Impact of European Union Label Changes for Fluoroquinolone-Containing Medicinal Products for Systemic and Inhalation Use: Post-Referral Prescribing Trends

Abstract

Introduction: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018-2019 had an impact on fluoroquinolone prescribing rates.

Methods: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC).

Results: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC - 33.3%, 95% confidence interval [CI] - 35.9 to - 30.7; Germany: February/May 2019, MPC - 12.6%, 95% CI - 13.7 to - 11.6]; UK: January/April 2016, MPC - 4.9%, 95% CI - 6.2 to - 3.6).

Conclusion: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care.

Fig. 1

Schematic depiction ascertainment of treatment episodes. A gap of more than 30 days between prescriptions signalled the end of the treatment episode (Case A). If the interval between fluoroquinolone prescriptions was ≤ 30 days (Case B), these will be considered the same treatment episode and attributed to the first fluoroquinolone type prescribed (drug A in this case). As the choice of 30 days was somewhat arbitrary, sensitivity analysis was conducted by varying the look-back window to 60, 90 and 180 days. The exact period to determine an incident prescription depends on the average duration of treatment, and the average fluoroquinolone treatment duration depends on the indication. Durations may vary from 3 days for acute uncomplicated cystitis, up to 4–6 weeks for osteomyelitis; on average, treatment duration is between 7 and 14 days

Fig. 2

Incidence rate of all fluoroquinolone use with segmented regression for Belgium. The grey shaded interval represents the SmPC implementation period for the fluoroquinolone warnings (24 February 2019–17 April 2020) and the associated DHPC (1 April 2019) [blue line]. SmPC summary of product characteristics, DHPC direct healthcare professional communication

Fig. 3

Incidence rate of all fluoroquinolone use with segmented regression for France. The grey shaded interval represents the SmPC implementation dates for the fluoroquinolone warnings (2 August 2019–28 May 2020) and the associated DHPC date (10 April 2019) [blue line]. Although several dates were reported for the SmPC implementations in France (see Table 1 for the exact dates), the graph shows the interval between the first and last dates. SmPC summary of product characteristics, DHPC direct healthcare professional communication

Fig. 4

Incidence rate of all fluoroquinolone use with segmented regression for Germany. The grey shaded interval represents the SmPC implementation period for the fluoroquinolone warnings (22 March 2019–11 December 2019) and the associated DHPC date (8 April 2019) [blue line]. SmPC summary of product characteristics, DHPC direct healthcare professional communication

Fig. 5

Incidence rate of all fluoroquinolone use with segmented regression for the Netherlands. The grey shaded interval represents the SmPC implementation period (14 February 2019–30 March 2020) for the fluoroquinolone warnings and the associated DHPC date (9 April 2019) [blue line]. SmPC summary of product characteristics, DHPC direct healthcare professional communication

Fig. 6

Incidence rate of all fluoroquinolone use with segmented regression for Spain. The grey shaded interval represents the SmPC implementation dates/period for the fluoroquinolone warnings (27 March 2019–2 July 2020 and 31 July 2020) and the associated DHPC date (8 April 2019) [blue line]. SmPC summary of product characteristics, DHPC direct healthcare professional communication

Fig. 7

Incidence rate of all fluoroquinolone use with segmented regression for the UK. The grey shaded interval represents the SmPC implementation periods for the fluoroquinolone warnings (25 April 2019–23 December 2019 and 1 April 2020–18 May 2020) and the associated DHPC date (21 March 2019) [blue line]. SmPC summary of product characteristics, DHPC direct healthcare professional communication