Tibisan Dosage/Direction for Use

Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies and malignant sarcomas, as appropriate. The prescribed dose should be administered orally with a meal and large glass of water to minimize the risk of gastrointestinal disturbances. Doses of 400 or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and 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 tablet(s).
Treatment should be continued as long as the patient continues to benefit.
Monitoring of response to TIBISAN therapy in Ph+ CML patients should be per formed routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Result of monitoring should guide appropriate CML management.
General target population: Dosage in CML: The recommended dosage of TIBISAN is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis.
Dose increase from 400 to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg daily in 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 hematological response after at least 3 months of treatment; failure to achieve cytogenetic response after 12 months of treatment; or loss of previously achieved hematological and/or cytogenetic response.
Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse events at higher dosages.
Dosage in Ph+ ALL: The recommended dose of TIBISAN is 600 mg/day for adult patients with Ph+ ALL. See Special Population for children.
Dosage in MDS/MDP: The recommended dose of TIBISAN is 400 mg/day for adult patients with MDS/MDP.
Dosage in SM: The recommended dose of TIBISAN is 400 mg/day for adult patients with SM without the D186V c-Kit mutation or mutational status unknown or not responding satisfactory to other therapies.
For patients with SM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR-alpha, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Dosage in HES/CEL: The recommended dose of TIBISAN is 400 mg/day for patients with HES/CEL.
For HES/CEL patients with demonstrated FIP1L1-PDGFR alpha fusion kinase, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patient may be considered in the absence of adverse drug reactions if assessment demonstrate an insufficient response to therapy.
Dosage in DFSP: The recommended dose of TIBISAN is 800 mg/day for adult patients with DFSP.
Dose adjustments for adverse drug reactions.
Non-hematological adverse drug reactions: If a severe non-hematological adverse drug reaction develop with TIBISAN use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, TIBISAN should be withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase level to < 2.5 x IULN. Treatment with TIBISAN may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg, or from 600 to 400 mg, or from 800 mg to 600 mg.
Hematological adverse drug reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1 as follows.


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Special populations: Children: There is no experience with the use of TIBISAN in children with Ph+ ALL below 1 year of age. There is very limited to no experience with the use of TIBISAN in children in other indications.
Dosing in children should be on the basis of body surface are (mg/m²). The dose of 340 mg/m² daily is recommended for children with chronic phase and advance phase Ph+ ALL (not to exceed the total dose of 600 mg daily). Treatment can be given as once daily dose in Ph+ ALL.
Hepatic insufficiency: TIBISAN is mainly metabolized through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated.
Renal insufficiency: TIBISAN and its metabolites are not significantly excreted via kidney. Since the renal clearance of TIBISAN is negligible, a decrease in free drug clearance is not expected in patients with renal insufficiency. Patients with mild or moderate renal dysfunction should be given the minimum recommended dose of 400 mg daily as starting dose. Although very limited information is available, patients with severe renal dysfunction or on dialysis could also start at the same dose of 400 mg. However, in these patients caution in recommended. The dose can be reduced if not tolerated, or increased for lack of efficacy.
Elderly patients: No specific dose recommended is necessary in the elderly.