Regulatory Safety Learning Driven by the Mechanism of Action: The Case of TNF-α Inhibitors.

The summary of product characteristics (SmPCs) is an important information source that includes the adverse drug reactions (ADRs) associated with the drug. Drugs with the same mechanism of action are expected to have a similar ADR profile and thus a substantial overlap of the described ADRs in the SmPC. The objective of this study is to assess this overlap. We extracted all ADRs (excluding hypersensitivity and administration site reactions) that were described in the first and all subsequent versions of the SmPCs of all approved TNF-α inhibitors in the European Union. The Medical Dictionary for Regulatory Activities was used to characterize the ADRs. At the end of follow-up, 293 unique ADRs (at high level term level) were described in the SmPCs of the 5 TNF-α inhibitors. There was substantial variation in the number of ADRs described in the SmPC among the TNF-α inhibitors. Of the 293 ADRs, 133 (45%) were described in the SmPC of one TNF-α inhibitor and 39 (13%) in the SmPCs of all 5 TNF-α inhibitors. Serious ADRs and ADRs classified as important risks were described approximately four times more often in a second SmPC than ADRs not classified as such. In conclusion, the ADRs described in the SmPCs of the TNF-α inhibitors differ considerably in number and type. In order to adequately inform prescribers and patients, acquired knowledge of the safety profile of drugs with the same mechanism of action should increasingly be taken into account in the assessment of all drugs within the class.

Exploring the Association between Monoclonal Antibodies and Depression and Suicidal Ideation and Behavior: A VigiBase Study.

INTRODUCTION: Several monoclonal antibodies (mAbs) have been linked to neuropsychiatric adverse effects in patients, including depression and suicidal ideation and behavior. OBJECTIVE: The aim of this study was to quantify and characterize spontaneously reported adverse drug reactions (ADRs) of depression and suicidal ideation and behavior related to mAb users, and to explore a possible association with their mechanism of action. METHODS: We included mAb ADRs that were reported in VigiBase, and identified those related to depression and suicidal ideation and behavior. Reporting odds ratios (RORs) were estimated for each mAb (bevacizumab as the reference) and according to their influence on the immune system (not directly targeting [reference], stimulating, or suppressing). Those suppressing the immune system were further divided into their intended indication (auto-immune diseases, cancer). RESULTS: Overall, 2,924,319 ADRs for 44 mAbs were included; 9455 ADRs were related to depression and 1770 were related to suicidal ideation and behavior. The association was strongest for natalizumab and belimumab, both for depression (ROR 5.7, 95% confidence interval [CI] 5.0-6.4; and ROR 5.1, 95% CI 4.2-6.2) and suicidal ideation and behavior (ROR 12.0, 95% CI 7.9-18.3; and ROR 20.2, 95% CI 12.4-33.0). Those suppressing the immune system showed higher ROR, i.e. 1.9 (95% CI 1.8-2.0) for depression and 3.6 (95% CI 3.0-4.4) for suicidal ideation and behavior. This finding was only seen for mAbs used for treating autoimmune diseases. CONCLUSION: Depression and suicidal ideation and behavior are seen in patients using mAbs, particularly mAbs used for treating autoimmune diseases that suppress the immune system. For interpretation of these data, the indications for use and other characteristics require further consideration.

Post-marketing dosing changes in the label of biologicals.

AIM: The aim of this study was to evaluate post-marketing label changes in dosing information of biologicals. METHODS: Biologicals authorized between 2007 and 2014 by the European Medicines Agency (EMA) were included and followed up from marketing authorization until 31 December 2016 or date of withdrawal of the marketing authorization. The primary outcome of the study was defined as label change in dosing information for the initially approved indication. Incidence of changes, type of change and mean time to change were assessed. As a secondary outcome, label changes in dosing information for extended indications were assessed. RESULTS: A total of 71 biologicals were included. Dosing information in the label changed for the initial indication during follow-up for eight products (11%). In one of the eight products the change concerned an increase in dose. Also, a change in dosing frequency was identified in three products, for one product a recommendation was added that therapy could be initiated with or without a loading dose, and for one product the minimum dose was removed and a maximum dose was added. For the remaining product the dose was decreased due to safety issues. For 30 products (42%) the indication was extended at least once. No changes in dosing information were observed for the extended indications (n = 59) during follow-up. CONCLUSIONS: This study showed that in 11% of the biologicals, the dosing for the initial indication in the label was changed. In contrast to small molecules, the dose was rarely reduced for safety reasons.

Predicting rehospitalization in patients treated with antipsychotics: a prospective observational study.

BACKGROUND: Prediction of rehospitalization in patients treated with antipsychotics is important for identifying patients in need of additional support to prevent hospitalization. Our aim was to identify factors that predict rehospitalization in patients treated with antipsychotics at discharge from a psychiatric hospital. METHODS: Adult patients suffering from schizophrenia, psychotic or bipolar I disorders who had been hospitalized in a psychiatric hospital for ⩾7 days and were treated with oral antipsychotics at discharge were included. The main outcome was rehospitalization within 6 months after discharge. A prediction model for rehospitalization was constructed including: patient/disease and medication characteristics, patients' beliefs about medicines, and healthcare-professional-rated assessment for all patients. The patients were stratified by diagnosis (schizophrenia and nonschizophrenia). Area under the receiver operating characteristic curve (AUCROC) was also assessed. RESULTS: A total of 87 patients were included and 33.3% of them were rehospitalized within 6 months after discharge. The variables that predicted rehospitalization were duration of hospitalization, patients' attitude towards medicine use, and healthcare-professional-rated assessment with an AUCROC of 0.82. Rehospitalization for patients with schizophrenia could be predicted (AUCROC = 0.71) by the Global Assessment of Functioning score, age, and harm score. Rehospitalization was predicted (AUCROC = 0.73) for nonschizophrenia patients with, for example rehospitalization predicted by the nurse. CONCLUSIONS: Rehospitalization was predicted by a combination of variables from the patient/disease and medication characteristics, patients' attitude towards medicine use, and healthcare-professional-rated assessment. These variables can be assessed relatively easily at discharge to predict rehospitalization within 6 months.