, 3 years of imatinib is recommended. The optimal treatment duration with imatinib is not known.
Unresectable and/or metastatic, malignant GI stromal tumors: Usual dosage: 400 mg/day.
Dosage adjustment: A dosage increase of up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.
Hypereosinophilic syndrome: 400 mg/day.
Hypereosinophilic syndrome with demonstrated FIP1L1-PDGF receptor alpha fusion kinase: Initial dosage: 100 mg/day.
Dosage adjustment: A dose increase from 100 to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Myelodysplastic/Myeloproliferative diseases: 400 mg/day.
Children: Children 2 years and older: Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia chronic phase: Usual dosage: 340 mg/m2/day.
Maximum dose: 600 mg/day.
Renal Function Impairment: Mild renal impairment (creatinine clearance 40 to 59 mL/min): Dose more than 600 mg are not recommended.
Moderate renal impairment (creatinine clearance 20 to 39 mL/min): Maximum dose: Doses of more than 400 mg are not recommended.
Initial dosage: Decrease recommended starting dose by 50% and increase as tolerated.
Severe renal impairment (creatinine clearance less than 20 mL/min): Use with caution. A dosage of 100 mg/day was tolerated in 2 patients with severe renal impairment.
Hepatic Function Impairment: Severe hepatic impairment: Decrease recommended dose by 25%.
Concomitant Therapy: The use of concomitant strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifampicin) should be avoided. If patients must be coadministered strong CYP3A4 inducers, based on pharmacokinetic studies, the dosage of imatinib should be increased by at least 50%, and clinical response should be carefully monitored.
Dosage Adjustment: Hematologic: Adults: (see Table 1.)

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Children: See Table 2.

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Hepatotoxicity: Adults: See Table 3.

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Children: See Table 4.

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Duration of Therapy: Continue treatment as long as there is no evidence of progressive disease or unacceptable toxicity.
Preparation for Administration: Imatinib is considered a cytotoxic agent. Follow Safe Handling procedures when preparing, administering, or dispensing imatinib.
Do not crush imatinib tablets. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Personnel should avoid exposure to crushed tablets.
Administration: Administer orally with a meal and a large glass of water. Doses of 400 or 600 mg should be administered once daily; a dose of 800 mg should be administered as 400 mg twice per day. For daily dosing of 800 mg and higher, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. In children, imatinib treatment can be given as a once-daily dose or, alternatively, the daily dose may be split into 2 (once in the morning and once in the evening).
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablets.
Overdosage
Symptoms: A patient with myeloid blast crisis experienced grade 1 elevations of serum creatinine, grade 2 ascites and elevated liver transaminase levels, and grade 3 elevations of bilirubin after inadvertently taking imatinib 1200 mg daily for 6 days. Therapy was temporarily interrupted, and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dosage of imatinib 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking imatinib 1600 mg daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient who was prescribed imatinib 400 mg daily took 800 mg on day 1 and 1200 mg on day 2. Therapy was interrupted, no adverse reactions occurred, and the patient resumed therapy.
Adult overdosage: Imatinib 1200 to 1600 mg (duration varying between 1 to 10 days): Abdominal pain, decreased appetite, diarrhea, edema, fatigue, headache, muscle spasms, nausea, pancytopenia, rash erythema, swelling thrombocytopenia, vomiting.
Imatinib 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Bilirubin increased, creatinine phosphokinase increased, GI pain, myalgia, weakness.
Imatinib 6400 mg (single dose): One case in the literature reported 1 patient who experienced abdominal pain, facial swelling, increased transaminases, nausea, neutrophil count decreased, pyrexia, vomiting.
Imatinib 8 to 10 g (single dose): GI pain and vomiting have been reported.
Pediatric overdosage: One boy 3 years of age exposed to a single dose of imatinib 400 mg experienced vomiting, diarrhea, and anorexia, and another boy 3 years of age exposed to a single dose of imatinib 980 mg experienced decreased white blood cell count and diarrhea.
Treatment: In the event of overdosage, observe the patient and give appropriate supportive treatment.
Contraindications
Hypersensitivity to imatinib or any component of the formulation.
Special Precautions
Fluid retention and edema: Imatinib is often associated with edema and, occasionally, serious fluid retention. Weigh and monitor patients regularly for signs and symptoms of fluid retention. Carefully investigate an unexpected rapid weight gain and provide appropriate treatment. The probability of edema was increased with higher imatinib dose and age older than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed patients with CML taking imatinib and in 2% to 6% of other adults with CML taking imatinib. In addition, other severe fluid retention (eg, ascites, pericardial effusion, pleural effusion, pulmonary edema) reactions were reported in 1.3% of newly diagnosed patients with CML taking imatinib and in 2% to 6% of other adults with CML taking imatinib. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib for GI stromal tumor.
Hematologic toxicity: Treatment with imatinib is often associated with anemia, neutropenia, or thrombocytopenia. Perform complete blood cell counts (CBCs) weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (eg, every 2 to 3 months) . The occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic-phase CML. In pediatric patients with CML, the most frequent toxicities observed were grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These generally occur within the first several months of therapy.
Cardiovascular effects: Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking imatinib. Most of the patients with reported cardiac reactions have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international, randomized, phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib compared with 0.9% of patients taking interferon-alpha + cytarabine. Carefully monitor patients with cardiac disease or risk factors for cardiac failure and evaluate and treat any patient with signs or symptoms consistent with cardiac failure.
Hepatotoxicity: Hepatotoxicity, occasionally severe, may occur with imatinib. Cases of fetal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term uses of imatinib. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly thereafter, or as clinically indicated. Manage laboratory abnormalities with interruption and/or dose reduction of the treatment with imatinib. When imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.
Hemorrhage: In the newly diagnosed CML trial, 1.8% of patients had grade 3/4 hemorrhage. In the phase 3 unresectable or metastatic GI stromal tumor studies, 12.9% of patients reported grade 3/4 hemorrhage at any site. In the phase 2 unresectable or metastatic GI stromal tumor study, 5% of patients had a total of 8 common toxicity criteria (CTC) grade 3/4 hemorrhages: GI (3 patients), intratumoral (3 patients), or both (1 patient). GI tumor sites may have been the source of GI hemorrhages.
GI effects: Imatinib is sometimes associated with GI irritation. Instruct patients to take imatinib with food and a large glass of water to minimize this problem. There have been rare reported, including fatalities, of GI perforation.
Hypereosinophilic cardiac toxicity: In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporary withholding of imatinib. Myelodysplastic/ myeloproliferative diseases and systemic mastocytosis may be associated with high eosinophil levels. Therefore, consider performing an echocardiogram and determining serum troponin in patients with hypereosinophilic syndrome/chronic eosinophilic leukemia and in patients with myelodysplastic/myeloproliferative diseases or aggressive systemic mastocytosis associated with high eosinophilic levels. If either is abnormal, consider the prophylactic use of systemic steroids (1 to 2 mg/kg) for 1 to 2 weeks concomitantly with imatinib at the initiation of therapy.
Dermatologic effects: Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during post-marketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib therapy after resolution or improvement of the bullous reaction. In these instances, imatinib was resumed at a dose lower than that at which the reaction occurred, and some patients also received concomitant treatment with corticosteroids or antihistamines.
Hypothyroidism: Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib. Closely monitor thyroid- stimulating hormone levels in such patients.
Tumor lysis syndrome: Cases of tumor lysis syndrome, including fatal cases, have been reported in patients with CML, GI stromal tumor, ALL, and eosinophilic leukemia receiving imatinib. The patients at risk of tumor lysis syndrome are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate cautions.
Renal function impairment: Use with caution in patients with severe renal impairment. Dosage reductions are necessary for patients with moderate and severe renal impairment.
Hepatic function impairment: A reduced dose is recommended in patients with severe hepatic impairment.
Use in Children: Imatinib safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic-phase CML. There are no data in children younger than 2 years.
Growth retardation has been reported in children and preadolescents receiving imatinib. The long-term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under imatinib treatment is recommended.
Use in the Elderly: The incidence of edema was increased with age older than 65 years in the CML and GI stromal tumor studies.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category D.
Imatinib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. Advise women of childbearing potential to avoid becoming pregnant while taking imatinib. Instruct sexually active women taking imatinib to use adequate contraception. If this drug is used during pregnancy or if the patient becomes pregnant while taking imatinib, apprise the patient hazard to the fetus.
Use in Lactation: Imatinib and its metabolites are excreted in human milk. Based on data from 3 breast-feeding women taking imatinib, the milk to plasma ratio is approximately 0.5 for amanitins and approximately 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breast-fed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in breast-feeding infants, decide whether to discontinue breast-feeding or the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
See Table 5.

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Drug Interactions
See Table 6.

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Storage
Store below 30°C and protect from moisture.
ATC Classification
L01EA01 - imatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 400 mg (brownish orange colored, oval, biconvex scored, bevel edged, debossed with H on one side and 4 on the other side with score line) x 30's.
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