FDA's risk evaluation and mitigation strategy for fluoroquinolone antibiotics requires manufacturers to survey patients and prescribers to make sure they understand the risks of tendon injury associated with the products.

Patients will also be asked whether they have received a newly required medication guide. In addition to the REMS, FDA announced July 8 that it was requesting manufacturers to add a boxed warning to fluoroquinolone labeling.

The patient survey is an example of how FDA's new REMS powers under the FDA Amendments Act will transform drug marketing and distribution in coming years.

Medication guides are not new, but they are not something that the system has been particularly good at getting into the hands of patients, with sponsors, FDA and pharmacies all looking to each other to resolve distribution problems (¹ Also see "As Medication Guide Requirements Increase, FDA Considers Electronic Delivery" - Pink Sheet, 9 April, 2007., p. 20).

But with industry now obliged to show the agency survey results of how well the task is being accomplished, it will have a strong incentive to remove the road blocks that kept MedGuides from being consistently dispensed.

The REMS for fluoroquinolones also requires that physicians be surveyed for their understanding of the risks. Here too the agency's new powers may rewrite the job description of a sales rep.

Now valued for the ability to increase prescription volume, sales reps may soon also be judged for their ability to increase physician recall of new safety information.

There is a commercial bright side to all of these changes, though: Several firms already see that having sales reps communicate drug risks enables them to connect more with doctors and patients, and enables companies to better understand how their products are being used, how to position them and how to develop new ones.

For fluoroquinolones, FDA said manufacturers must conduct surveys at the standard intervals specified in the law: at a minimum of 18 months, three years and seven years after their REMS is approved.

Several products have been approved with REMS since the FDAAA provisions went into effect at the end of March (² Also see "FDA Learns By Doing In Using REMS Powers; Guidance In “Future”" - Pink Sheet, 7 July, 2008., p. 9); a number of approved drugs with existing risk management plans were deemed to have REMS and brought under the rubric of the new powers (³ Also see "REMS Take Effect; FDA Identifies 16 Products With RiskMAPs That Qualify" - Pink Sheet, 31 March, 2008., p. 7).

But the fluoroquinolones appear to be the first existing products that have been given a REMS since FDA could require them.

This REMS may also break new ground in what companies must do to assess the effectiveness of the strategy. The REMS for Adolor/GlaxoSmithKline's Entereg (alvimopan) also requires surveys, but the postoperative constipation therapy is supposed to be used only in hospitals and only for a short time, so the surveys will ask physicians and pharmacists only about their understanding of how the product should be administered (⁴ Also see "Entereg’s REMS To Assess Off-Label Use In Quarterly Reports To FDA" - Pink Sheet, 9 June, 2008., p. 10).

In a press call about the new requirements for fluoroquinolones, FDA officials said that despite the current warning on labeling about the risk of tendon rupture, the agency has continued to receive reports of a considerable number of adverse events.

FDA Uses New Tools

Edward Cox, director of the Office of Antimicrobial Products in the Center for Drug Evaluation and Research, said the agency conducted a new analysis of the literature and post-marketing adverse event reports that reconfirmed use of fluoroquinolones is associated with increased risk of tendon rupture.

As a result of this analysis and continued reports of adverse reactions, he said the agency decided to use the new authority it was granted under FDAAA to request manufacturers to include a box warning on the labeling and provide a medication guide to patients.

Under FDAAA, companies must submit new warning language to the agency within 30 days or state why they believe changes are unnecessary. The agency first used its new labeling authority last month when it directed manufacturers of antipsychotics to update their labeling (⁵ Also see "Boxed Warning For Antipsychotics First Public Use Of FDA Labeling Authority" - Pink Sheet, 23 June, 2008., p. 19).

Prior to passage of FDAAA, the agency could ask for a labeling change but did not have the authority to mandate the change.

Public Citizen Suit Remains Intact

FDA may also have been prompted to take action by Public Citizen, which sued the agency in January for failing to act on its August 2006 petition requesting a black box warning on fluoroquinolone products (⁶ Also see "Seeking Stronger Antibiotic Warnings, Public Citizen Sues FDA" - Pink Sheet, 7 January, 2008., p. 28).

The public interest group also demanded a medication guide and a letter to doctors warning them of the risk of tendon injuries. Sidney Wolfe, director of Public Citizen's Health Research Group, said the suit would remain in effect since the agency did not request manufacturers to send a letter to physicians.

"Without all three, a system of informing patients and preventing tendon injuries won't work," Wolfe said. "Practicing doctors won't get a medication guide or know there is a new black box warning."

Wolfe said that at the time of Public Citizen's petition there were 262 cases of tendon ruptures and 258 cases of tendonitis. As of the end of 2007, he said, there have been an additional 145 tendon ruptures and 83 more cases of tendonitis.

In the press call, FDA was asked why it had not requested that companies send a letter to physicians. "There are vehicles to get information," Cox said. He cited MedWatch, FDA's safety information and adverse event reporting program, labeling changes and postings on the agency's website.

Cox said FDA expects that some manufacturers would choose to send a letter to physicians and that the agency would assist them.

Bayer said it may issue a letter to health care providers if it deems it necessary. The company said it would work with FDA on developing the medication guide and make the guide available to U.S. physicians and health care professionals.

"Bayer will continue its dialogue with the FDA on these programs and will work with the agency to determine if distribution of a more general, broad-based communication such as a Dear Health Care Provider letter is appropriate," the company said.

Bayer manufactures two fluoroquinolone antibiotics, Cipro (ciprofloxacin) and Avelox (moxifloxacin). The other drugs in the class include Oscient Pharmaceuticals' Factive (gemifloxacin), Ortho McNeil's Levaquin (levofloxacin), Bayer's Avelox (moxifloxacin), Merck's Noroxin (norfloxacin), Ortho-McNeil's Floxin (ofloxacin), Cipro XR and DepoMed's Proquin XR (extended-release ciprofloxacin) as well as generics of Cipro and Floxin.

The new labeling will also note risk of injury increases in those over the age of 60, in those who have received kidney, heart and lung transplants, and in those taking corticosteroid drugs. The warning applies to pills, tablets, capsules and injectable formulations, but not topical or ear or eye drop formulations.

The Extent of the Problem

Renata Albrecht, director of the Division of Special Pathogen and Transplant Products in the Office of Antimicrobial Products, said the risk of tendon ruptures is three- to fourfold higher among those receiving fluoroquinolones compared to those not receiving the drugs. She estimated the background incidence of tendon ruptures as 1 in 100,000.

Ruptures occur most frequently in the Achilles tendon and have also been reported to occur in the shoulder, hand, biceps and thumb. They can occur up to several months after completion of drug therapy.

Albrecht said it is not clear how the drugs cause tendon injuries, but said they may be the result of a direct toxic effect or the result of ischemic damage to the joints. She said recent studies show the products may interfere with collagen tissue in the joints, making them more susceptible to tendon injuries.

FDA said it was premature to speculate what the agency would do if it continued to receive reports of ruptures after implementation of the boxed warning and REMS.

- Brenda Sandburg (b.sandburg@elsevier.com)

Fluoroquinolone REMS Will Survey Patients, Doctors on Understanding of Risk

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