Apo-Gefitinib Overdosage

A limited number of patients were treated with daily doses of up to 1000 mg in phase I clinical trials. An increase in frequency and severity of some adverse reactions was observed, mainly diarrhoea and skin rash.
In one study, a limited number of patients were treated weekly with doses from 1500 mg to 3500 mg (17 patients total / 3 to 4 patients per cohort) and twice weekly with doses from 1500 mg to 2000 mg (6 patients total / 3 patients per cohort). In this study, gefitinib exposure (mean C_max) was approximately 3- to 4-fold that observed on multiple dosing of the therapeutic dose (i.e. 250 mg daily).
The mean QTcB appeared to increase approximately 10 msec at 3 hours postdose in 17 subjects receiving weekly doses of gefitinib tablets. The study was not designed as a 'thorough QTc' study and the QTc data should be approached with caution. No QTcB ≥500 msec was found during the study.
Adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of gefitinib. The frequency of some AEs, namely nausea, diarrhoea, vomiting, and fatigue appeared to have increased, however the patients enrolled in this study were end stage cancer patients with multiple confounding co-morbidities. Two out of the 6 patients in the twice weekly cohorts (one subject in Cohort 6 on 1500 mg twice weekly; the other in Cohort 7 on 2000 mg twice weekly) developed grade 3 total bilirubin increases however these were not reported as adverse events. Both of these patients had pre-existing liver metastases before start of treatment with gefitinib.
There is no specific treatment in the event of overdose of APO-GEFITINIB. Adverse reactions associated with overdose should be treated symptomatically; in particular, severe diarrhoea should be managed as clinically indicated.
In non-clinical studies, the median lethal oral dose in rats was 2000 mg/kg (approximately 400 times the clinically recommended daily dose in humans on a mg/kg basis). The median lethal oral dose in mice was found to be in excess of 2000 mg/kg.
For management of a suspected drug overdose, seek medical help immediately.