Released by FDA: 3/8/01.  Posted by FDA:  3/13/01

Kimberly Davis 
US Drug Regulatory Affairs, Marketed Products 
Aventis Pharmaceuticals Inc. 
399 Interpace Parkway 
Mailstop: PNJ4-M1364 
Parsippany, NJ 07054

RE:   Amaryl® (glimepiride) Tablets 
        NDA 20-496 
        MACM1S ID#9731

Dear Ms. Davis:

This letter concerns several promotional materials (sales aids 50059159/20144201 /3443R0 and 50059158/20142501 /3337R06, brochure 20058305/2196M0, and web site www.amaryl.com) for Amaryl tablets (glimepiride) disseminated by Aventis Pharmaceuticals Inc. (Aventis).  As part of its monitoring program, the Division of Drug Marketing, Advertising and Communications (DDMAC) has reviewed these materials and has concluded that they are false or misleading, in violation of the Federal Food, Drug, and Cosmetic Act and its implementing regulations.  Our specific objections follow.

Misleading Mechanism of Action Presentation

According to the P1, “The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells.  In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride.”   However, your materials (sales aids 50059159/20144201/3443R0 and 50059158/20142501/3337R06 and web site) prominently display headlines such as “Amaryl is tailored to improve insulin sensitivity,”  “Amaryl is tailored to demonstrate an insulin-sensitizing effect,” and “Tailored glucose control with Amaryl means....Improving insulin sensitivity and targeting insulin resistance.”   These claims and related presentations are misleading because they strongly suggest that Amaryl works primarily by improving insulin sensitivity and targeting insulin resistance when such is not the case.

Misleading Efficacy Claims

Promotional materials are misleading if they suggest that a drug is more effective than has been demonstrated by substantial evidence.  Your sales aids (50059159:20144201/34431W and 50059l58/2014250l/3337R06) prominently present efficacy claims that are unsubstantiated and inconsistent with the approved product labeling (Pl).   For example, you present claims that Amaryl decreased HbA1c by 2.4% and 3.7% in patients with baseline HbA1c of  9.l and 11.3, respectively.  The claim supposedly demonstrating the 3.7% decrease in HbAlc is based on a study that involved a total of 30 patients with baseline HbAlc of 11.3.   In contrast, the Pl indicates that the average net reduction in HbAlc with Amaryl in 720 patients treated with 8 mg once daily was 2.0% compared with placebo treated patients.  Therefore, your presentations are misleading because they suggest that Amaryl is more effective than has been demonstrated by substantial evidence.

Your brochure (20058305/2196M0) and web site include claims that “84% [of patients on Amaryl] with mean baseline HbAlc of 9.1% achieved HbAlc <8.0%,” “82% of these patients achieved HbAlc <7.2%,” and “Amaryl achieves tight HbAlc control (HbAlc <7.2%)..."    However, your claim that 82% of patients had “tight glycemic control "as defined by HbAlc <7.2% is misleading because only 69% of patients treated with Amaryl had this level of response according to the study offered in support of the claim.   Moreover, you fail to disclose that 32% of placebo treated patients also achieved this level of response.

Requested Action

Aventis should immediately discontinue these and all other promotional materials for Amaryl that contain the same or similar claims or presentations.  We request that Aventis respond, in writing, with its intent to comply with the above.   DDMAC should receive your written response no later than March 22, 2001.  This response should list all similarly violative materials with a description of the method for discontinuation and the discontinuation date

If you have any questions or comments, please contact me by facsimile at (301)594-6771, or at the Food and Drug Administration, Division of Drug Marketing, Advertising and Communications, HFD-42, Rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857.   DDMAC reminds you that only written communications are considered official.

In all future correspondence regarding this particular matter, please refer to MACMIS ID #9731 in addition to the NDA number.

Sincerely,

Barbara S. Chong, Pharm.D., BCPS 
Regulatory Review Officer 
Division of Drug Marketing, 
       Advertising, and Communications