se reactions according to the FDA Prescribing Information include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, Tandutinib MLN518 diarrhea, asthenia, fever, dizziness, abnormal coordination, viral infection, amnesia, and insomnia.5 Under postmarketing experience, the FDA PI mentions that cases of hepatotoxicity have been reported, including elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.5 The purpose of this report is to present a case of severe sustained cholestatic hepatitis following TZM treatment and to present a review of cases reported to the FDA Adverse Event Reporting System. Methods Patient data were collected in the Center for Pharmacovigilance Berlin Case Control Surveillance Study of Serious Rare Diseases with Possible Drug Etiology, which is supported by the Federal Institute for Drugs and Medical Devices in Germany.
The aim of PVZ FAKOS is to generate signals of rare adverse drug reactions in the postmarketing period. A detailed methodology of the project can be found elsewhere.6 Our analysis of the AERS database of the FDA comprised the period between the first quarter of 2007 and the last quarter of 2010. The first search criteria were the names of TZM containing drugs: Temozolomide, Temodal, Temodar, and Temozomide. We used the TZM drugs labeled primary suspect. TZM drugs specified as secondary suspect or concomitant were not considered in our analysis. The second search criteria were adverse events listed as preferred terms in the Medical Dictionary for Regulatory Activities.
Reports containing the following terms were analyzed: hepatic failure, acute hepatic failure, hepatitis, hepatitis acute, hepatitis fulminant, hepatic function abnormal, hepatic encephalopathy, hepatotoxicity, hepatitis cholestatic, cholestatic hepatitis, cholestasis, hepatic steatosis, hepatic enzyme increased, hepatic necrosis, cholelithiasis, hepatic lesion, liver disorder, liver injury, jaundice, hepatic injury, cholestatic liver injury, and jaundice cholestatic. Multiple reports of the same adverse event were identified and consolidated by linking the Individual Safety Report code, unique for every single report, with a case report code, unique for every single case of adverse event. Case Report A 51 year old male came to the emergency room in mid July 2008 because of impaired vision to the left side, gait disturbance, and right sided temporal headache.
The patient reported that he had noticed the first symptoms a couple of days ago. Ophthalmologic examination revealed homonymous hemianopsia to the left side. Magnetic resonance tomography demonstrated a right occipital lesion suspect of a malignant brain tumor. Serum level of aspartate aminotransferase was normal. After tumor resection, histological examination of the tumor confirmed the diagnosis of GBM. Immediately after the surgery, therapy was initiated consisting of dexamethasone for prevention of brain edema, pantoprazole for prevention of gastroduodenal ulcer, and paracetamol for postoperative pain. By the end of July, the patient was discharged from the hospital, and paracetamol was discontinued. In mid August 2008, fractionated radiotherapy with concomitant TZM was initiated. The radiochemotherapy regimen was completed by