What is the change and variation in prescribing following a regulatory safety warning on mirabegron?

Problem

Safety issues detected after marketing of medications can trigger regulatory action such as direct healthcare professional communications (DHPC) warning of new adverse effects or contraindications. Mirabegron, for treatment of overactive bladder (OAB), was subject to European Medicines Agency DHPC in September 2015. This informed healthcare professionals of updates to mirabegron’s product licence, contraindicating its use in severe uncontrolled hypertension and cautioning with elevated blood pressure (diastolic ≥160mmHg or systolic ≥100mmHg). DHPCs can be effective in changing prescribing behaviour, however the extent to which prescribers vary in their response to DHPCs is unknown. Therefore this study aims to evaluate changes in prescribing and variation in prescribing among GP practices following a DHPC on mirabegron’s safety.

Approach

This is an interrupted time series study of English GP practices from 2014-2017. The Health and Social Care Information Centre provided monthly statistics on aggregate practice-level prescribing and available practice characteristics included practice staff and registered patient profiles, Quality & Outcomes Framework indicator performance, and index of multiple deprivation of the practice area. The outcome was monthly mirabegron items as a proportion of all OAB drug items. Between-practice variation in prescribing before and after the September 2015 DHPC was assessed using the systematic component of variation (SCV). Multilevel segmented regression with random effects quantified the change in level and trend of prescribing after the DHPC, and practice characteristics were assessed for their association with a reduction in prescribing.

Findings

This study included 7,408 practices. Before the DHPC, 87.6% of practices prescribed mirabegron in August 2015 and mirabegron composed a mean of 7.9% (SD 6.66) of OAB items. Variation between practices was classified as very high and mean SCV did not change significantly in the 6 months after the September 2015 DHPC (12.4) compared to before (11.6). Before the DHPC, there was a monthly trend of 0.294 (95%CI, 0.287, 0.301) percentage points increase. There was no significant change immediately after the DHPC (0.0157, 95%CI -0.079, 0.111) however there was a significant reduction in trend (-0.038, 95%CI -0.051, -0.025). Deprivation of the practice area, lower proportion of older patients, and fewer registered patients were associated with a practice having a significant decrease in level of mirabegron prescribing immediately post-DHPC.

Consequences

Variation in mirabegron prescribing was high and this did not change significantly following a DHPC. There was no immediate prescribing change post-DHPC, although the monthly growth in mirabegron items did slow. For practices with older patient populations, reluctance to switch to alternative OAB drugs, which have anticholinergic effects, may have contributed to continued mirabegron prescribing. Knowledge of variation in and the determinants of response to regulatory safety communications may allow for those that do not change prescribing to be provided with tailored information and supports to promote safe medication use.