The presence of acetaminophen in OTC/dietary supplement combination products renders them drugs, FDA says in recent warning letters to two companies.

Three products combining the OTC analgesic and one or more of the dietary supplement ingredients glucosamine, chondroitin and melatonin are cited by the Center for Drug Evaluation & Research's Office of Compliance in Oct. 16 letters.

The warning letters were issued to Omni Nutraceuticals for its Inholtra Joint Pain Caplets and Inholtra Joint Pain Plus Caplets, and to B.F. Ascher for its Melagesic PM Caplets.

Melagesic PM's labeling positions it as a nighttime pain reliever that will "promote natural, restful sleep and relieve pain," while "combin[ing] the pain medicine most recommended by physicians with nature's own sleep enhancer, melatonin." Each caplet contains 500 mg acetaminophen and 1.5 mg melatonin.

Labeling for the Inholtra products state they are "for long-term joint health" and "temporarily relieve minor aches and pain." Joint Pain Caplets contain 325 mg acetaminophen and 375 mg glucosamine sulfate, while the Joint Pain Plus Caplets contain 325 mg acetaminophen, 187.5 mg glucosamine sulfate and 150 mg chondroitin sulfate.

The warning letters sent to both companies maintain: "Notwithstanding [the] attempt to market these... products as combination drug-dietary supplements, the presence of the acetaminophen, with its intended use to relieve...pain, renders the entire product a drug."

"This is true even though the acetaminophen in these... products is combined with other ingredients...that separately could be marketed as dietary supplements," FDA says.

Concerning the Inholtra items, FDA notes the "glucosamine sulfate and chondroitin sulfate used in combination with the acetaminophen are also drugs since they are components of the finished drug product."

The Dietary Supplement Health & Education Act does not explicitly state dietary supplement/drug combination products may be marketed, the agency adds. Moreover, both warning letters note none of DSHEA's provisions amend the FD&C Act with regard to how such products must be labeled.

FDA asserts that neither the products' formulations nor their intended uses have ever been commercially marketed before, rendering all three items "new drugs...not generally recognized as safe and effective for their respective labeled uses."

Although the final monograph for nighttime sleep-aids allows them to be combined with internal analgesics, since melatonin is not an approved OTC sleep-aid it "may not legally be used as such in any OTC nighttime sleep-aid product," FDA says.

The warning letters also address the three items' labeling. The back panel for both Inholtra products features split labeling, devoting equal space to standard "Drug Facts" labeling for acetaminophen and a "Supplement Facts" box and the DSHEA disclaimer for the glucosamine and chondroitin ingredients.

Melagesic PM's back panel also displays the DSHEA disclaimer, but provides information on both the acetaminophen and melatonin ingredients in one panel.

FDA especially takes issue with the Inholtra products' duration of use warnings. While both products note consumers should "stop use and ask a doctor if...pain gets worse or lasts more than 10 days," the agency criticizes the warning's positioning and size.

"This 'stop use' statement is much less prominent than other, conflicting statements on the respective bottle labels, cartons and carton inserts that promote the 'long term' use of these products for maintaining joint health," FDA notes.

Such contradictions in Inholtra's labeling could prove harmful, the agency says, maintaining "use of the phrase '[l]ong [t]erm' implies the products should be taken consistently over a long period of time," when acetaminophen should not be consumed for more than 10 days without a doctor's supervision.

The letter continues: "This contradiction raises serious safety concerns because...acetaminophen...if used incorrectly, [has] the potential to cause hepatotoxicity."

Claims referring to the combined effects of acetaminophen, glucosamine and chondroitin also imply the latter two ingredients are "intended to cure or mitigate a disease...[and] affect the structure or function of the body," FDA maintains.

One such claim reads: "Combine the fast pain relief of acetaminophen with the healthy long-term joint support of Inholtra Glucosamine."

Referring to Melagesic PM, the agency notes that while labeling mentions the product should not be taken for more than 10 days for pain, "labeling does not bear a warning limiting use for sleeplessness. Protracted sleeplessness may be a symptom of a more serious underlying condition."

In addition, the Inholtra and Melagesic PM products fail to include specific warnings regarding the dangers of dispensing acetaminophen to children under three years of age.

The warning letters could be interpreted as a de facto policy statement regarding OTC/dietary supplement combination products, as both were issued the same day and signed by FDA Office of Compliance Acting Director David Horowitz.

It appears unlikely a formal guidance on the topic will appear in the Federal Register anytime soon, even though industry has expressed interest in such a document.

Last year, the National Nutritional Foods Association requested the Center for Food Safety & Applied Nutrition make the issue one of its FY 2001 program priorities (¹ Also see "OTC/Supplement Combination Marketing Guidance Requested By NNFA" - Pink Sheet, 4 September, 2000.).

FDA has not been completely silent on the issue, however. In May 2000, it wrote letters to B.F. Ascher and several other parties recommending firms refrain from marketing combination products until a review of the subject had been completed (² Also see "OTC/Supplement Combinations "Serious Concern" For FDA" - Pink Sheet, 12 June, 2000.).

It remains unclear whether the companies will meet with FDA to iron out their differences. If not, both firms' responses to the warning letters conceivably could come in the form of litigation; a court ruling at least would provide clarity on what has long been a confusing and contentious topic. The issue also could be raised in future congressional hearings.

OTC/Dietary Supplement Combos Cited In FDA Warning Letters

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