Pack Size: 1 x 10
Drug Class: protein-tyrosine kinase inhibitor
Dosage and Administration:
The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be adminstered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.
Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. Adult Patients with Ph+CML CP.AP and BC
The recommended dose of Zimitib is 400mg/day for adult patents in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast orisis.
In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hermatologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.
Pediatric Patients with Ph+ CML
The recommended dose of Zimitib for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg). The recommended Zimitib dose is 260 mg/m2/day for children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon-alpha therapy.
The recommended dose of Zimitib is 600 mg/day for adult patients with relapsed/refractory Ph+ALL Kit+ Gastrointestinal Stromal Tumors (GIST).
The recommended dose of Zimitib is 400 mg/day or 600 mg/day for adult patients with unresectable and /or metastatic, malignant GIST.
Dose Modification Guidelines:
Concomitant strong CYP3A4 Inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g dexamethasone, phenybin, carbamazepine, infarrpin, rifabutin, rifarnapacin, phenobarbital). It patients must be co-adminsitered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Zimitib should be increased by at least 50%, and clinical response should be carefully monitored.
Hepatic Impairment : Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treat as per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic Impairment.
Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions
If alevations in Infubin>3xinstitutional upper limit of normal (IULN) or in liver transminases>5xIUL N occur, Zimitib should be withheld until bilarubin levels have returned to a <1.5 x[ULN and transminase levels to <2.5 X IULN. In adults treatment with Zimitib may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg., 600 mg to 00 mg or 800 mg to 600 mg ), In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day or from 260 mg/m2 day to 200 mg/m2 respectively.
If a sevee non-hematotogic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention).
Zimitib should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
Cold Storage: no
Imatinib is a small molecule kinase inhibitor. Gleevec film-coated tablets contain imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is:
Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. Its molecular formula is C29H31N7O • CH4SO3 and its molecular weight is 589.7. Imatinib mesylate is soluble in aqueous buffers less than or equal to pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile.
Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML)
Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.
Ph+ CML In Blast Crisis (BC), Accelerated Phase (AP) Or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy
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 Ph+ Acute Lymphoblastic Leukemia (ALL)
Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)
Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.
Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)
Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
Aggressive Systemic Mastocytosis (ASM)
Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
keep out of the reach of children
Read the label carefully before use
Pregnancy: Pregnancy Category D:
Women of childbearing potential should be advised to avoid becoming pregnant while taking Zimitib . If the patient becomes pregnant while taking this drug. the patient should be apprised of the potential hazard to the fetus.
Fluid Retention and Edema:
Zimitib is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Zimitib dose and age>65 years in the CML patients. Severe superficial edema and severe fluid retention (pieural effusion, pulmonary edema and ascities) were reported in 1% -6% of patients taking Zimitib for GIST.
Treatment with Zimitib is associated with anemia, neutropenia, and thrombocytopenia complete blood counts should be performed weekly for the first month, on weekly for the second month, and periodically thereafter as clinically indicated (for exarmple, every 2-3 months) In CML, the occurrence of these cytopenias is depended 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 CML patients 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.
Severe Congestive Heart failure and Left Ventricular Dysfunction.
Severe congestive heart failure and left ventricular dysfunctionhave occasionally been reported in patients taking Zimitib . Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease.
Hepatotoxicity, occasionally severe, may occur with Zimitib , Liver function (transaminases, billirubin, and alkaline phosphatase) should be moniored before initiation of treatment and monthly) or as clinically indicated. Laboratory abnormalities should be managed with interruption and /or dose reduction of the treatment with Zimitib .
In CML Patients 1.8% of patients had Grade 3/4 hemorrhage. In GIST patients, seven patients (5%) four in the 600 mg dose group and three in the 400 mg dose group, had a total of eight reactions of CTC Grade 3/4 gastrointestinal (GI) bleeds (3 patients), intra-tumpral bleeds (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of Gl bleeds
Zimitib is sometimes associated with GI irritation. Zimitib should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.
In patients with hyperesoinophilic 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 imatinib.
Bullous dermatologic reactions, including erythmamultiforme and Stevens – Johnson syndrome, have been reported with use of Zimitib .
Carcinogenesis, Mutagenesis, Impairment of Fertility
Human studies on male patients receiving Zimitib and its affect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on Zimitib treatment should consult with their physician.
It is not known whether imatinibmesylate or its metabolities are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Zimitib safely and efficacy have been demonstrated in children with newly diegnosedPh+ chronic phase CML and in children with Ph+ chronic phase CML with recurrence after stem-cell transplantation or resistance to interferon-alpha therpy.
No difference was observed in the safely profile in patients older than 65 years as compared to younger patients, with the exception of a higher-frequency of edema. The efficacy of Zimitib was similar in older and younger patients.
The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was asessed in 84 cancer patients with varying degrees of hepatic Impairment at Imatinib dose ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45% respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function.
No clinical studies were conducted with Zimitib in patients with decreased renal function (studies excluded patients with serum creatinine concentration more than 2 times the upper limit of the normal range)