Released by FDA: 11/7/02.  Posted by FDA:  11/14/02

Eileen T. Valenta
Manager, Regulatory Affairs Promotion, Surveillance & Communications
Takeda Pharmaceuticals North America, Inc.
475 Half Day Road, Suite 500
Lincolnshire, IL 60069

RE:   NDA 21-073
        Actos (pioglitazone hydrochloride) Tablets
        MACMIS 10933

Dear Ms. Valenta.

This letter concerns promotional materials disseminated by Takeda Pharmaceuticals America, Inc. (Takeda).   As part of its routine monitoring program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed promotional materials for Actos (pioglitazone hydrochloride) Tablets and has concluded that these materials are in violation of the Federal Food, Drug, and Cosmetic Act and its implementing regulations.   Specifically, DDMAC has identified two Sales Aids for Actos (SS01-0013-1; SSOI-0028-1), distributed in the promotional exhibit hall at the 2002 American Pharmaceutical Association (APhA) Annual Meeting and Exposition on March 16 -- 19.   The Sales Aids are misleading in that they omit safety information critical to appropriate use of the drug and promote effects on outcome that have not been demonstrated.   Our specific objections follow.:

Background

Actos is indicated "as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM).   Actos is indicated for monotherapy.   Actos is also indicated for use in combination with a sulfonylurea, metformin; or insulin when diet and exercise plus the single agent does not result in adequate glycemic control.   Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.   These efforts are important not only in the primary treatment of type 2 diabetes but also to maintain the efficacy of drug therapy."

As you know, since February 2000, the Actos approved product labeling (PI) was revised twice.   In May 2001, the PI was revised to include important new risk information regarding serious adverse hepatic events associated with Actos.   Specifically, the May 2001 revision added the following information, "In postmarketing experience with ALTOS, reports of hepatitis and hepatic enzyme elevations to 3 or more times the upper limit of normal have been received.   Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established."   In January 2002, the PI was again revised, this time to include important information regarding cardiac safety concerns with Actos.   Specifically, a new Warnings section was added to address concerns about fluid retention, which may contribute to heart failure, with particular concern when Actos is used in combination with insulin:   In addition, the Precautions and Adverse Reactions sections were revised with respect to cardiac effects of Actos monotherapy and combination therapy, weight gain, and edema.   In a letter dated January 18, 2002, DDMAC informed Takeda that all promotional materials should be revised to include the new risk information no later than February 7, 2002:

Omission of Important Safety Information

Your sales representatives at the APhA meeting on March 16 - 19, 2002, distributed the Sales Aids listed above.   These Sales Aids are misleading in that they fail to present any of the important risk information from the changes to the PI.   Specifically, these materials make no reference to the following new information from the PI:''

Cardiovascular:

WARNINGS
"Actos, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure.  Patients should be observed for signs and symptoms of heart failure.  Actos should be discontinued if any deterioration in cardiac status occurs."

PRECAUTIONS
"In postmarketing experience with Actos, cases of congestive heart failure have been reported in patients both with and without previously known heart disease."

"In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with Actos in combination with insulin."

Edema

PRECAUTIONS
"In all U.S. clinical trials, edema was reported more frequently in patients treated with Actos than in placebo-treated patients.  In postmarketing experience, reports of initiation or worsening of edema have been received."

ADVERSE REACTIONS
"In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone."

Hepatic Effects

PRECAUTIONS
"In postmarketing experience with Actos, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received.  Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established."

Moreover, these materials were distributed with outdated PIs (dated February 2000) that do not include any of the new risk information.

Promotion of Effects on Outcome That Have Not Been Demonstrated

These claims are misleading because they fail to distinguish between a mechanism you hope will prove to be of value in type 2 diabetes (beyond simply helping to control blood sugar and HbAlc, which Actos does do) and evidence of such value.   Absent data demonstrating these outcomes, the suggestion that Actos can help prevent micro- and macrovascular complications of diabetes, including cardiovascular disease; is misleading:   The PI states "Actos is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin dependent diabetes mellitus; NIDDM)."   FDA is not aware of any data to suggest that Actos has a favorable effect on any complications of type 2 diabetes.

Requested Action

Takeda should immediately cease distribution and publication of these Sales Aids, and all other promotional materials for Actos that omit important safety information and that contain the same or similar claims or presentations.  Please submit a written response to DDMAC, on or before November 21, 2002, describing your intent and plans to comply with the above.  In its letter to DDMAC, Takeda should include a list of all promotional materials that were discontinued, and the discontinuation date.

If you have any questions, please contact me by telephone at (301) 827-2831, by facsimile at (301) 594-6771, or write to me at the Division of Drug Marketing, Advertising, and Communications, HFD-42; Room 8B-45 5600 Fishers Lane; Rockville, MD 20857.   DDMAC reminds Takeda that only written communications are considered official.   In all future correspondence regarding this matter, please refer to MACMIS # 10933 and NDA 21-073.

Sincerely,

Marci C. Kicster, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
    Advertising, and Communications