Accidental and Intentional Overdose of Imatinib: a Report of Outcome and Side Effect of 46 Cases.

In the initial phase I trials maximum tolerated dose with imatinib was not reached. However based on the clinical results, imatinib at doses of 400 mg to 800 mg has been registered for the treatment of various malignancies such as adult and paediatric patients (pts) with newly diagnosed chronic myeloid leukaemia (CML) or CML in blast crisis, accelerated phase, or in chronic phase after IFN-failure, adult pts with Ph+ acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, systemic mastocytosis, hypereosinophilic syndrome, malignant gastrointestinal stromal tumours or dermatofibrosarcoma protuberans. Using the recommended doses of 400 to 800 mg for adults and 340 mg/m² of body surface area for children, a number of hematological and non-hematological side-effects with imatinib have been reported which are more common with higher doses and easily manageable. Clinical experience with dose of imatinib higher than that recommended is limited. There are isolated cases of overdose reported in the literature. Suicidal attempt or accidental overdoses are the main causes of overdose. The management of theses cases is proposed based on this preliminary report.

A cumulative search of the Novartis ARGUS safety database was performed with a cut off date of April 2008 and revealed 125 cases of overdose, out of which 30 cases had minimal information, another 25 cases were determined to be therapeutic or prescribed doses and 26 cases were overdose related to concomitant drugs known to increase the plasma concentration. Out off the 46 cases selected for this analysis, 38 were spontaneous reports, 5 were clinical trial reports, 2 were literature reports and 1 a personal case (Dr F Millot).

Four subcategories of overdose are described: accidental overdose adults cases (n=22) (In 21 reports overdose was due to intake of 400 mg instead of 100 mg).; intentional overdose adult's cases (n=11); unknown type of overdose adults cases (n=6) and accidental overdose paediatric cases n=7). Adult overdose side effect :1,200 to 1,600 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; 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. The literature reported one pt who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases after the absorption of 6,400 mg (single dose). Other pts took 8 to 10 g (single dose): vomiting and gastrointestinal pain have been reported. Attempts of suicide was the reason for overdose for 11 pts with doses ranging from 800 mg to 10 000 mg; the outcome was satisfactory for all pts. One 20 year old girl attempted suicide with the absorption of 2.4 grams. Plasma concentration was monitored several days with a maximum concentration of 2381 ng/ml. Imatinib was then resumed at 400 mg. In 6 cases the reason for taking overdose was unknown: 5 cases took 1600 mg (in all these cases pts mistook 400 mg in place of 100 mg 4 time per day), I additional case was a 14 year old girl who adsorbed 4 grams without effect. The final set of pts is paediatric cases (n=7). 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 dose experienced decreased white blood cell count and diarrhea.

With the limited experience available following overdose of imatinib, most of the pts had complete recovery. Even with dose up to 10 grams the outcome was good. In the event of overdose, pts should be closely observed and appropriate symptomatic care administered. Suicide risk assessment should be performed. In addition to clinical support, monitoring with frequent blood counts, renal and liver function measurements should be performed. Intravenous fluids to maintain hydration and imatinib plasma monitoring might be considered, if available. Based on these reports there is no need for hematopoietic growth factors.

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