Pharmacia should issue a Celebrex "Dear Healthcare Provider Letter" to correct violative safety information disseminated about the COX-2 inhibitor during an audioconference series and in two professional sales pieces, a Feb. 1 FDA warning letter states.

FDA's Division of Drug Marketing, Advertising and Communications requested that the company submit by Feb. 15 an action plan to the agency that includes a plan for disseminating corrective messages to the audiences that received the misleading messages.

"After agreement is reached on the content and the audience, the [Dear Doctor] letter should be disseminated by direct mail to all healthcare providers who were, or may have been, exposed to the violative promotion," FDA said.

The warning letter follows three notice of violation letters sent by FDA's ad division during the past 18 months regarding Pharmacia and marketing partner Pfizer's Celebrex promotions.

Ad division letters issued Oct. 6, 1999 and April 6, 2000 cite unsubstantiated comparative claims and misleading safety information in "homemade" promotional sales aides (¹ [A#00620170007]). A Nov. 14 letter addresses efficacy claims in TV ads (² Also see "Celebrex TV Ads Modified After FDA Says Pharmacia Overstated Efficacy" - Pink Sheet, 11 December, 2000.).

The Feb. 1 warning letter cites a series of five promotional audioconferences given on behalf of Pharmacia by James McMillen, MD, Central Pennsylvania Clinical Research (Philadelphia), between March 7 and May 16, 2000.

The agency issued a separate letter to McMillen, whose consulting relationship with Pharmacia has been terminated. FDA wrote Pharmacia May 5 asking about its involvement with the presentations. The company responded May 19.

"We did have a report that Dr. McMillen was not adhering to all of our instructions, and in fact, brought him in to corporate headquarters in November 1999 for retraining on these issues," Pharmacia wrote. "Subsequent to our meeting with Dr. McMillen, we monitored his speeches and were reassured that he understood his obligations and was following company policy." Pharmacia conducted further retraining with McMillen after receipt of FDA's May letter, the company said.

The warning letter cites audioconference statements that minimized the risk of concomitant use of Celebrex and warfarin (Dupont's Coumadin and generics).

In a March 23 audioconference, McMillen "claimed that" Celebrex and Merck's COX-2 inhibitor Vioxx "'have different reactions in the body....Celebrex has shown drug interactions with lithium and [Pfizer's] Diflucan. Vioxx has not shown any interactions with lithium and Diflucan. Vioxx has shown drug interactions with Rifampin, Coumadin, and methotrexate. Celebrex - no interactions with those drugs.'"

FDA pointed out that Celebrex labeling was revised in June 1999 to add a precaution concerning concomitant Coumadin use, and the agency's October 1999 and April 2000 letters have previously objected to the minimizing of this risk in Celebrex promotions.

The letter also cites comparative gastrointestinal safety claims over Vioxx. "In your audioconferences, you claim that 'going from a dose of 100 mg of Celebrex a day to an increase of eight times that dose to 800 mg a day, there was no increase in endoscopic ulcers, no increase in edema, no increase in blood pressure. This information becomes extremely important to all of us if you compare this to the Vioxx research data.'"

"Your suggestion that Celebrex is safer, or has fewer side effects than Vioxx is false or misleading because such conclusions have not been demonstrated by substantial evidence," FDA said. The agency also noted that 800 mg per day is an unapproved dose and twice the recommended daily dose.

Pharmacia is seeking modification of Celebrex' NSAID class warning regarding GI safety. At its Feb. 7-8 meeting, FDA's Arthritis Advisory Committee said the company could include data from its CLASS trial showing a mixed GI safety effect with regard to diclofenac and ibuprofen (³ Also see "Celebrex, Vioxx GI Safety Differences May Be Indistinguishable - FDA Cmte." - Pink Sheet, 12 February, 2001.).

FDA also cited comparative efficacy claims over naproxen (Roche's Naprosyn and generics), and promotion of an unapproved indication of acute pain. Other suggestions in the audioconferences and two sales pieces that Celebrex is unlikely to cause allergic reactions in patients allergic to sulfonamides are violative, FDA said, because Celebrex labeling carries a contraindication against use in patients who have experienced an allergic reaction to sulfonamides.

Celebrex GI Safety, Warfarin Claims Over Vioxx Need Corrective Letter - FDA

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