Link:  Pharm/Biotech Resources

Released by FDA:  3/22/05.  Posted by FDA:  3/23/05

Daniel T. Coleman, Ph.D.
Associate Director, Drug Regulatory Affairs
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road
P.O. Box 368
Ridgefield, CT 06877-0368

RE:   NDA # 20-884
         Aggrenox® (aspirin/extended-release dipyridamole) Capsules
         MACMIS ID # 12917

Dear Dr. Coleman:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a journal ad (AG-8951R) for Aggrenox® (aspirin/extended-release dipyridamole) Capsules submitted by Boehringer Ingelheim Pharmaceuticals, Inc. (Boehringer Ingelheim) under cover of Form FDA 2253 on September 19, 2004.  The journal ad is false or misleading because it contains unsubstantiated superiority claims and fails to include pertinent information about risks associated with Aggrenox, and, therefore, misbrands the drug in violation of section 502(n) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. § 352(n), and FDA's implementing regulations, 21 CFR 202.1(e)(3)(i); (e)(5)(ii); (e)(6)(ii).

Background

According to the FDA-approved product labeling (PI), Aggrenox is an oral combination antiplatelet agent indicated "to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis."

The PI for Aggrenox contains several Contraindications, Warnings, Precautions, and Adverse Reactions, including Warnings regarding the consumption of alcohol, coagulation abnormalities, gastrointestinal (GI) side effects (including ulceration and bleeding), peptic ulcer disease, and pregnancy, as well as a Precaution regarding the risk of gastrointestinal bleeding and intracranial hemorrhage.

Unsubstantiated Superiority Claim

The journal ad claims that "Based on indirect comparisons, [Aggrenox] may be more effective than clopidogrel, 75 mg..." This claim, in the context of the other claims in the ad, suggests that Aggrenox is more effective than Plavix (clopidogrel). As the journal ad states, this claim is based on "indirect comparisons" (a review of studies directly comparing ticlopidine, clopidogrel, and dipyridamole/aspirin with aspirin alone).  Drug comparisons that represent or suggest that a drug is safer or more effective than another drug are misleading if the representation or suggestion has not been demonstrated by substantial evidence obtained from adequate and well-controlled head-to-head clinical trial(s). See 21 CFR 202.1(e)(6)(ii).  The paper referenced in the ad as support for this claim is, in effect, a historically controlled trial that is inadequate to support a superiority claim.  We are not aware of substantial evidence or substantial clinical experience demonstrating that Aggrenox is superior to Plavix.

Omission of Risk Information

The main part of the ad contains various safety and effectiveness claims for Aggrenox. The headline, "People With Prior Stroke Or TIA Have The Greatest Need For BIG Protection Against Stroke Recurrence" is followed by: "Aggrenox Prevents Twice As Many Strokes As Aspirin" and other efficacy claims regarding Aggrenox's ability to prevent strokes.  The main part of the ad also includes a reference to the brief summary of prescribing information for Aggrenox on the adjacent page, and the following statement of risk information:

"The most common adverse event with Aggrenox was headache (39.2% vs 32.9% for placebo), which was more frequent at the onset of therapy, but diminished over time. GI bleeding with Aggrenox was comparable to aspirin (4.1 % vs 3.2%)."

The main part of the ad fails to include information on the major risks associated with Aggrenox, including information about the Warnings concerning alcohol consumption, coagulation abnormalities, peptic ulcer disease, and pregnancy.  Additionally, the ad fails to disclose the Precaution from the PI concerning the risks of intracranial hemorrhage. Although some of these risks relate to aspirin, this does not diminish the need to reflect them in promotion of Aggrenox, which contains aspirin as well as dipyridamole. See 21 CFR 202.1(e)(3)(i) and (e)(5)(ii).

Conclusion and Requested Action

The journal ad contains unsubstantiated superiority claims and omits information on the risks associated with Aggrenox, and, therefore, misbrands the drug in violation of section 502(n) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. § 352(n), and FDA's implementing regulations, 21 CFR 202.1(e)(3)(i); (e)(5)(ii); (e)(6)(ii).

DDMAC requests that Boehringer Ingelheim immediately cease the dissemination of promotional materials for Aggrenox the same as or similar to those described above. Please submit a written response to this letter on or before April 05, 2005, describing your intent to comply with this request, listing all promotional materials for Aggrenox the same as or similar to those described above, and explaining your plan for discontinuing use of such materials.  Please direct your response to me at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 8B-45, 5600 Fishers Lane, Rockville, MD 20857, facsimile at (301) 594-6771. In all future correspondence regarding this matter, please refer to MACMIS # 12917 in addition to the NDA numbers.  We remind you that only written communications are considered official.  If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion.

The violations discussed in this letter do not necessarily constitute an exhaustive list.  It is your responsibility to ensure that your promotional materials for Aggrenox comply with each applicable requirement of the Act and FDA implementing regulations.

Sincerely,

Lance McLeroy, Pharm.D., M.S.
Regulatory Review Officer
Division of Drug Marketing,
   Advertising, and Communications