Prescribers’ compliance is part of benefit-risk assessment of medicines and it can lead to failure of risk minimization measures and withdrawals of medicines

The manuscript of Kaplan et al.¹, titled The impact of risk minimization measures on compliance and prescribing practices of flupirtine in Germany, reports results about compliance and prescribing practices of analgesic flupirtine before and after risk minimization measures (RMM) implementation.

Flupirtine is an analgesic that was first approved in Germany in 1984. It is neither an opioid nor a non-steroidal anti-inflammatory drug (NSAID); acting as an opener of KCNQ (Kv7) potassium channels and blocker of glutamate N-methyl-D-aspartate receptor^2,3. Therefore, flupirtine served as an alternative for other painkillers, primarily for treating pain associated with chronic musculoskeletal conditions. It was touted as an analgesic that has no cardiac, renal, or gastrointestinal adverse effects, and other complications that may limit therapeutic use of NSAIDs in the treatment of pain. Additionally, flupirtine was not associated with typical concerns associated with opioids, such as respiratory depression or constipation⁴.

However, it has been known for a while that flupirtine-containing medicines can be associated with rare severe hepatotoxicity. Because of this signal, the European Medicines Agency (EMA) severely restricted the use of flupirtine-containing medicines in 2013⁵. Multiple restrictions that EMA imposed for flupirtine-containing medications, included restriction to be used under 14 days because cases of liver failure or liver transplantation were not reported until then in patients that took flupirtine-containing medicines for 14 days or less⁵. However, new signals emerged, indicating that severe cases of hepatotoxicity cannot be ruled out, even within 14 days from the onset of therapy with flupirtine⁶.

In 2018 EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended withdrawal of marketing authorization for flupirtine-containing medicines in the European Union⁷. This recommendation followed a review of flupirtine medicines, which included analysis of the effect of restrictions imposed in 2013, as well as cases of serious liver damage that were reported since the 2013 review⁷.

EMA’s public information contains limited details about the effect of imposed RMMs, indicating simply

Restrictions introduced in 2013, which included limiting flupirtine use to 2 weeks and regular monitoring of liver function tests, have not been sufficiently followed in clinical practice. While the use of flupirtine-containing products has decreased, the measures implemented have not been effective at minimizing the risk⁷.

For this reason, the manuscript of Kaplan et al.¹ is valuable for providing detailed information about the uptake of RMMs in Germany, and the scope of failure to comply with those measures.

Kaplan et al.¹ describe results about six RMMs that were introduced in Germany; they compared a pre-implementation period from January–December 2012 with the post-implementation period from April 2015–March 2016. Six RMMs that were followed refer to indication, duration, contraindications for use of other analgesics, history of liver disease, concomitant use of drugs known to have a potential hepatotoxic effect (prescription level), and liver function test (LFT) monitoring at the prescription level¹. The Kaplan et al.¹ report that most RMM elements had a moderate-to-high degree of compliance, except liver function testing, which had a low degree of compliance. However, Kaplan et al.¹ did not report results for the six RMMs as a composite endpoint, and it is likely that this percentage would be very low. Therefore, despite moderate-to-high compliance with some RMM measures, physicians prescribing flupirtine-containing medicines did not comply sufficiently with all these RMMs, and, therefore, sub-optimal prescribers’ compliance has contributed to the negative benefit–risk assessment of this medicine.

Lowest compliance among the six RMMs was reported for LFT monitoring. Among all flupirtine prescriptions with a treatment duration longer than 7 days, 9.6% and 8.6% of patients had at least one LFT in the pre- and post-implementation periods, respectively. Kaplan et al.¹ suggested that the apparent low compliance of liver function testing could be a reflection of the structure of the monitoring database and the organization of the healthcare system rather than the engagement of the physicians.

RMMs are public health interventions whose intention is to prevent or reduce adverse reactions associated with exposure to a medicine or to reduce their severity or impact on a patient if adverse reactions do occur. Planning and implementing RMMs and assessing their effectiveness are crucial elements of risk management for medical interventions⁸.

Most of the safety concerns related to medicinal products may be assuaged with routine RMMs, including pack size restrictions, adequate wording in patient information leaflets (PILs) which are included in the pack with medicine, and a summary of product characteristics (SmPC)—a legal document approved as part of the marketing authorization of a medicinal product, which includes information for healthcare professionals on how to use the medicine⁹.

Sometimes these routine RMMs are not sufficient and additional RMMs (aRMM) need to be introduced. The aRMMs are medicine-specific and they depend on the important safety issue that is being addressed⁹. A recent analysis of implementation and effectiveness of aRMMs in the UK indicated that healthcare professionals had a reasonable awareness of the analyzed aRMMs, but that reliance on voluntary feedback about aRMMs may not necessarily yield sufficient response rates for measuring the effectiveness of those measures⁹.

For each product, there might be additional mitigating factors contributing to the insufficient implementation of aRMMs⁹. For example, it has been recognized that compliance with RMM may be compromised if such measures present the undue burden on healthcare systems¹⁰. In the case of flupirtine-containing medicines, a massive failure of prescribers to adhere to the measure regarding LFT monitoring may be an indication that it was considered an undue burden.

Suggested solutions for better adherence with RMMs include adequate training and education, building strong network and communication channels that allow practitioners to engage with regulators, and building trust that will create an atmosphere of risk awareness without undermining trust¹⁰.

The case of flupirtine is the important lesson for prescribers. If prescribers are not compliant with RMMs, they are negatively affecting the benefit-risk balance of a medicine and may contribute to the withdrawal of medicine from the market. Prescribers may not perceive their lack of or limited compliance with RMMs as a potential threat to a medicine and, therefore, there is a need to increase prescribers’ awareness about this issue. If a medicine, such as flupirtine, has adverse reactions that can be avoided or significantly reduced with RMMs, prescribers should be part of the solution and not part of the problem.

Transparency

Declaration of funding

This commentary was not funded.

Declaration of financial/other relationships

From July 2018, Livia Puljak has been a member of the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) as an independent expert appointed by the European Commission. The topic for this editorial was suggested before this appointment and it contains personal views. A reviewer on this commentary has been the principal investigator in the trial of flupirtine in overactive bladder patients that was discontinued prematurely due to a high fraction of patients experiencing liver toxicity, i.e. the only placebo-controlled trial documenting the risk of flupirtine to cause liver problems.

Acknowledgements

None reported.