Tibisan

Each film-coated tablet contains: Imatinib Mesilate equivalent to Imatinib 100 mg.

Pharmacology: Imatinib is a small molecule protein-tyrosin kinase inhibitor that potently inhibits the activity of the BCR-ABL tyrosin kinase (TK), as well as several receptor TKs; KIT, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2) the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

TIBISAN is indicated for the: Treatment of patients with newly diagnosed Philadelphia chromosome (BCR-ABL) positive (Ph+) chronic myeloid leukemia (CML), as well as for the treatment of patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
Treatment of adult and pediatric above 1 year of age patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) integrated with chemotherapy.
Treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
Treatment of adult patients with myelodysplastic/myeloproliferative disease (MDS/MDP) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.
Treatment of adult patients with systemic mastocytosis (SM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.
Treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL).
Treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).
The effectiveness of TIBISAN is based on overall hematological and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in PH+ALL, MDS/MDP, on hematological response rates in SM, HES/CEL, and on objective response rates in DFSP.

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.

In the event of overdosage the patient should be observed and appropriate symptomatic treatment should be given.

Use in patients with a hypersensitivity to the active substance or to any of the excipients is contraindicated.

Imatinib should be taken with food and a large glass of water to minimize the risk of gastrointestinal disturbances. When Imatinib is co-administered with other medications, there is potential for drug interactions.
Hypothyroidism: Hypothyroidism have been reported in thyroidectomy patients undergoing Levothyroxine replacement during treatment with Imatinib. TSH levels should be closely monitored in such patients.
Hepatotoxicity: In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored.
When Imatinib is combined with high doses chemotherapy regimens, transient liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally there have been uncommon reports of acute liver failure. Monitoring of hepatic function is recommended in circumstances where Imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction.
Fluid retention: Occurrences of severe fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial edema) have been reported. Therefore, it is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken.
Patients with cardiac disease or renal failure: Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imatinib.
Myelodysplastic (MDS)/myeloproliferative (MPD) diseases and systemic mastocytosis might be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or SM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imatinib should be considered at the initiation of therapy.
Tumor lysis syndrome: Cases of tumor lysis syndrome (TLS) have been reported in patients treated with Imatinib. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acids levels are recommended prior to initiation of Imatinib.
Hepatitis B reactivation: Reactivation of Hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as Imatinib. Some cases involving drugs of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Patients should be tested for Hepatitis B infection before initiating treatment with Imatinib. Patients currently on Imatinib should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of Hepatitis B should be consulted before the treatment is initiated in patients with positive Hepatitis B serology (including those with active disease) and for patients who test positive for Hepatitis B infection during treatment. Carries of Hepatitis B virus who require treatment with Imatinib should be closely monitored for signs and symptoms of active Hepatitis B infection throughout therapy and for several months following termination of therapy.
Laboratory test: Complete blood counts must be performed regularly during therapy with Imatinib. Treatment of CML patients with Imatinib has been associated with neutropenia or thrombocytopenia. However the occurrence of these cytopenias is dependent on the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with Imatinib may be interrupted or the dose be reduced, as recommended in section Dosage & Administration.
Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving Imatinib. As recommended in section Dosage & Administration, non-hematological adverse drug reactions, these laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Imatinib.
Imatinib and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCl) is known to decrease with age, and age did not significantly affect Imatinib kinetics. In patients with impaired renal function, Imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an Imatinib-binding protein, in these patients. There is no correlation between Imatinib exposure and the degree of renal impairment, as classified by the measurement of creatinine clearance (CrCl), between patients with mild (CrCl: 40-59 ml/min) and severe (CrCl: < 20 ml/min) renal impairment. However, as recommended in section Dosage & Administration, the starting dose of Imatinib can be reduced if no tolerated.
Effects on ability to drive and use machines: Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Imatinib. Therefore, caution should be recommended when driving a car or operating machine.
Use in children and adolescents: There have been case reports of growth retardation occurring in children and pre-adolescents 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.
Women of child-bearing potential, pregnancy, breastfeeding and fertility women of child-bearing potential: Women of child-bearing potential must be advised to use highly effective contraception during treatment. Highly effective contraception is a method of birth control which results in a low failure rate (i.e. less than 1% per year), when used consistently and correctly.
Fertility: Male patients concerned about their fertility on Imatinib treatment should consult with their physician.
Use in pregnancy: Imatinib should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.
Use in breastfeeding: Both Imatinib and its active metabolite can be distributed into human milk. Since the effects of low-dose exposure of the infant to Imatinib are unknown, women taking Imatinib should not breastfeed.

Women of child-bearing potential, pregnancy, breastfeeding and fertility women of child-bearing potential: Women of child-bearing potential must be advised to use highly effective contraception during treatment. Highly effective contraception is a method of birth control which results in a low failure rate (i.e. less than 1% per year), when used consistently and correctly.
Fertility: Male patients concerned about their fertility on Imatinib treatment should consult with their physician.
Use in pregnancy: Imatinib should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.
Use in breastfeeding: Both Imatinib and its active metabolite can be distributed into human milk. Since the effects of low-dose exposure of the infant to Imatinib are unknown, women taking Imatinib should not breastfeed.

See Tables 2a and 2b.


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Observed interactions resulting in a concomitant use not recommended.
Drugs that may decrease Imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity could increase metabolism and decrease Imatinib plasma concentration. Co-medications which induce CYP3A4 (e.g. Dexamethasone, Phenytoin, Carbamazepine, Rifampicin, Phenobarbital or Hypericum Perforatum also known as St. John’s Wort) may significantly reduce exposure to Imatinib. In patients where Rifampin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered.
Other interactions that may effect exposure to Imatinib or other drugs.
Drugs that may increased Imatinib plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g Ketoconazole, Itraconazole, Erythromycin, Clarythromycin) could decrease metabolism and increase Imatinib concentrations. Caution should be taken when administering Imatinib with inhibitors of the CYP3A4 family.
Drug that may have their plasma concentration altered by Imatinib: Imatinib increases the mean Cmax and AUC of Simvastatin (CYP3A4 substrate), indicating an inhibition of the CYP3A4 by Imatinib. Therefore, caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. Cyclosporin or Pimozide). Imatinib may increase plasma concentration of other CYP3A4 metabolized drugs (e.g.Triazolo-Benzodiazepines, Dihydropyridine Calcium Channel Blockers, certain HMG-CoA Reductase Inhibitors, i.e. Statins, etc.).
Imatinib also inhibits CYP2C9 and CYP2C19 activity.

Do not store above 30°C.
Store in the original package in order to protect from moisture.

Targeted Cancer Therapy

L01EA01 - imatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.

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