An FDA advisory panel has agreed overwhelmingly that evidence does not support some indications for systemic antibiotics.
Data on the risks and benefits of the drugs do not support their use in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis in patients with COPD, or uncomplicated urinary tract infections, members of agreed.
The 21-member panel, often interrupted by applause from the gallery during the voting, voted unanimously that support for fluoroquinolone use in acute bacterial sinusitis was lacking. On the bronchitis/COPD indication, the panel voted 18-2, with one abstention, that evidence was insufficient. And for uncomplicated urinary tract infections, the vote was 20-1.
What the FDA might do with the advice is uncertain, although the vote certainly raises the likelihood of new label language concerning use of fluoroquinolones for these indications, perhaps even revoking approval for these indications. The FDA is not obliged to accept the advice of its committees but usually does.
The fluoroquinolones -- mainly , , and -- have been indicated for some or all of the three disease entities for several years but there is rising concern that they are being used inappropriately, putting patients at risk for often serious side effects, the panel was told.
In those indications, guidelines recommend them for second-line use -- in patients for whom other therapy is contraindicated -- as long as the bacterial etiology is established. But the drugs have known adverse events flagged in their labels, including tendinopathy, cardiac arrhythmias, and peripheral neuropathy.
Physicians have long been aware of the class effects of the drugs, commented Helen Boucher, MD, of Tufts University in Boston, speaking for the Infectious Diseases Society of America.
In general, she said, physicians don't have "grave concerns" about the safety of the drugs, but they are concerned about over-use, which can lead to drug resistance, and inappropriate use for patients who don't need the medications.
And another issue sparking the joint meeting, she told ڴŮ, is that there "might be something else" -- reports of a syndrome associated with the drugs that goes beyond the generally known adverse effects.
The panel was told that the from Nov. 1, 1997 through May 30, 2015 included 178 reports of a "constellation of symptoms" that led to disability, according to Debra Boxwell, PharmD, of the agency's division of pharmacovigilance.
Boxwell told the panel that cases of so-called fluoroquinolone-associated disability (FQAD) had adverse events in at least two body systems that lasted at least 30 days after the end of fluoroquinolone treatment and had a reported outcome of disability.
But none of the three major drugs had any greater association with the cases than any other, she said.
Most of the individual adverse events reported to the system are already part of the boxed warning on the drugs, she said, but the "constellation of symptoms" is not.
The approach to describing the possible syndrome was unusual, said Susan Nicholson, MD, vice president for safety surveillance and risk management for Johnson and Johnson, which markets levofloxacin as Levaquin.
Instead of looking for cases with similar symptoms and examining them for possible cause and effect, the FDA analysis began by selecting cases based on the outcome of disability, she said -- "an outcome which could result from any number or combination of circumstances."
She also noted some 84% of the 178 cases were reported directly from the public -- much higher than the average in the FAERS database of between 2.4% and 6% -- and just 12% by healthcare professionals.
Such reports usually leave out clinical data and are difficult to follow up, she said.
As well, the high number of direct reports, Nicholson said, is "consistent with stimulated reporting" -- sparked by such things as media reports, litigation, new product approvals, and social media -- and might not reflect the true number of such cases.
Even so, she said, the numbers are low: "On average, there are about 10 cases received each year with approximately 10 million courses of treatment for the three indication types," she said.
About a third of fluoroquinolone courses -- some 10.2 million a year -- are prescribed in the three indications under scrutiny, said Jeff Alder, PhD, of Bayer HealthCare Pharmaceuticals, which markets ciprofloxacin as Cipro and moxifloxacin as Avelox.
And, he added, most of those -- about 9.3 million courses -- are prescribed for uncomplicated urinary tract infections. "This is the largest piece of the pie," he said.
Ciprofloxacin, despite being recommended in guidelines as a second-line therapy for such infections, was actually the most commonly prescribed antibiotic in uncomplicated urinary tract infections in 2014, Alder noted.
Patients affected by the side effects and their advocates expressed anger and anguish during nearly two hours of public comments, urging the panel to vote against use of the drugs in what are often mild infections with other treatment options.
Panel members were disturbed by suggestions that the fluoroquinolones are being used inappropriately and urged that new labeling should emphasize that they should only be given in the three indications as second-line therapy.
"Risk-benefit here is mediated by the fact that current guidelines are not necessarily followed," commented of the University of Florida in Gainesville.
She added that there is "sufficient evidence" of a treatment benefit with fluoroquinolones in all three indications, but only when first-line therapies have failed.
Many also urged the FDA to make warnings about the possible side effects more prominent to ensure that both doctors and patients are aware of the risks.
"It was very apparent in the testimonials today that the current labeling does not communicate the risks clearly and that most if not all the patients that made statements today did not knowingly take on these risks," said of Rutgers University in New Brunswick, N.J.
He added that the evidence for FQAD is "quite weak" and more study of the possible syndrome is needed.