If unwanted side-effects arise in a drug, mechanisms are put in place at an EU level to minimise risks. The BfArM brings its expertise to the committees of the European Medicines Agency (EMA). Fluoroquinolones are an example which demonstrates the need for longterm input: after sometimes irreversible side effects arose in its application, the BfArM repeatedly put these antibiotics to the test. And it was successful.
New findings on the safety of medicines can arise over the entire life cycle of a drug, therefore also a long time after their licensing. A significant tool for identifying possible risks in medicines is the closemeshed evaluation of reports of suspected side effects. If this results in a risk signal for a drug which is approved in several or all EU member states, processes are put in place at a European level for closer evaluation of such signals.
This is where Dr. Martin Huber comes in. He is the deputy chair of PRAC, the EMA Pharmacovigilance Risk Assessment Committee. PRAC works on the identification, assessment, minimisation and communication of drug risks. At the end of the process, the committee gives a recommendation on the drug‘s future.
Fluoroquinolones: highly effective, but not without risk
Drugs from the fluoroquinolone class have kept PRAC busy for some years. Fluoroquinolones are synthetic antibiotics which have a wide range of therapeutic applications. They have been in use for decades and play an important role in the treatment of severe bacterial infections. In addition to their antibiotic action, serious side effects have also been identified. In the worst cases, these can be permanent. Infections, tendon tears, difficulty with eyesight, or depression have been among the described issues.
As some of the observed side effects can be long-lasting and possibly permanent, in 2017 the BfArM approved a European risk assessment process for fluoroquinolones. The aim of such a risk assessment is to check whether the benefit of a drug continues to outweigh the risks. This is performed based on the reporting of suspected side effects. In addition to this, experts evaluate the current scientific literature and other available data.
Far-reaching application restrictions
As a consequence of this process, the PRAC announced clear recommendations in 2018. Martin Huber: “There were farreaching restrictions to the areas of application for fluoroquinolones; a few active ingredients even had their license rescinded. In addition to this, we have obligated the licence owners to update their product information so that they give information on the restrictions of approved application areas and on the application risks.”
Members of health professions have been informed of the findings and recommendations of the process by way of a Direct Healthcare Professional Communication (DHPC). This concerns an important form of information for those working in the healthcare sector, which provides clarification on newly identified, significant drug risks and measures to mitigate those risks. In the case of fluoroquinolones, there had already been another DHPC issued which specifically addressed the risk of the incidence of aortic aneurysms and dissections. A further DHPC followed in October 2020 to draw attention to the risk of a cardiac valve regurgitation/insufficiency.
It has been known for some time that fluoroquinolones are associated with severe side effects. In the public domain, criticism is often made of the fact that, in spite of this, these antibiotics are still allowed to be used at all. “This is completely understandable,” says Martin Huber. “But it needs to be said that fluoroquinolones are highly effective antibiotics with a wide range of therapeutic applications. In practice, they can be a treatment of last resort and therefore save lives. For example, once all other antibiotics have not worked or bacteria have developed resistance against other antibiotics.” Doctors therefore need to weigh up on a case-by-case basis whether the benefit versus the risk of using medications containing fluoroquinolones are justified.
The study shows that fluoroquinolones are still prescribed off-label.
Dr. Martin Huber, Deputy chair of PRAC
Prescribing behaviour under the microscope
Among the antibiotics, the fluoroquinolones, which are still authorised in Germany, were the fourth strongest class of active substances in 2021 with around twelve million defined daily doses. Fluoroquinolone antibiotics should only be prescribed forAmong the antibiotics, the fluoroquinolones, which are still authorised in Germany, were the fourth strongest class of active substances in 2021 with around twelve million defined daily doses. Fluoroquinolone antibiotics should only be prescribed for the approved indications and after careful weighing up of the risks and benefits. Martin Huber: “If we look at the previous application restrictions, it is clear that many are targeted as the treatment of last resort for patients. This means that there must not be any alternative therapeutic options available. The comparatively high prescription figures, however, suggest that fluoroquinolones are often used above and beyond these stipulations.”
The PRAC therefore decided to evaluate the introduced measures for risk minimisation using a medications application study. The study included data from six European countries, including Germany, and came to the conclusion that the number of prescriptions was slightly on the decline. While the interpretation of data from the medications application study is associated with restrictions, the observed tendency of a decline in the number of prescriptions in Germany is covered by other available data, such as the drug prescription report.
Monitoring after licensing
In particular during the period corresponding to the start of the risk assessment procedure and the resulting measures, a significant decline is recorded for Germany. “But we still cannot be satisfied with this,” says Martin Huber. “The study shows that fluorquinolones are still prescribed off-label.” Against this backdrop, PRAC recommended a renewed DHPC letter in Spring 2023 to once more draw attention to the application restrictions and the severe side effects.
The fluoroquinolones are a good example of how strictly medications are monitored, even after licensing. At the same time, the latest scientific knowledge must be observed consistently in the prescribing behaviour. “The prescription of a drug – in this case an antibiotic – is a decision made by a medical professional for a specific patient,” Martin Huber stresses. “Application risks therefore always have to be discussed on an individual basis. The BfArM will continue to provide its expertise here, so that the knowledge of drug risks grows and patients can receive optimal and safe treatment.”
Dr. Martin Huber
Studied Pharmacy at the Goethe University Frankfurt am Main, as well as postgraduate studies in health sciences – Public Health at the Technical University Dresden. Started as a scientific member of staff, including in hospital. In 2010 he switched to the BfArM in the pharmacovigilance department. Involvement in the working groups and committees at European level from an early stage. Member of PRAC since 2012. Deputy chair of this committee since 2018.
