The appropriateness of combination products containing OTC drug and dietary supplement ingredients is under review at FDA. In the interim, the agency is discouraging firms from marketing such items.

"FDA strongly recommends that firms refrain from marketing products that combine both drug and dietary supplement ingredients," the agency writes in three May 30 letters to two manufacturers and a law firm.

Two of the letters refer to specific analgesic/supplement combinations, namely B.F. Ascher's Melagesic PM, a product with acetaminophen and melatonin, and Kansas City-based NTCO's Good News Andy Pill, an aspirin and vitamin B12 blend. The third letter responds to a general inquiry on the topic from Washington, D.C. law firm Morgan Lewis & Bockius.

"These combination products raise a number of significant public health and policy issues. For example, the addition of a new ingredient to a legally marketed drug product could affect the safety and efficacy of the drug component," FDA states.

The letters, virtually identical except for the products cited and recipients, outline the "serious concerns" FDA has with the "marketing of any such combination product."

In addition to advising against continued sales of the products, FDA says that in the period prior to issuing a policy, it "intend[s] to take appropriate measures including, if necessary, regulatory action with respect to any such product that violates the FD&C Act or the agency's implementing regulations."

The "number of inquiries" received by FDA on the matter has "made resolution of these issues a priority at the agency," the letters say. Many of the inquiries came from industry representatives.

Officials from the commissioner's office, the Center for Food Safety & Applied Nutrition and Center for Drug Evaluation & Research have formed a joint working group to tackle the issue. FDA aims to release a more formal position in about two months.

Among its "serious concerns," FDA points to possible consumer confusion regarding the "degree of scrutiny FDA gives such combination products." Consumers may be under the impression that both OTC and supplement ingredients "have been subject to stringent drug regulatory requirements when, in fact, only the drug component may have been reviewed by the agency for safety and effectiveness," the letters say.

In addition, it is "uncertain under what circumstances" the labeling disclaimer required under the Dietary Supplement Health & Education Act could be used "without furthering consumer confusion," FDA notes.

"The agency must determine what regulatory standards are appropriate...[and] what safety and effectiveness standards apply and how such products will be labeled," the letters conclude.

The letters appear to represent the first time FDA has publicly expressed concern with over-the-counter drug/dietary supplement combinations.

In the past, industry attention has been more focused on appropriate labeling for such products. Speaking at the Functional Foods for Health annual conference a year ago, Washington, D.C. attorney Peter Barton Hutt (Covington & Burling) opined that such products would be permissible under DSHEA and OTC drug law (¹ Also see "OTC/Dietary Supplement Combination With "Split Label" Fits FDA Rules - Hutt" - Pink Sheet, 24 May, 1999.).

The former agency chief counsel suggested a "split label" approach would satisfy relevant FDA rules, saying a divided label would allow manufacturers to avoid problems that imply a supplement ingredient treats, for instance, the common cold. Hutt cited cosmetic drug products as a precedent for OTC/supplement combinations.

It now appears FDA is moving to concentrate on the potential reactions between actual ingredients, be they drugs (either Rx or OTC) or supplements including herbals, vitamins and minerals.

Publicity on interactions between herbal products and Rx drugs surfaced upon publication in the Feb. 12 Lancet of two studies involving St. John's wort. The articles showed the botanical affected the concentration of the HIV-1 protease inhibitor indinavir, and reduced the plasma concentration of cyclosporin, causing acute heart transplant rejection in two patients (² Also see "St. John's Wort/HIV Protease Inhibitor Use Warnings Issued By FDA, NIH" - Pink Sheet, 14 February, 2000.).

Following release of the study, FDA and the National Institutes of Health warned against use of the herbal among HIV patients taking protease inhibitors.

Soon after, the Consumer Healthcare Products Association adopted an Rx drug use warning on labeling for St. John's wort supplements (³ Also see "St. John's Wort, Rx Drug Use Warning Adopted By CHPA" - Pink Sheet, 8 May, 2000.).

In addition, NIH's National Center for Complementary & Alternative Medicine is considering funding research on botanical/drug interactions. A project concept for efforts ranging from animal studies to Phase III clinical trials was approved by the center's advisory council at a meeting in May (⁴ Also see "Botanical/Drug Interactions To Be Studied By NCCAM" - Pink Sheet, 15 May, 2000.).

Possible interactions cited in the NCCAM initiative include St. John's wort with stimulant ingredients, black cohosh with hypertensive medications and kava kava or valerian use with barbiturates.

FDA's initial position on OTC/supplement products may seem at odds with its view on the use of OTC monograph claims for supplements. In the final rule on supplement claims published in the Jan. 6 Federal Register, FDA deems certain monograph claims to be acceptable as structure/function statements providing they do not refer to a disease (⁵ Also see "Certain OTC Drug Monograph Claims May Be Structure/Function Claims - FDA" - Pink Sheet, 17 January, 2000.).

For example, the nighttime sleep aid claim "For relief of occasional sleeplessness" is permitted, while "Helps you fall asleep if you have difficulty falling asleep" is not because it implies treatment of insomnia.

Claims on B.F. Ascher's Melagesic PM combine both types of claims. "Promotes natural, restful sleep* while relieving pain" includes a structure/function claim and a drug claim, with the mid-phrase asterisk referring to the DSHEA disclaimer.

CHPA believes combination products are acceptable assuming the manufacturer has determined a product is safe, the supplement ingredient has been shown to have a positive effect as required by DSHEA and the usage is consistent with OTC drug requirements.

The association has yet to formally react to the letters, but intends to encourage FDA to settle the issue in a positive way.

OTC/Supplement Combinations "Serious Concern" For FDA

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