FDA warns Bayer HealthCare that its two products combining aspirin with dietary supplement ingredients are unapproved new drugs.

With its Oct. 27 letters to Bayer, FDA answers questions from members of Congress and the dietary supplement industry about whether the agency will enforce its policy against the marketing of products that combine drug and supplement ingredients, or whether combo products would be allowed.

The letters concern Bayer Aspirin With Heart Advantage , which combines 81 mg of aspirin and 400 mg of "cholesterol lowering" phytosterols, and Bayer Women's Low Dose Aspirin + Calcium , which combines 81 mg of aspirin and 300 mg of elemental calcium to "fight osteoporosis," according to the product packages.

The warnings also attracted the attention of class-action attorneys looking for clients.

Seattle-based Hagens Berman Sobol Shapiro is investigating Bayer's marketing of the drug-supplement combos and is asking consumers who have used the products to contact the firm, according to an Oct. 29 release.

Bayer launched Aspirin With Heart Advantage this year, but Women's Low Dose Aspirin + Calcium has been on the market since 2002.

Bayer says in an Oct. 28 statement it is reviewing FDA's warnings.

Drug And Dietary Ingredient Combos Are Drugs

In the letters to Bayer, FDA reaffirms its policy that when a drug and a dietary ingredient "are combined into a single dosage form," the combination is deemed a drug, which requires an approved new drug application, according to the letter. The agency notes that neither product has an approved NDA.

FDA's Center for Drug Evaluation and Research acknowledged that the 2002 launch of the aspirin and calcium combination conflicts with the agency's position stated in 2001 warning letters about other firms' combo products.

However, CDER did not enforce the position in reference to Bayer's combination products until after the aspirin-phystosterols product hit the market.

"When Bayer introduced Heart Advantage, the agency focused once again on drug-dietary supplement combination products," CDER said in an e-mail.

"At this time, the agency included both products in its review in order to articulate a consistent approach for drug-dietary supplement combination products."

The letters also state that both Bayer products have inadequate directions for use and are misbranded because they do "not bear adequate warnings," are "misleading" and send consumers "mixed messages" through their dual "Drug Facts" and "Supplement Facts" information boxes.

For example, FDA notes that the Drug Facts box on the Women's Low Dose Aspirin + Calcium warns against use by children and teens because of the risk of Reye's syndrome. However, in a different space the label says that children 12 years and over should take up to four caplets per day for calcium nutrition.

Bayer adds that it stands by both products and the marketing claims.

The products' labels "prominently feature information for consumers to check with their physicians to determine if the product is right for them, and, in the case of Aspirin With Heart Advantage, highlight the fact that the product is not a replacement for cholesterol-lowering medication," Bayer says.

Mixed Reaction In Field

Supplement industry reaction to the warning letters is mixed.

Attorney Marc Ullman said food and drug law does not support the firm's marketing because there is "no statutory category into which you can jam these products."

Thus, the warning letters "are more than justified," said Ullman, of New York-based Ullman, Shapiro & Ullman.

The American Herbal Products Association also questioned whether Aspirin With Heart Advantage violated FDA regulations by asking the agency to indicate whether other firms could also market combination drug-supplement products.

"It is not surprising, given its limited resources, that FDA took the simplest and least creative approach to this issue by enforcing the current rules without any modification," AHPA President Michael McGuffin said after the agency warned Bayer.

"FDA could have developed a streamlined science-based policy to control the introduction of health promoting products, rather than forbid all combination products," he added.

Steve Mister, president and CEO of the Council for Responsible Nutrition - of which Bayer is a member - also lamented FDA's "overly formalistic interpretations of labeling regulations," which keeps "beneficial products" that combine dietary and OTC drug ingredients from consumers.

"CRN continues to believe that combination dietary supplement-OTC drug products have a useful and important role to play in integrated healthcare and wellness," Mister said in an Oct. 28 statement.

"Our hope is that FDA will assist companies attempting to maneuver the regulatory challenges of developing products that combine these ingredients and meet the labeling and formulation requirement of both drugs and dietary supplements, as required by the law," said Mister.

He said combination products "offer consumers added convenience and incentives to maintain their wellness regime."

The Consumer Healthcare Products Association also sees room for combo products.

"In general, CHPA believes that under the existing regulatory framework there is a place and a role for combination drug and dietary supplement products and that these combination products can have significant benefits for American consumers," the group says.

Bayer's Options

Bayer has 15 days to address the violations listed in the letters, according to CDER. If the company does not respond or fails to satisfy FDA's questions, the agency could seize the products and request an injunction against their distribution and sale.

CDER says Bayer and other companies warned about noncompliant OTC drugs can revise a product's formulation and indications to comply with FDA's OTC Drug Review and agency regulations.

Ullman noted other than discontinuing the products, Bayer's other options include arguing in court that FDA's prohibition violates its right to free commercial speech, or pursuing a change in the law to allow these kinds of products.

However, FDA attempts to pre-empt a potential freedom of commercial speech defense.

In its letter regarding Heart Advantage, FDA argues the products' labeling is not protected by the First Amendment because it is false and misleading. In addition, the agency argues its new drug approval process and the OTC Drug Review in general do not violate the right to free speech because the government has a substantial interest in ensuring drug labels and marketing are safe and effective.

Congress' Interest Piqued

Ullman said the letters' timing is "interesting" since the House Energy and Commerce Committee voiced concern about Aspirin With Heart Advantage last month (¹ Also see "Congress Presses FDA To Speak Up On OTC/Supplement Combo Products" - Pink Sheet, 20 October, 2008., p. 4).

The committee sent letters in October to Bayer HealthCare and FDA asking whether Bayer submitted an NDA for Aspirin With Heart Advantage and whether the agency changed its May 2000 policy "that firms refrain from marketing products that combine both drug and dietary supplement ingredients" without an approved NDA.

In response to the warning letters, the committee Oct. 28 said it will continue its investigation.

"We remain curious as to why Bayer, in light of previous, well-publicized FDA decisions on such combination products, decided to market its product without prior FDA approval," said committee Chairman John Dingell, D-Mich.

CDER said its staff began investigating Bayer's Heart Advantage before Dingell inquired about the product.

"The investigation began when FDA became aware of the launch of Bayer Heart Advantage product in March 2008," according to CDER.

- Elizabeth Crawford (e.crawford@elsevier.com)

Bayer Warning Letters Reinforce FDA Ban On Supplement/Drug Combinations

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