Rx Care

Calls mount for black box warning on fluoroquinolones

Are fluoroquinolones safe? They should be used with caution, according to Jay Cohen, M.D., associate professor of family and preventative medicine and psychiatry at the University of California San Diego.

Cohen is calling on the Food & Drug Administration to require a black box warning of severe, multisystem reactions on all fluoroquinolone package inserts. "A small percentage of patients seem to get multisystem effects from a variety of fluoroquinolones," he said. "Physicians don't believe that the drug is at fault because no syndromes are reported in the literature. Current package insert warnings just don't make the dangers clear."

Public Citizen's Health Research Group petitioned the FDA to require health warnings on all fluoroquinolones in 1996. There is no question that some fluoroquinolones are dangerous. In 1992, Omniflox (temafloxacin, Abbott Laboratories) was withdrawn after 50 severe adverse drug reactions (ADRs) and three deaths were reported in just three months.

In 1999, Raxar (grepafloxacin, Glaxo Wellcome) was taken off the market after reports surfaced of cardiac arrhythmias and seven deaths. The same year, the FDA restricted the use of Trovan (trovafloxacin/alatrofloxacin, Pfizer) following more than a dozen reports of acute liver failure, including five fatalities.

Cohen studied fluoroquinolone reactions in 2001. The study, published in The Annals of Pharmacotherapy, found that fluoroquinolone ADRs can be severe and disabling and can occur after a single dose. The study examined 45 patients who reported peripheral nervous system effects, such as tingling, numbness, burning pain, twitching, or spasms. More than 90% also reported adverse effects on other systems.

Central nervous system symptoms such as dizziness, agitation, impaired cognitive function, or hallucinations were reported by 78% of patients studied. Musculoskeletal symptoms such as joint or muscle pain or tendon rupture were reported by 73%. Adverse events involving cardiovascular or gastrointestinal systems, skin, and special senses were reported by 18% to 42% of patients.

Eighty percent of the reactions were severe, involving chronic pain and/or significantly limited function. Symptoms were typically long term, Cohen found, 91% lasting more than one month, 58% lasting more than one year, and 27% persisting for more than two years. The reactions occurred in an otherwise young and generally healthy population, he said. The average patient age was 42, and 62% had no other medical disorder beyond an infection that prompted fluoroquinolone therapy.

"I looked only at patients with peripheral nervous system involvement," Cohen said. "If I had taken all the cases of serious multisystem reactions, I could have reported hundreds of patients. Clinicians don't realize that fluoroquinolones can have these significant toxicities."

In Cohen's study, 40% of patients reported that their physicians either failed to recognize their neuropathy or dismissed symptoms as minor; 31% of patients said their physicians prescribed multiple courses of fluoroquinolones despite the occurrence of significant adverse events in the initial course of treatment.

One reason physicians dismiss serious fluoroquinolone ADRs is their relative rarity. The package insert for Cipro (ciprofloxacin, Bayer), for example, notes that treatment was discontinued due to adverse events in 1.0% of patients in clinical trials. Medically important events were reported in less than 1% of Cipro patients.

"If the ADR rate is 1% or less, it is entirely possible that a prescriber would never see an adverse fluoroquinolone event in an entire career," noted Daniel Albrant, president of consulting firm Pharmacy Dynamics.

Cohen's numbers are significantly higher because he looked at the minority population that suffered one or more ADRs from fluoroquinolone use. It's a minority with a few high-profile members.

One of the best-known cases is that of Philadelphia writer Diane Ayres. She took a single Floxin tablet in 1992 for a minor urinary tract infection and landed in an emergency room with delirium six hours later. The antibiotic triggered persistent manic-depressive disease that requires regular drug therapy.

Ayres' husband Stephen Fried called her condition "friendly fire in the war on disease" in his award-winning 1998 book Bitter Pill: Inside the Hazardous World of Legal Drugs. The book sparked Congressional hearings on fluoroquinolone ADRs, but the only result was minor wording changes on package inserts.

Reaction to Cohen's call for a black box warning is varied. Cipro maker Bayer did not return telephone calls. A spokeswoman for Ortho-McNeil, maker of Levaquin (levofloxacin) and Floxin (ofloxacin), said the company had no comment.

At the other end of the spectrum, some patients said a black box warning is not enough. Helen Gordon suffered multiple tendon injuries following Levaquin treatment for a mild infection in 1997. Gordon and other patients with significant fluoroquinolone reactions are lobbying the FDA and Congress for a "Dear Doctor" letter to warn prescribers of potential ADRs.

"I have been on crutches for six years because of fluoroquinolones," Gordon said. "Countries in Europe and other parts of the world have issued Dear Doctor letters and medical bulletins to get the warning out. There has not been a single Dear Doctor letter in the United States. When we go to the FDA, they just reply with the same generic letter saying they are looking at the issue, and nothing happens."

Gordon and fellow patient Vince Mulé took their campaign to Capitol Hill in February. Mulé has intractable peripheral pain, tendon damage, and a pacemaker to control cardiac arrhythmias linked to fluoroquinolone therapy.

"They were requesting that we ask the FDA to direct a Dear Doctor letter to highlight the side effects of these drugs," said a spokesman for Rep. Rush Holt (D, N.J.). "We could well end up talking with FDA."

Pharmacists are in the middle. Albrant said fluoroquinolones could be extremely useful in treating community-acquired pneumonia and other serious infections but should be prescribed with greater caution. "It is a good thing to raise the issue," he said. "Whether it is serious enough to warrant a black box, I'm not sure, but these things are not candy. The information needs to get into drug databases where pharmacists and prescribers look."

Some fluoroquinolone ADRs are commonly acknowledged, Albrant said, including CNS disruption, tendon problems, superinfections, and significant diarrhea. Peripheral nervous system problems are less well known and not always recognized as ADRs. "Peripheral neuropathy in a patient with diabetes is likely to be overlooked as an ADR," he noted. There is real merit in drawing attention to these adverse events."

Fred Gebhart

 

Fred Gebhart. Calls mount for black box warning on fluoroquinolones. Drug Topics Apr. 5, 2004;148:43.