Agomelatine Drug Utilisation Study in Selected European Countries: A Multinational, Observational Study to Assess Effectiveness of Risk-Minimisation Measures

Abstract

Background Hepatotoxic reactions are an important identified risk listed in the agomelatine risk management plan. This postauthorisation safety study evaluated the effectiveness of additional risk-minimisation measures (aRMMs) for agomelatine. Objective The objective of this study was to evaluate, among physicians prescribing agomelatine and their patients, liver function monitoring adherence, compliance with contraindications and patients' reasons for non-compliance with liver monitoring. Methods A non-interventional cohort study was conducted among adults initiating agomelatine in routine clinical practice in Denmark, France, Germany and Spain through a retrospective medical record abstraction (MRA) before and after implementation of aRMMs and a cross-sectional patient survey. Results Fifty-four sites contributed data on 437 and 404 patients in the before-and after-RMM periods, and 237 patients completed the survey. No patient had cirrhosis in either study period; 98.2% of patients in the before-and 98.0% in the after-RMM period had no active liver disease reported at initiation or during treatment. Compliance to contraindicated medications was > 99% in both periods. The adherence to the liver-monitoring regimen was similar in both periods (15.1% before RMM and 16.3% after RMM). In the after-RMM period, 25.2% of patients had a liver test before or at treatment initiation; 61.5% had a liver test during treatment. Among patients surveyed who did not have a blood test before treatment initiation or during treatment, the most frequently cited reason was a test ordered but not yet performed. Conclusions The overall adherence to liver-monitoring recommendations remained weakly influenced by aRMMs. However, patients treated with agomelatine are in compliance with relevant contraindications.

Effect of regulatory interventions on agomelatine use in Spain: A multiple intervention time‐series analysis in a nationwide electronic healthcare record database

“…Our results suggest a progressive decrease on the use of agomelatine even before restrictive measures were communicated, in line with the results from the study of Jacquot et al 5 According to this study, contraindications and precautions for use of agomelatine were largely followed even before the updated prescriber guide and dissemination of the patient booklet, potentially indicating that physicians were already aware of the hepatic risk related to agomelatine, and may have already prevent treatment to patients at high risk of hepatic injury or prefer the use of other alternative treatment 5,14 …”

“…The incidence of use after the fourth intervention was 8.1 and 9.2 per 100 000 patients for patients below and above 75 years, respectively. Our results suggest a progressive decrease on the use of agomelatine even before restrictive measures were communicated, in line with the results from the study of Jacquot et al 5 According to this study, contraindications and precautions for use of agomelatine were largely followed even before the updated pre- The progressive decrease in the use of agomelatine did not differ significantly between users below and above 75 years of age, despite the warning to restrict the use in patients aged ≥75 was put in place in 2013 and communicated in several occasions. Factors, such as higher cost, additional burden for the patient, and time spent in clinical practice by healthcare professionals with liver monitoring, might explain the steep downward trend starting before interventions took place masking the impact of specific regulatory actions.…”

“…Updated physicians' guides were also distributed in the EU 4 . In 2014, suboptimal adherence to liver monitoring at initiation and during treatment was observed in a prospective observational cohort study 5 . Based on these results and other post‐marketing data, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested additional RMMs.…”

“…4 In 2014, suboptimal adherence to liver monitoring at initiation and during treatment was observed in a prospective observational cohort study. 5 Based on these results and other post-marketing data, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested additional RMMs. The message regarding precautions of use in patients with risk factors for hepatic injury was reinforced and the prescriber guide was then distributed 6 monthly along with a patient booklet for patients.…”

“…scriber guide and dissemination of the patient booklet, potentially indicating that physicians were already aware of the hepatic risk related to agomelatine, and may have already prevent treatment to patients at high risk of hepatic injury or prefer the use of other alternative treatment 5. Quarterly cumulative incidence of agomelatine use per 100,000 according to age.…”