Nexstar DaunoXome corrective promotion letter requested in FDA warning letter to company.

NEXSTAR DAUNOXOME CORRECTIVE LETTER REQUESTED BY FDA in response to concerns outlined in a Feb. 21 warning letter over the company's promotion of DaunoXome (daunorubicin citrate liposome injection). "Nexstar should propose a corrective action plan, including the mailing and publication of a `Dear Healthcare Provider' letter to correct the false and/or misleading messages" cited by FDA, the warning letter states.

The company hopes to discuss the issues brought up in the letter with the agency but said it intends to comply with the agency's requests. DaunoXome sales were approximately $4 mil. in 1996, according to Nexstar.

"The `Dear Healthcare Provider' letter and Nexstar's corrective action plan should be submitted to DDMAC for approval," the warning letter says. Following such approval, "the letter should be disseminated by both direct mail and through a paid advertisement in all journals that contained advertisements for DaunoXome during the 12 months prior to the date of this letter."

In addition, the agency has requested that Nexstar "immediately ceas[e] the dissemination of all materials that state, suggest or imply (1) that DaunoXome is less toxic than other therapies; (2) that DaunoXome has reduced risk, or has no risk, of cardiac toxicity; (3) that DaunoXome is more effective than has been demonstrated by substantial evidence; (4) that DaunoXome is safe and effective for unapproved uses or doses; or (5) that otherwise contain violative claims of the type discussed in this letter." The agency asked for a written statement of "Nexstar's intent to comply" with this request. Nexstar said it has discontinued all promotional materials with messages cited in the letter.

FDA has also requested that Nexstar provide the agency with "a complete listing of all advertising and promotional materials that will remain in use and those that will be discontinued." The company is also asked to "provide two copies of all promotional materials for DaunoXome that Nexstar intends to continue to distribute."

The letter requests that "within 15 days of the date of this letter" Nexstar should disseminate "a message to all Nexstar sales representatives and marketing personnel involved in the marketing and sales of DaunoXome, instructing them to immediately cease dissemination of all promotional materials and messages discussed in this letter and providing each person with a copy of this letter." Nexstar said that its sales representatives have read the letter.

FDA's Division of Drug Marketing, Advertising & Communications Deputy Director Norm Drezin discussed the warning letter at a Drug Information Association meeting in New York City on Feb. 28. Drezin highlighted DDMAC's concerns that Nexstar failed "to provide fair balance about safety issues," made "claims of reduced or no cardiac toxicity" and advertised "unsubstantiated effectiveness claims" ("The Pink Sheet" March 3, T&G-1).

Drezin maintained that Nexstar promoted "unapproved uses and doses" of DaunoXome. "Labeling specifically says this drug is indicated in advanced HIV-related Kaposi's sarcoma, but [Nexstar was] handing out information that [DaunoXome is] effective in early Kaposi's sarcoma," Drezin said. "They don't have substantiation for that."

The warning letter cites a reprint of an article by Uthayakumar et al., (AIDS, 1996) entitled "Randomized cross-over comparison of liposomal daunorubicin versus observation for early Kaposi's sarcoma," and "an abstract that concludes that: `Liposomal daunorubicin is a well tolerated and efficacious treatment for early KS; however, the duration of response is brief.'" The agency commented that "the abstract is misleading because it does not accurately summarize the article, and is inconsistent with the approved product labeling."

Drezin also said that Nexstar "was handing out information that promoted doses of one and a half times the recommended dose." However, "there is evidence to establish that there is no benefit gained by increasing the dose," he maintained.

The warning letter cites an article reprint and abstract "that promote the use of DaunoXome at doses up to 60 mg/m2 every two weeks." However, the agency continues, "the approved product labeling states that DaunoXome should be administered at a dose of 40 mg/m2 every two weeks." FDA concludes that "promotion of DaunoXome at a dose of 60 mg/m2 promotes an unapproved dosage."