Imatero

Imatero

imatinib

Manufacturer:

Amarox
Full Prescribing Info
Contents
Imatinib.
Description
IMATERO Film coated tablet 100 mg, each film coated tablet contains: Imatinib mesilate equivalent to Imatinib 100 mg.
IMATERO Film coated tablet 400 mg, each film coated tablet contains: Imatinib mesilate equivalent to Imatinib 400 mg.
Action
Pharmacotherapeutic group: Protein-tyrosine kinase inhibitor.
Pharmacology: Mechanism of action: Mechanism of action Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine 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.
Pharmacodynamic: Imatinib is a protein-tyrosine kinase inhibitor, which potently inhibits the breakpoint cluster region-Abelson (Bcr-Abl) tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGFR, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. Constitutive activation of the PDGFR receptor or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of myelodysplastic/myeloproliferative (MDS/MPD), hypereosinophilic syndrome/chronic eosinophilic leukaemia (HES/CEL) and dermatofibrosarcoma protuberans (DFSP). In addition, constitutive activation of c-Kit or the PDGFR has been implicated in the pathogenesis of systemic mastocytosis (SM). Imatinib inhibits signalling and proliferation of cell driven by dysregulated PDGFR and Abl kinase activity.
Organ function impairment: Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The free drug clearance of Imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represent only a minor elimination pathway for Imatinib (see DOSAGE & ADMINISTRATION, PRECAUTIONS).
Pharmacokinetics: This study was an open label, balanced, randomized, two treatment, two period, two sequence, crossover, single oral dose, bioequivalence study in healthy, adult, human male subjects under fed conditions. The study was conducted following an oral administration of one tablet 400 mg of the Test Product or one tablet 400 mg of the Reference Product.
Based on the pharmacokinetic parameters of Imatinib (N = 35), mean ± SD for Test Product and Reference Product showed: Tmax values were 3.000 (1.500 - 6.017) and 3.667 (2.000 - 8.000) hours, respectively; Cmax values were 1863.516 ± 597.8907 and 1877.598 ± 624.9066 ng/mL, respectively; AUC0-t values were 35209.652 ± 11864.6972 and 34795.946 ± 12311.5359 ng.h/mL, respectively; AUC0-∞ values were 36877.054 ± 12685.6667 and 36499.566 ± 13134.5348 ng.h/mL, respectively; λz values were 0.046 ± 0.0088 and 0.047 ± 0.0083 l/h, respectively; t1/2 values were 15.639 (3.0747) and 15.091 ± 3.0018 hours, respectively; AUC_%Extrap_obs values were 4.358 ± 3.5698 and 4.466 ± 3.3739 %, respectively.
Results from bioequivalence study for Test Product and Reference Product were as following: 90.00% Confidence Intervals of geometric means ratio of the two bioavailability parameters of Imatinib were 93.67 - 105.41% for Cmax, 97.15 - 107.33% for AUC0-t, and 97.09 - 107.14% for AUC0-∞.
Conclusion: These results showed that 400 mg Imatinib film coated tablet was bioequivalent to the reference product.
Indications/Uses
IMATERO is indicated for the: Treatment of patients with newly diagnosed Philadelphia chromosome (Bcr-abl) positive (Ph+) chronic myeloid leukaemia (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 leukaemia (Ph+ ALL) integrated with chemotherapy.
Treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
Treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
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 IMATERO is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in SM, HES/CEL. Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML.
Dosage/Direction for Use
Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate.
The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances. Doses of 400 mg 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 IMATERO therapy in Ph+ CML patients should be performed routinely and when therapy is modified, to identity suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.
General target population: Dosage in CML: The recommended dosage of IMATERO is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis.
Dose increases from 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or form 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-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: Disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response.
Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.
Dosage in Ph+ ALL: The recommended dose of IMATERO is 600 mg/day for adult patients with Ph+ ALL.
Dosage in MDS/MPD: The recommended dose of IMATERO is 400 mg/day for adult patients with MDS/MPD.
Dosage in SM: The recommended dose of IMATERO is 400 mg/day for adult patients with SM without the D816V c-Kit mutation or mutational status unknown or not responding satisfactorily to other therapies.
For patients with SM associated with eosinophilia, a clonal haematological 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 IMATERO 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 patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Dosage in DFSP: The recommended dose of IMATERO is 800 mg/day for adult patients with DFSP.
Dose adjustments for adverse drug reactions: Non haematological adverse reactions: If a severe non-haematological adverse reaction develops with IMATERO 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, IMATERO should withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with IMATERO may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 mg to 300 mg or from 600 mg to 400 mg, or from 800 mg to 600 mg.
Haematological adverse reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table as follows. (See table.)


Click on icon to see table/diagram/image


Special populations: Children: There is no experience with the use of IMATERO in children with Ph+ ALL below 1 year of age. There is very limited to no experience with the use of IMATERO in children in other indications.
Dosing in children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase Ph+ ALL (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose in Ph+ ALL.
Hepatic insufficiency: Imatinib is mainly metabolised 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 (see PRECAUTIONS).
Renal insufficiency: Imatinib and its metabolites are not significantly excreted via the kidney. Since the renal clearance of Imatinib 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. Patients with severe renal dysfunction or on dialysis could also start at the same dose of 400 mg. However, in these patients caution is recommended. The dose can be reduced if not tolerated, or increased for lack of efficacy (see PRECAUTIONS).
Elderly patients: No specific dose recommendation is necessary in older people.
Overdosage
Experience with higher than therapeutic dose is limited. Isolated cases of Imatinib overdosage have been reported spontaneously. Generally the reported outcome in these cases was improvement or recovery. In the event of overdosage the patient should be observed and appropriate symptomatic treatment should be given.
Events that have been reported at different dose ranges are as follows: Adult overdose: 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash. Erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase (CPK), increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): Nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases.
8 to 10 g (single dose): Vomiting and gastrointestinal pain.
Pediatric overdose: One 3 year-old male exposes to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia and another 3 year old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhea.
Contraindications
Use in patients with a hypersensitivity to the active substance or to any of the excipients is contraindicated.
Special Precautions
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 a potential for drug interactions.
Hypothyroidism: Cases of 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 (see DOSAGE & ADMINISTRATION, ADVERSE REACTIONS).
When Imatinib is combined with high dose chemotherapy regimens, transient 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 in circumstances where Imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see DOSAGE & ADMINISTRATION, ADVERSE REACTIONS).
Fluid retention: Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) can occur in newly diagnosed CML patients taking Imatinib. An unexpected rapid weight gain should be carefully investigated and if necessary, appropriate supportive care and therapeutic measures should be undertaken. Increased incidence of these events in elderly patients and those with a prior history of cardiac disease can occur.
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.
Tumour lysis syndrome: Cases of tumour lysis syndrome (TLS) have been reported in patients treated with Imatinib. Due to possible occurrence of TLS, correction of significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Imatinib (see ADVERSE REACTIONS).
Laboratory tests: 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 may be reduced, as recommended in DOSAGE & ADMINISTRATION.
Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving Imatinib. As recommended dose in DOSAGE & ADMINISTRATION, non-haematological adverse drug reactions, these laboratory abnormalities should be managed with interruption and/or 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/minute) and severe (CrCL: < 20 mL/minute) renal impairment. However, as recommended in DOSAGE & ADMINISTRATION, the starting dose of Imatinib can be reduced if not tolerated.
Effects on ability to drive and use machines: Reports of motor vehicle accidents have been received in patients receiving Imatinib. 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 machinery.
Use in Children & Adolescents: There can be occur 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 (see ADVERSE REACTIONS).
Use In Pregnancy & Lactation
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.
Pregnancy: There are no clinical trials on the use of Imatinib in pregnant women. There can be occur of spontaneous abortions and infant congenital anomalies from women who have taken 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.
Breast-feeding: Both Imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio 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 of 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 taking Imatinib should not breast feed.
Fertility: Male patients concerned about their fertility on Imatinib treatment should consult with their physician.
Adverse Reactions
Adverse reactions for CML: Infections and infestations: Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis and fungal infection.
Blood and lymphatic system disorders: Neutropenia, thrombocytopenia, anaemia, pancytopenia, febrile neutropenia, thrombocytopenia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy, haemolytic anaemia.
Metabolism and nutrition disorder: Anorexia, hypokalemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricemia, hypercalcaemia, hyperglycaemia, hypernatremia, hyperkalaemia, hypomagnesaemia.
Psychiatric disorders: Insomnia, depression, libido decreased, anxiety and confusional state.
Nervous system disorders: Dizziness, paraesthesia, taste disturbance, hypoaesthesia, migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage, increased intracranial pressure, convulsions, optic neuritis.
Eye disorders: Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision, eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema, cataract, glaucoma, papilloedema.
Ear and labyrinth disorders: Vertigo, tinnitus, hearing loss.
Cardiac disorders: Palpitations, tachycardia, cardiac failure congestive2, pulmonary oedema, arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.
Vascular disorders3: Flushing, haemorrhage, hypertension, haematoma, subdural hematoma, peripheral coldness, hypotension, Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, epistaxis, cough, pleural effusion4, pharyngolaryngeal pain, pharyngitis, pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage.
Gastrointestinal disorders: Nausea, diarrhoea, vomiting, dyspepsia, flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis, stomatitis, mouth ulceration, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis, colitis, inflammatory bowel disease, ileus.
Hepatobiliary disorders: Increased hepatic enzymes, hyperbilirubinemia, hepatitis, jaundice, hepatic failure6, hepatic necrosis6.
Skin and subcutaneous tissue disorders: Periorbital oedema, dermatitis/eczema/rash, pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruption, acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-johnson syndrome, acute generalised exanthematous pustulosis (AGEP).
Musculoskeletal and connective tissue disorders: Muscle spasm and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain5, joint swelling, joint and muscle stiffness, muscular weakness, arthritis.
Renal and urinary disorders: Renal pain, haematuria, renal failure acute, urinary frequency increased.
Reproductive system and breast disorders: Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema.
General disorders and administration site conditions: Fluid retention and oedema, fatigue, weakness, pyrexia, anasarca, chills, rigors, chest pain, malaise.
Investigations: Weight increased, weight decreased, blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased, blood amylase increased.
Note: 1 Pneumonia was reported in patients with transformed CML.
2 Cardiac events including congestive heart failure were observed in patients with transformed CML than in patients with chronic CML.
3 Bleeding (haematoma, haemorrhage) was reported in patients with transformed CML (CML-AP and CML-BC).
4 Pleural effusion can be occur in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.
5 Musculoskeletal pain and related events can be occur in patients with CML.
6 Some fatal cases of hepatic failure and hepatic necrosis can be occur.
Description of selected adverse drug reactions: Myelosuppression: Myelosuppression is reported in cancer patients treated with Imatinib. Myelosuppression, thrombocytopenia, neutropenia and anemia were reported grade 3 and 4 laboratory abnormalities. Overall, the myelosuppression experienced with Imatinib in CML patient was generally reversible and in most patients did not result in dose interruption or doe reduction. Few patients required drug discontinuation. Other events of pancytopenia, lymphopenia and bone marrow depression have also been reported.
Hematologic depression appeared greatest at the highest doses and also appeared to the dependent on stage of CML disease, with grade 3 or 4 neutropenia and thrombocytopenia between 4 and 6 times higher in blast and accelerated phase as compared to newly diagnosed patients in CP CML.
These events can usually be managed with either a reduction of the dose or an interruption of treatment with Imatinib, but require discontinuation. The incidence of hematologic toxicities is less in patients with solid tumors than in patients with Ph+ leukemias, with Grade ¾ neutropenia and thrombocytopenia occurring approximately 10% and 1% respectively.
Hemorrhage: CNS and GI hemorrhages are not uncommon in CML patients with compromised marrow function at baseline. Hemorrhages are well-recognized part of the disease complications in an acutely ill population of leukemia patients and may result from thrombocytopenia, or less commonly, platelet dysfunction. However, not all patients experiencing CNS and GI hemorrhages during therapy with Imatinib are thrombocytopenic.
The most common manifestation of clinically significant bleeding was GI haemorrhage, which occurred most commonly in advanced CML patients where bleeding might occur as part of the underlying disease due to tumor bleeding from tumor haemorrhage/tumor necrosis. In first line CML, the observed frequencies of GI haemorrhage were generally the lowest. Gastric antral vascular ectasia (GAVE) is also rarely occur with Imatinib use.
Edema and fluid retention: Edema is a common toxicity of Imatinib appearing in greater than 50% of all patients across all indications. Edema is dose-related and there appears to be a correlation with its occurrence and plasma levels. The most common manifestations is periorbital edema and lower extremity edema. Specific therapy is not usually required. Other fluid retention events occur much less, but due to the location of the anatomic site may be potentially serious. The most frequent fluid retention event was pleural effusion, most commonly observed in advanced CML. The frequency of cardiac failure was generally low in patients with edema and fluid retention. It was higher in advanced CML than in other groups. This could be explained by the worse medical condition of advanced patients. The same trend was observed for renal failure in patients with edema and fluid retention. Most patients with edema and fluid retention were elderly (> 65 years old).
The frequency of events suggesting congestive heart failure was appreciably higher in patients with transformed CML (accelerated phase or blast crisis), higher age or with baseline haemoglobin of less than 8g/dL. Congestive heart failure (CHF) and left ventricular dysfunction have since been continuously monitored in the PSUR.
Skin rashes and severe cutaneous adverse reactions: A generalized erythematous, maculopapular, pruritic skin rash that can fade despite continued therapy, has been reported. Some patients may have pruritus without accompanying rash, and sometimes there is an exfoliative component. Re-exposure in some patients has resulted in reappearance of rash, but not in all patients. These eruptions generally respond to antihistamines and topical steroids. Occasionally, systemic steroids are required.
Skin rashes have been observed in patients treated with Imatinib across all indications. These are frequently pruritic and most commonly appear as erythematous, maculopapular lesions on the forearm, the trunk or the face. Skin biopsies have revealed a toxic drug reaction with a mixed cellular infiltrate. Although most rashes are mild and self limiting, more severe cases may require interruption or discontinuation of treatment.
Hepatotoxicity: Hepatotoxicity, occasionally severe, may occur, and has been observed. LFT abnormalities usually consisted of mild elevations in transaminases, although a minority of patients had elevated levels of bilirubin. Onset is generally within the first two months of therapy, but has occurred as late as 6 to 12 months after commencing therapy. The levels generally normalize after withholding therapy for 1 to 4 weeks.
Hypophosphatemia: Low serum phosphate and hypophosphatemia (up to Grade ¾) can be occur relatively commonly across all indications, however the origin and the significance of this finding have not been established. Imatinib has been shown to inhibit the differentiation of human monocytes into osteoclasts. The decrease was accompanied by a decrease in the resorptive capacity of these cells. A dose-dependent decrease of RANK-L was observed in osteoclasts in the presence of Imatinib. Sustained inhibition of osteoclastic activity may lead to counter regulatory response resulting in increased levels of PTH. The clinical relevance of the preclinical findings is yet unclear and an association with skeletal AEs such as bone fractures has not been demonstrated.
Gastrointestinal obstruction, perforation or ulceration: GI ulceration, which can be occur local irritation by Imatinib, has been occur in a small proportion of patient. Tumor haemorrhage/tumor necrosis, obstruction and GI perforation seem to be disease-related.
Tumor lysis syndrome: A causal relationship between tumor lysis syndrome and Imatinib treatment is deemed possible, although some cases were confounded by concomitant medications and other independent risks (see PRECAUTIONS).
Growth retardation in children: Imatinib appears to affect the stature of children, especially children who are pre-pubertal. A causal relationship between growth retardation in children and Imatinib treatment could not be ruled out although for some cases of growth retardation there was limited information.
Severe respiratory adverse drug reaction: Severe respiratory events, sometimes fatal, have been observed with Imatinib treatment, including acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. Pre-existing cardiac or pulmonary conditions that may be associated with severe respiratory events can be occur.
Drug Interactions
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 concentrations. Co-medications that 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. While taking enzyme-inducing anti epileptic drug (EIAEDs) such as Carbamazepine, Phenytoin, Fosphenytoin, Phenobarbital and Primidone. 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 affect exposure to Imatinib or other drugs.
Drugs that may increase Imatinib plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. Ketoconazole, Itraconazole, Erythromycin, Clarithromycin) could decrease metabolism and increase Imatinib concentrations. Caution should be taken when administering Imatinib with inhibitors of the CYP3A4 family.
Drugs that may have their plasma concentrations altered by Imatinib: Increasing Simvastatin (CYP3A4 substrate) 2- and 3,5-fold, respectively, indicating and inhibition of the CYP3A4 by Imatinib. Therefore, caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. Cyclosporine or Pimozide). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. Triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. Statins, etc).
Imatinib also inhibits the CYP2C9 and CYP2C19. PT prolongation was observed following co-administration with Warfarin. When giving Coumarins, short-term PT monitoring is therefore necessary at the start and end of Imatinib therapy and when altering the dosage. Alternatively, the use of low-molecular weight Heparin should be considered.
Imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity, Imatinib at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated Metoprolol metabolism. Co-administration of Imatinib with CYP2D6 substrates, such as Metoprolol, does not seem to be a risk factor for drug-drug interactions and dose adjustment may not be necessary.
Storage
Store below 30°C.
ATC Classification
L01XE01 - imatinib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
FC tab 100 mg x 6 x 10's. 400 mg x 1 x 10's.
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