Suspension of the marketing authorisation and restrictions on the use of quinolone and fluoroquinolone antibiotics: maximum caution when prescribing
A widely used class of antibiotics
Quinolones and fluoroquinolones are broad-spectrum synthetic antimicrobials that are highly effective in treating a wide range of infections. Although these drugs represent a class of antibiotics of considerable medical importance, their use as a first-line treatment has been limited due to possible antibacterial resistance and the risk of clinically relevant side effects. Nevertheless, these drugs, especially fluoroquinolones, remain among the most prescribed and clinically used categories of antibiotics. In 2017, quinolone antibacterial drugs represented the third category of antibiotics for consumption in Italy, preceded only by penicillins and macrolides and lincosamides.1
The actions of the EMA
Recently, quinolones have again been subject to control by regulatory agencies for reasons of safety of use. The recent press release (12 April 2019) issued by the Italian Medicines Agency (AIFA) ends a lengthy process of reviewing safety data for quinolones and fluoroquinolones at EU level, announcing the withdrawal of some quinolones from the market and the implementation of use restrictions for all fluoroquinolones.2
The procedure was initiated by the European Medicines Agency (EMA) in 2017, following a request from the Federal German Institute for Drugs and Medical Devices (BfArM), which had detected the presence of reports of long-term, disabling and potentially permanent side effects in association with the use of these antibiotics in the national pharmacovigilance database.3
The EU review, which focused in particular on the persistence of serious side effects on the musculoskeletal system and the central and peripheral nervous system, covered the following drugs used systemically or inhaled: cynoxacin, ciprofloxacin, enoxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin.
Based on the available evidence, the EMA concluded that the drugs under investigation are associated with serious, known, debilitating, long-term (months to years) and potentially irreversible side effects on one or more organs/systems, such as tendonitis, tendon failure, arthralgia, extremity pain, gait disorders, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders and impairment of hearing, vision, taste and smell.
Following this review, in November 2018 the EMA Committee for Medicinal Products for Human Use (CHMP), confirming the recommendation of the Pharmacovigilance Risk Assessment Committee (PRAC), requested the suspension of the quinolones examined and specific restrictions on the use of fluoroquinolones.4 This decision was subsequently confirmed and made binding by the European Commission and implemented in Italy by the aforementioned measure of 12 April 2019.2
In particular, the EMA decided to suspend the marketing authorisation for quinolone medicinal products containing cinoxacin, flumequine, nalidixic acid and pipemidic acid, and restricted the use of fluoroquinolone antibiotics. Prescribers should no longer use fluoroquinolones to treat infections that are not serious or could be improved without treatment (e.g. pharyngitis, tonsillitis and acute bronchitis), non-bacterial infections, or to prevent traveller’s diarrhoea or recurrent infections of the lower urinary tract. Fluoroquinolones are also contraindicated for the treatment of mild or moderately severe infections (including uncomplicated cystitis, acute exacerbation of chronic bronchitis and chronic obstructive pulmonary disease, acute bacterial rhinosinusitis and acute otitis media), unless other antibacterial drugs commonly recommended for these infections can’t be used, and in patients who have in the past experienced severe adverse reactions to any antibiotic of the same pharmacological class.
Precautions for use
Although only a few cases have been reported at present, it is likely that the frequency of potentially permanent disabling adverse reactions detected during the review will be higher due to possible underreporting. For this reason, the decision to prescribe quinolones and fluoroquinolones must be carefully weighed against a careful assessment of the risk-benefit balance in each individual patient.
For example, fluoroquinolones should be used with particular caution in the elderly, in patients with renal impairment or who have previously undergone solid organ transplantation. Co-administration of fluoroquinolones with corticosteroids should be avoided, as this association is a known risk factor for the onset of tendonitis and tendon rupture, especially in elderly patients. Patients should also be advised to discontinue treatment with these antibiotics at the first signs of possible serious adverse reactions, such as those affecting the musculoskeletal and nervous systems.
Another important alert on the safety of systemic and inhalation fluoroquinolones was issued by the Food and Drug Administration (FDA)5 and AIFA in 20186 to warn healthcare professionals and patients of the risk of aneurysm and aorta dissection which, based on the results of some epidemiological studies,7-10 was higher in patients taking systemic fluoroquinolones than in patients not treated with antibiotics or treated with antibiotics of other pharmacological classes (amoxicillin). Elderly people also represent the highest risk category.
Conditions predisposing to aneurysm and aorta dissection include a family history of aneurysm, aortic aneurysm or pre-existing aortic dissection, Marfan’s syndrome, Ehlers-Danlos vascular syndrome, Takayasu’s arteritis, giant cell arteritis, Behçet’s disease, hypertension and atherosclerosis.6
In conclusion, recent data confirm that the benefits of fluoroquinolones continue to outweigh the risks for the treatment of severe infections caused by susceptible bacteria, such as pneumonia or intra-abdominal infections, while the risk-benefit ratio becomes unfavourable in the treatment of less severe infections (e.g. uncomplicated cystitis, acute exacerbation of chronic bronchitis, etc.) for which safer therapeutic alternatives are available.
However, it should be remembered that the excessive use of fluoroquinolones has so far been a major problem, especially in Italy, where extremely high levels of inappropriate prescription have been observed, for example in the elderly and in women for the treatment of acute cystitis.1
Through the latest decisions on restrictions on the use of fluoroquinolones, regulatory agencies are taking all possible measures to minimise the risks. However, in order to protect public health, it will be essential that these measures are immediately implemented by prescribing physicians and transposed by the public.
CRFV Sicilia - UOSD Farmacologia Clinica, AOU Policlinico di Messina
- Osservatorio Nazionale sull’impiego dei Medicinali. L’uso degli antibiotici in Italia. Rapporto Nazionale 2017. Roma, Agenzia Italiana del Farmaco, 2019.
- Agenzia Italiana del farmaco (AIFA). Nota Informativa Importante (8 aprile 2019) “Antibiotici chinolonici e fluorochinolonici per uso sistemico e inalatorio. Rischio di effetti indesiderati invalidanti, di lunga durata e potenzialmente permanenti e restrizioni d’uso.
- European Medicines Agency (EMA). EMA revisiona la persistenza di effetti indesiderati noti che si verificano con gli antibiotici fluorochinoloni e chinoloni. EMA/85325/2017, 10 febbraio 2017.
- European Medicines Agency (EMA). Effetti indesiderati invalidanti e potenzialmente permanenti hanno comportato la sospensione o restrizioni nell’uso di antibiotici chinolonici e fluorochinolonici. EMA/795349/2018, 16 Novembre 2018.
- Food and Drug Administration (FDA). Safety announcement (20/12/2018). FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients.
- Agenzia italiana del Farmaco (AIFA). Nota Informativa Importante (23 Ottobre 2018). Fluorochinoloni ad uso sistemico ed inalatorio: rischio di aneurisma e dissezione dell’aorta.
- Lee C, Lee M, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med 2015;175:1839-47. CDI
- Pasternak B, Inghammar M, et al. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ 2018;360:k678. CDI
- Daneman N, Lu H, et al. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open 2015;5:e010077. CDI
- Lee C, Lee M, et al. Oral fluoroquinolone and the risk of aortic dissection. J Am Coll Cardiol 2018;72:1369-78. CDI NS