FDA Panel Says Fluoroquinolones Need Stronger Warnings

Troy Brown, RN

November 06, 2015

Fluoroquinolone labels need much stronger warnings about the risks for serious adverse events, including tendinitis and tendon rupture, prolongation of the QT interval, and peripheral neuropathy, according to a joint panel of the US Food and Drug Administration (FDA).

The FDA's Antimicrobial Drugs Advisory Committee (ADMAC) and the Drug Safety and Risk Management Advisory Committee met jointly to discuss the use of fluoroquinolone antibacterial drugs for treatment of acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis in those with chronic obstructive pulmonary disease (ABECB-COPD), and uncomplicated urinary tract infection.

Fluoroquinolone labeling currently has warnings about the risks for tendonitis, tendon rupture, central nervous system effects, peripheral neuropathy, myasthenia gravis exacerbation, QT prolongation and Torsades de Pointes, phototoxicity, and hypersensitivity. But panel members called for stronger wording, with some suggesting the risks be called out with a black box warning.

The panel also voted overwhelmingly that the benefits and risks for the systemic fluoroquinolone antibacterial drugs do not support the current labeled indications for the treatment of ABS (unanimous), ABECB-COPD (2 yes, 18 no, 1 abstention), or uncomplicated urinary tract infection (1 yes, 20 no).

Fluoroquinolones currently approved for one or more of these illnesses are ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, and gemifloxacin.

These adverse effects have been seen in larger numbers of patients since the FDA approved fluoroquinolone drugs, and many believe the FDA should update the labels accordingly. More than 30 individuals spoke at an open public hearing about their own experiences with these effects, many saying they had lost years of their lives.

"Very rare side effects will be magnified when we abuse an antibiotic millions of times," voting ADMAC member Antonio Carlos Arrieta, MD, division chief, Division of Infectious Diseases, Children's Hospital of Orange County, Orange, California, said.

The Infectious Diseases Society of America recommends fluoroquinolones for second-line treatment of patients with allergies to other antibiotics, patients with treatment failure to primary antibiotics, and patients with pathogens that are resistant to first-line antibacterials.

The treatment benefits of antibacterial medications for ABS and mild ABECB-COPD are, at best, very moderate.

Acute Bacterial Sinusitis

It can often be difficult to differentiate patients with viral sinusitis from patients with bacterial sinusitis. Even in studies of patients more likely to have ABS, the treatment effect of the drug was often small, although a large proportion of patients treated with placebo had favorable clinical responses.

A meta-analysis of nine randomized trials among 2547 patients with ABS was unable to identify patients for whom antibacterial treatment would be beneficial, and found that antibacterial treatment might even be harmful.

Current reviews and published meta-analyses question the benefit of antibacterials for ABS treatment, and the treatment effect seems to be at best very modest.

A practice guideline from the Infectious Diseases Society of America recommends antibacterial treatment for patients with more severe symptoms that are probably ABS, and encourages the use of beta-lactam antibacterial drugs instead of respiratory fluoroquinolones.

"I actually do think there is a role for these antibiotics in cases of sinusitis. I think part of the problem is that the recommendations that are out there are not being followed," voting ADMAC member and chairperson Capt. Monica E. Parise, MD, chief, Parasitic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, said.


For mild ABECP-COPD, the treatment effect of antibacterial therapy is at best very moderate.

For moderate to severe ABECB-COPD, the treatment effect of antibacterial therapy is robust; antibacterial treatment is recommended in these patients, who are often hospitalized.

Two literature reviews have found that antibacterial drugs are effective for the treatment of acute bacterial infections in patients with COPD who are moderately or severely ill.

Clinical guidelines from the American Thoracic Society and the European Respiratory Society on the management of COPD recommend antibacterial drug therapy for outpatients with ABECB-COPD on the basis of severe symptoms.

The clinical guidelines for ABECB-COPD treatment promulgated by the American College of Physicians state, "Among patients with mild attacks, there were no significant differences between those who received antibiotics and those who received placebo."

Most adverse reactions were mild, but they occurred more frequently in the groups treated with antibiotics.

"I heavily recommend that we do define better the differences between a moderate and severe infection in this category," voting Drug Safety and Risk Management Advisory Committee member Kelly Besco, PharmD, health-system medication safety coordinator, Ohio-Health Pharmacy Services, Dublin, Ohio, said.

"I don't think the indication is worded appropriately, but I think we need to think really...hard and the FDA needs to think really hard about how this can be worded so that patients do get this medication, and if it is not in the package insert label indication, there is a huge risk that patients may not get this drug paid for," voting ADMAC member Amanda H. Corbett, PharmD, BCPS, FCCP, clinical associate professor, University of North Carolina, Eshelman School of Pharmacy and School of Medicine, Chapel Hill said.

Uncomplicated Urinary Tract Infection

In placebo-controlled studies, antibacterial therapy for uncomplicated urinary tract infection is effective for microbiological eradication of bacteria and symptom resolution. In an ibuprofen-controlled study, antibacterial drug therapy was effective for microbiological eradication, but both treatment groups had similar symptom resolution.

"From the perception of guidelines, this is the indication for which fluoroquinolones seem to be most misused...we need to look at the label to make a change, because it's not just about the side effects but it's about the fact that we're exposing people to these drugs and we need to save them for other indications as well," voting ADMAC member Demetre C. Daskalalkis, MD, MPH, assistant commissioner, Bureau of HIV Prevention and Control, New York Department of Health and Mental Hygiene, Queens, New York, explained.


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