FDA requires black-box warnings for fluoroquinolones

Associated risk of tendon injuries is higher among older patients, those on steroids and transplant recipients.

By — Posted July 28, 2008

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The Food and Drug Administration has notified the makers of fluoroquinolone antimicrobials that they need to place boxed warnings on the labels of seven drugs in this class because they pose a risk for tendinitis and tendon rupture.

The FDA said a medication guide to inform patients also is necessary.

These medicines need the black-box warnings, the strongest issued by the agency, due to continued reports of tendon injuries associated with their use despite existing, but less prominent, label warnings, explained Edward Cox, MD, director of FDA's Office of Antimicrobial Products, at a July 8 press briefing.

Bayer Healthcare, which makes Cipro -- one of the most well-known fluoroquinolones -- said in a statement that it was implementing the changes and preparing the revised warning text.

Tendon ruptures are relatively rare. They occur spontaneously, often from sports injuries, at an estimated annual rate of six to as many as 37 per 100,000 people, according to recent studies. The use of fluoroquinolones increases the likelihood of a rupture by three to four times that rate, said FDA officials.

The tears or ruptures may occur in the Achilles, shoulder, hand or other tendons, sometimes with a dramatic pop or snap.

"Fluoroquinolones are effective in treating certain bacterial infections, but health care professionals and patients need to be aware of the increased risk associated with the use of these drugs ... particularly for certain patient populations," said Dr. Cox.

Those most at risk

The risk increases for patients older than 60, those taking corticosteroids, and patients who have received kidney, heart or lung transplants, said Renata Albrecht, MD, director of the FDA's Division of Special Pathogen and Transplant Products.

Patients who experience pain, swelling, inflammation of a tendon or tendon rupture should stop taking the medications and call their physicians, she added.

The manufacturers also have been told to develop a risk evaluation and mitigation strategy, or REMS, to ensure that the benefits of the drugs outweigh the risks. Under the FDA Amendments Act of 2007, the agency may require manufacturers to submit REMS when a drug first comes on the market, or later if the FDA becomes aware of new safety data about the drug.

A Bayer spokeswoman noted that the fluoroquinolones the company sells have been reported in clinical trials to provide "significant benefits over standard therapy."

The heightened warnings come two years after a petition was filed by the Washington, D.C.-based watchdog group Public Citizen and Illinois Attorney General Lisa Madigan that asked the FDA to require the black-box label warnings, a medication guide for patients and a "Dear Doctor" letter from manufacturers detailing the tendon risks. The FDA agreed with the first two requests but did not address the third.

"As the only state to petition the FDA to require additional product labeling information, we are pleased with the FDA's decision that will better inform patients and medical providers of the potential risks these drugs pose," said a spokeswoman for Madigan.

Public Citizen, which also filed a lawsuit in January because the FDA had not yet responded to the petition, welcomed the agency's actions, but wants more. "The FDA is silent on our request that it also send a warning letter to physicians clearly describing possible adverse reactions, such as tendon pain, so that patients can be switched to alternative treatments before tendons rupture," said Sidney Wolfe, MD, director of the Public Citizen's Health Research Group.

When asked why the FDA hadn't required a letter to doctors, Dr. Cox said the agency would be "happy to work with" manufacturers interested in sending such a communication.

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Fluoroquinolone warning

On July 8 the Food and Drug Administration notified the manufacturers of fluoroquinolone antimicrobials that black-box warnings must be added to the drugs' labels to emphasize the increased risk they pose for developing tendinitis and tendon ruptures.

  • The warning applies to seven drugs: ciprofloxacin (marketed as Cipro and generic ciprofloxacin), ciprofloxacin extended release (Cipro XR and Proquin XR), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin) and ofloxacin (Floxin and generic ofloxacin).
  • The risk for tendon problems is heightened in patients 60 and older; those on steroid therapy; and kidney, heart or lung transplant recipients.
  • The medications should be stopped if a patient has tendon pain or inflammation, as these are symptoms that may precede a rupture.

Source: Food and Drug Administration, July 8

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