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The safety profile of imatinib mesylate (Imachron) in adult and pediatric patients with Ph+ Leukemias is similar.
The differences in the safety profile between Ph+ leukemias and solid tumors are a higher incidence and severity of myelosuppression in Ph+ leukemias, and GI and intra-tumoral hemorrhages in GIST patients and are probably due to disease-related factors. Myelosuppression, GI adverse events, edema, and rashes are common between these two patient populations. Other GI conditions, such as gastrointestinal obstruction, perforation and ulceration, appear to be more indication-specific. Other prominent adverse events that have been observed after exposure to imatinib mesylate (Imachron), and which may be causally related, include hepatotoxicity, acute renal failure, hypophosphatemia, severe respiratory adverse reactions, and tumor lysis syndrome and growth retardation in children.
Depending on severity of events, dose adjustment may be required. In very few cases will the medication have to be discontinued based on ADRs.
Adverse reactions (Table 13 and Table 14) are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports.
Adverse reactions and their frequencies reported in Table 13 are based on the registration studies for CML and GIST. (See Table 13.)
Click on icon to see table/diagram/imageThe following types of ADRs have been reported from post-marketing experience and from additional clinical studies with imatinib mesylate (Imachron). They include spontaneous case reports as well as serious ADRs from smaller or ongoing clinical studies and the expanded access programs. Because these ADRs are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib mesylate (Imachron) exposure. (See Table 14.)
Click on icon to see table/diagram/imageDescription of selected Adverse Drug Reactions: Myelosuppression: Myelosuppression is very common in cancer patients treated with imatinib mesylate (Imachron). Myelosuppression, thrombocytopenia, neutropenia and anemia were the most frequently reported Grade 3 and 4 laboratory abnormalities. Overall, myelosuppression experienced with imatinib mesylate (Imachron) in CML patients was generally reversible and in most patients did not result in dose interruption or dose 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 be dependent on the stage of CML disease, with Grade 3 or 4 neutropenia and thrombocytopenia between 4 and 6 times higher in blast and accelerated phase (44% and 63%, respectively) as compared to newly diagnosed patients in CP CML (16.7% and 8.9%, respectively).
These events can usually be managed with either a dose reduction or interruption imatinib mesylate (Imachron), but they rarely require discontinuation of treatment with imatinib mesylate (Imachron). The incidence of hematologic toxicities is less in patients with solid tumors (i.e. GIST) than in patients with Ph+ leukemias, with Grade 3/4 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 leukemic 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 hemorrhage, which occurred most commonly in advanced CML patients and in metastatic GIST patients, where bleeding might occur as part of the underlying disease due to tumor bleeding from tumor hemorrhage/tumor necrosis. In first line CML and in adjuvant GIST setting, the observed frequencies of GI hemorrhage were generally the lowest. Gastric antral vascular ectasia (GAVE) is also rarely reported with imatinib mesylate (Imachron) use in the post-marketing setting.
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 manifestation is periorbital edema and somewhat less common is lower extremity edema. Specific therapy is not usually required. Other fluid retention events occur much less commonly, 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 and metastatic GIST patients. 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 CML patients. The same trend was observed for renal failure in patients with edema and fluid retention.
In a clinical study, the frequency of events suggesting congestive heart failure was 1.5% on imatinib vs. 1.1% on IFN-alpha in patients with newly-diagnosed CML. The frequency was appreciably higher in patients with transformed CML (accelerated phase or blast crisis), higher age, or with a baseline hemoglobin of less than 8 g/dL. Congestive Heart Failure (CHF) and left ventricular dysfunction have since been continuously monitored in the PSUR. Across all indications a higher frequency of CHF events observed in patients with CML than in patients with GIST might indicate differences of some of these disease-related risk factors. In addition, a recently published special safety analysis of cardiac events within the EORTC study of 942 patients with unresectable or metastatic GIST concluded that imatinib does not induce left ventricular failure in GIST patients where the observed rate was approximately 0.2% while it can be up to 2% in a population with pre-existing cardiac disease.
Skin Rashes and Severe Cutaneous Adverse Reactions: A generalized erythematous, maculopapular, pruritic skin rash has been reported that can fade despite continued therapy. 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 up to one third of patients treated with imatinib across all indications. These are frequently pruritic and most commonly appear as erythematous, maculopapular or exfoliative lesions on the forearm, the trunk or the face or generalized with systemic expression. Skin biopsies have revealed a toxic drug reaction with a mixed cellular infiltrate. Although most rashes are mild and self-limiting more severe rare cases such as Stevens-Johnson toxic epidermal necrolysis, Erythema multiforme or DRESS may require interruption or discontinuation of treatment. Not surprisingly skin reactions were seen at a higher rate than placebo in the adjuvant GIST trial.
Hepatotoxicity: Hepatotoxicity, occasionally severe, may occur, and has been observed preclinically and clinically. 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 3 or 4) has been observed relatively commonly across all indications, however the origin and the clinical 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.
In the clinical development program serum phosphate was not routinely measured in all studies. Although it was initially hypothesized that hypophosphatemia might be dose-dependent, 24 month interpretable results from the Phase III TOPS study designed to investigate dose dependency of safety endpoints in patients with newly diagnosed CML, have shown that Grade 3 or 4 decreased serum phosphate or serum calcium has been experienced by 19.1% vs.15.5% and 5.1% vs. 0.9% of patients receiving 400 mg and 800 mg, respectively.
Gastrointestinal Obstruction, Perforation or Ulceration: GI ulceration, which may represent in extreme cases local irritation by imatinib, has been observed in a small proportion of patients across all indications. Tumor hemorrhage/tumor necrosis, obstruction and GI perforation seem to be disease-related and have occurred exclusively or more frequently amongst GIST patients. In the case of metastatic GIST, tumor necrosis may occur in the context of tumor response, rarely leading to perforation. GI obstruction/ileus occurred most commonly in the GIST population where it may be caused by tumor obstruction from metastatic GIST and in the adjuvant setting by adhesions from previous GI surgery.
Tumor lysis syndrome: A causal relationship between tumor lysis syndrome and imatinib mesylate (Imachron) treatment is deemed possible, although some cases were confounded by concomitant medications and other independent risks (see Precautions).
Growth retardation in children: imatinib mesylate (Imachron) appears to affect the stature of children, especially children who are pre-pubertal. A causal relationship between growth retardation in children and imatinib mesylate (Imachron) treatment could not be ruled out although for some cases of growth retardation in CML there was limited information (see Precautions).
Severe respiratory adverse drug reaction: Severe respiratory events, sometimes fatal, have been observed with imatinib mesylate (Imachron) 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 have been reported in many of these cases.
Laboratory test abnormalities: Hematology: CML-associated cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients. The frequency of Grade 3 or 4 neutropenias (ANC <1.0x109/L) and thrombocytopenias (platelet count <50x109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59 to 64% and 44 to 63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML Grade 4 neutropenia (ANC <0.5x109/L) and thrombocytopenia (platelet count <10x109/L) were observed in 3.6% and <1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a dose reduction or an interruption of treatment with imatinib mesylate (Imachron), but can in rare cases lead to permanent discontinuation of treatment. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy.
In patients with unresectable or metastatic malignant GIST (study B2222), Grade 3 and 4 anemias were reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-tumoral bleeding in at least some of these patients. Grade 3 and 4 neutropenia were seen in 7.5% and 2.7% of patients, respectively, and Grade 3 thrombocytopenia in 0.7% of patients. No patient developed Grade 4 thrombocytopenia. The decreases in WBC and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter.
Biochemistry: Severe elevation of transaminases (<5%) or bilirubin (<1%) has been seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week) of imatinib mesylate (Imachron). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of Grade 3 or 4 SGPT (serum glutamic pyruvic transferase) elevations and 4.8% of Grade 3 or 4 SGOT (serum glutamic oxaloacetic transferase) elevations were observed. Bilirubin elevation was below 3%.There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of which outcome was fatal.
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