• 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/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
• Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFR a fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRa 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.

Adults with Ph+ CML CP: 400 mg/day

Adults with Ph+ CML AP or BC: 600 mg/day

Pediatrics with Ph+ CML CP: 340 mg/m2/day

Adults with Ph+ ALL: 600 mg/day

Pediatrics with Ph+ ALL: 340 mg/m2/day

Adults with MDS/MPD: 400 mg/day

Adults with ASM: 100 mg/day or 400 mg/day

Adults with HES/CEL: 100 mg/day or 400 mg/day

Adults with DFSP: 800 mg/day

Adults with metastatic and/or unresectable GIST: 400 mg/day

Adjuvant treatment of adults with GIST: 400 mg/day

Patients with mild to moderate hepatic impairment: 400 mg/day

Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Overdose Effects

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

• Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics.
• Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter.
• Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure.
• Severe hepatotoxicity, including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction.
• Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. Gl tumor sites may be the source of Gl bleeds in GIST. Gastrointestinal (Gl) perforations, some fatal, have been reported.
• Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Imatinib in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM).
• Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Imatinib.
• Hypothyroidism has been reported in thyroidectomy ZyvaxatX patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients.
• Fetal harm can occur when administered to a pregnant woman. Apprise women of the potential harm to the fetus, and to avoid pregnancy when taking Imatinib.
• Growth retardation occurring in children and pre-adolescents receiving Imatinib has been reported. Close monitoring of growth in children under Imatinib treatment is recommended.
• Tumor Lysis Syndrome. Close monitoring is recommended.
• Reports of motor vehicle accidents have been received in patients receiving Imatinib. Caution patients about driving a car or operating machinery.
• Renal Toxicity. A decline in renal function may occur in patients receiving Imatinib. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction.

Pregnancy & Lactation

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.