Comparison of Adverse Drug Reactions for Patients Treated with Tyrosine Kinase Inhibitors: Data Mining of the Public Version of the FDA Adverse Event Reporting System (AERS)

Abstract

Abstract 1698 Backgrounds:The consecutive approvals of tyrosine kinase inhibitors (TKIs) have been changing the landscape of treatment strategy for patients with chronic myeloid leukemia (CML). Currently, three TKIs are available worldwide, including imatinib (Glivec/Gleevec; Novartis Pharmaceuticals, East hanover, NJ), nilotinib (Tasigna; Novartis Pharmaceuticals) and dasatinib (Sprycel; Bristol-Myers Squibb, Princeton, NJ). Although second generation TKIs (nilotinib and dasatinib) have shown their efficacy and safety in recent clinical trials, additional data are needed for better understanding and differences in their safety profiles may be helpful when choosing a TKI. We compared the adverse drug reactions (ADRs) for patients treated with three TKIs using spontaneous adverse event reporting after approval to investigate the characteristics of safety profiles. Method:To compare adverse events characteristics among three TKIs, the case/noncase adverse events reports associated with TKIs use were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (AERS) between 2004 and 2010. We calculated the reporting odds ratio (ROR), which is known as one of data mining algorithms for signal detection techniques of ADRs, characterized by providing a fast and cost-efficient way of detecting possible ADR signals. All events in the AERS have been coded for data entry in accordance with the standardized terminology, known as Preferred Terms, in the Medical Dictionary for Regulatory Activities. The ROR is similar to the idea of odds ratio, calculating the odds of exposure of the suspected drug in patients who had events divided by the odds of exposure of the suspected drug in those without events. The ROR -1.96 standard error greater than 1 with at least 4 ADR reports was used as a signal criterion in this study. Results:We identified 18,979 ADRs for imatinib, 5,388 ADRs for nilotinib, and 2,482 ADRs for dasatinib. The number of ADRs flagged by our signal criterion was 91 for imatinib, 82 for nilotinib, and 109 for dasatinib. Top 10 lists of ADRs with higher ROR are shown in Table for each TKI. The safety profiles were almost different among TKIs. ADRs related to skin and hepatic function were noted for imatinib, whereas ADRs related to cardiac events were prominent for nilotinib, and ADRs related to lymphocytosis, edema and effusion were noticeable for dasatinib. The different dosing requirements of dasatinib and nilotinib may be an additional factor of ADRs.Table:Top 10 Lists of ADRs for TKIs, Imatinib, Nilotinib and DasatinibType of ADRs ranked by RORRORReported Number of Pts with ADRsImatinibImatinibNilotinibDasatinibImatinibNilotinibDasatinibTotal1HEPATITIS14.80.00.024252AMNESIA11.70.00.6191203INTERNATIONAL NORMALISED RATIO INCREASED9.90.30.0161174LICHEN PLANUS9.20.00.015165HEPATIC CIRRHOSIS8.60.30.0141156CHOLESTASIS8.00.00.9131147RASH MACULAR8.00.00.013148HIP ARTHROPLASTY7.40.40.0121139INJURY6.80.01.01111210DERMATITIS BULLOUS6.80.40.011112NilotinibImatinibNilotinibDasatinibImatinibNilotinibDasatinibTotal1CORONARY ARTERY STENOSIS0.141.30.24441492ARTERIAL STENT INSERTION0.137.50.01893HEPATITIS VIRAL0.137.50.01894INTERMITTENT CLAUDICATION0.137.50.01895LABELLED DRUG-FOOD INTERACTION MEDICATION ERROR0.032.80.00786CORONARY ARTERY BYPASS0.125.00.62161197ANGINA UNSTABLE0.123.50.01568DRUG ADMINISTRATION ERROR0.023.52.305169ELECTROCARDIOGRAM ST SEGMENT DEPRESSION0.218.80.03121510TROPONIN T INCREASED0.118.81.318110DasatinibImatinibNilotinibDasatinibImatinibNilotinibDasatinibTotal1LYMPHOCYTOSIS0.20.045.428102ACUTE PULMONARY OEDEMA0.20.59.5315113PLEURAL EFFUSION0.40.77.4130471403544OVERDOSE0.40.07.155135FULL BLOOD COUNT DECREASED1.00.06.85386PULMONARY EMBOLISM0.60.86.713410277ACUTE FEBRILE NEUTROPHILIC DERMATOSIS0.80.65.751398COLITIS1.00.05.2105169MIGRAINE0.41.65.26451610PULMONARY HAEMORRHAGE0.70.05.07413 Conclusions:ADRs reported in the AERS for each TKI were relatively consistent with known characteristics of ADRs reported in previous clinical trials. Our information would be supportive data for choosing a TKI for CML patients based on comorbidities and drug safety profiles. The choice of therapy in a given patient with CML may depend on age, past history and comorbidities as well as disease risk score and mutational analysis. Disclosures:Oshima:Sanofi Aventis: Employment.