FDA is requiring labeling for non-steroidal anti-inflammatory drugs include a warning on skin reactions, in addition to a boxed warning on cardiovascular and gastrointestinal risk.

Sponsors must submit revised labeling by July 15 - 30 days following a letter from FDA requesting supplements for labeling changes. Companies have three months to implement the labeling changes, the letter stipulates. The agency also released a labeling template and a ^FDL-1 medication guide June 15.

"If you deviate from the attached templates, we advise you to submit a prior approval supplement for our review and comment," the letter states.

The ^FDL-2 class labeling template applies to all prescription NSAIDs, including Pfizer's COX-2 inhibit: "¹ Prescription NSAIDs"or Celebrex (celecoxib) (see chart). For nonprescription NSAIDs, FDA is requesting "more specific" CV and GI labeling, noting that use for more than 10 days can increase risk of heart attack and stroke and expanding the warning on stomach bleeding.

In addition to the anticipated boxed warnings on CV and GI risk, FDA's letter calls for "revising the label to include a description of early symptoms associated with Stevens-Johnson Syndrome in the skin reactions section in warnings."

While a warning on skin reactions was not among the recommendations made by the Arthritis Drugs and Drug Safety & Risk Management Advisory Committees at its February review of COX-2/NSAID safety, FDA's labeling template is generally consistent with the committees' proposals (² Also see "Celebrex Should Stay On Market, FDA Panel Says, But Splits On Vioxx, Bextra" - Pink Sheet, 21 February, 2005., p. 3).

In April, FDA asked Pfizer to remove its COX-2 inhibitor Bextra (valdecoxib) from the market in part due to a "special risk" of severe skin reaction. The company plans to work with FDA to reintroduce the product (³ Also see "Bextra Withdrawn At FDA’s Request; Pfizer Holds Out Hope For Return" - Pink Sheet, 11 April, 2005., p. 5).

FDA's proposed warning on skin reactions states that NSAIDs "can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, which can be fatal."

"These events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity."

The "black box" warning contains the warnings on potentially fatal CV and GI events, and a contraindication against use in coronary artery bypass graft (CABG) surgery (see chart: " ⁴ FDA Boxes In NSAIDs', following pag e).

Although the labeling template will be uniform for all the products, Celebrex' label will also include safety data from long-term treatment trials with the drug.

Pfizer CEO Hank McKinnell has suggested that the additional data will help differentiate Celebrex, noting that of several long-term studies of the drug, only one of the colon polyp trials showed a CV safety signal (⁵ [A#00670210020], p. 26).

Because of the conflicting data to date, FDA has asked Pfizer to conduct additional safety studies. The company has committed to a Phase IV study to compare Celebrex to naproxen and "other appropriate drugs" (⁶ Also see "Celebrex Set For Rebound; Silver Lining For Pfizer After Bextra Pulled" - Pink Sheet, 11 April, 2005., p. 3).

Pfizer may be able to get the black box removed from Celebrex labeling eventually: the advisory committees said Pfizer should have the opportunity to remove the box if safety is demonstrated in post-marketing safety studies (⁷ Also see "Celebrex Proposed “Black Box” Could Be Removed With Safety Data – Cmte." - Pink Sheet, 28 February, 2005., p. 7).

Aside from skin reactions, the labeling template includes four other warnings that are new to Celebrex labeling: cardiovascular thrombotic events; hypertension; congestive heart failure and edema; and renal effects. Renal effects currently are listed as a precaution for Celebrex.

The updated labeling also will recommend that treatment should be taken at the lowest effective dose for the shortest possible duration.

Expanded hematological effect information will be added to the Precautions section. Labeling will note anemia is sometimes seen in patients receiving NSAIDs, and that the class inhibits platelet aggregation and has been shown to prolong bleeding in some patients.

An updated Drug Interaction section will note concomitant users of NSAIDs and warfarin have a risk of serious GI bleeding higher than users of either drug alone. Labeling also will state that concomitant administration of the NSAID and aspirin is not generally recommended.

Once the new labeling is finalized, Pfizer will presumably be able to resume advertising Celebrex to consumers.

Following the addition of a black box to antidepressant labeling, FDA agreed to permit direct-to-consumer broadcast advertising provided the "substance" of the warning is included (⁸ Also see "FDA Takes Relaxed Stance On DTC Ads For Products With “Black Box”" - Pink Sheet, 21 March, 2005., p. 8).

Celebrex, NSAID Labeling Must Include Skin Reactions Warning, FDA Says

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