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This article was originally published in The Tan Sheet

Executive Summary

"DAYTIME/NIGHTTIME" DOSING CONCEPT FOR OTC COUGH/COLD PRODUCTS is being closely monitored by FDA. Reportedly, the agency does not believe that the idea of dosing with two different combination cough/cold products in a 24-hour period is addressed in the 1988 Tentative Final Monograph for OTC Cough/Cold Combination Products. Most daytime/nighttime products are comprised of a "daytime" formulation, which includes a decongestant or other nonsedating cough/cold ingredient, and a different-color "nighttime" formulation, which usually contains a sedating antihistamine. Products that offer the day/night dosing concept include Burroughs Wellcome's Actifed Sinus Daytime/Nighttime, SmithKline Beecham's Contac Day & Night, and Bristol-Myers Squibb's Day & Night Comtrex. FDA has asked Burroughs Wellcome to design a clinical protocol to "demonstrate that people following this proposed dosing concept will maintain an acceptable level of clinical relief of symptoms over a 24-hour period" compared to an equivalent dose of a regular cough/cold combination product. An FDA memorandum of a Jan. 25 conversation between OTC Drug Evaluation Division Interdisciplinary Scientist Brenda Sturdivant and Burroughs Wellcome's Michael Dalton, who heads regulatory affairs for pharmaceutical and consumer products, states that FDA suggested that the clinical trial should consider placebo or a "least acceptable difference method" that would, "for example, demonstrate no more than a 10% difference from currently approved monograph around-the-clock combination products." Other study designs are acceptable "as long as equivalency [to monograph products] can be demonstrated," Sturdivant told the company. The FDAer also suggested to Burroughs Wellcome that the company "focus on labeling that would prevent confusion to consumers using this proposed daytime/nighttime dosing concept," the memo states. In addition to asking for an Actifed Sinus Daytime/Nighttime study, FDA approved a telephone survey protocol submitted by Burroughs Wellcome in November 1992. The survey, which has been contracted to PERT Research Survey of Milwaukee, has set a target of 500 eligible respondents split evenly by gender. The FDA memo states that Dalton said the phone survey was designed to determine: "the number of people who have used (or avoided using) a cough/cold product to avoid drowsiness during the day"; "those people who used sedating cough/cold products to help them to sleep"; and whether "consumers knew which ingredients in cough/cold products can cause drowsiness." Dalton said the survey is intended to "show that consumers are willing to 'trade off' less relief during the daytime rather than to experience drowsiness caused by an antihistamine used during the day," the memo states. The study also is geared to determine the "level of consumer interest in this type of product," Dalton noted. Dalton told FDA that "there is no advantage in doing clinical studies" on top of a phone survey, according to the memo. Dalton maintained that the "clinical relief of symptoms that consumers would get from [Actifed Sinus Daytime/Nighttime] would be the same" as what they would get if they used "different currently marketed single-ingredient products and combination products at different times during a 24-hour period to avoid the drowsiness caused by antihistamines during the day." Dalton contended that the daytime/nighttime concept is "merely a packaging convenience," the memo relates. Burroughs Wellcome disputed FDA's position that the daytime/nighttime dosing scheme is not covered by the TFM for cough/cold combinations in a letter sent with the survey proposal in November. The TFM "does not prohibit the marketing of two or more different products in the same package, especially when clearly labeled," the company stated in the letter. Actifed Sinus Daytime/Nighttime adheres to the TFM, Burroughs Wellcome asserted, because the product contains Category I (safe and effective) ingredients and "the labeling is in accord with monograph conditions." The labeling "clearly informs consumers that the package contains two separate products" and provides "accurate directions for successive dosing of two different products, directions which previously have not been available to consumers who choose this dosing regimen with two different brands," the company stated. FDA has been in communication with Burroughs Wellcome regarding the daytime/nighttime product for at least a year. FDA first met with Burroughs Wellcome representatives in March 1992 to inform the company of its position that the day/night dosing concept is not included in the cough/cold TFM. Burroughs Wellcome said it submitted its first medication behavior survey at that time, but FDA asked for additional research. Burroughs Wellcome began shipping Actifed Sinus Daytime/Nighttime (pseudoephedrine and acetaminophen for the day with the addition of diphenhydramine for the night) in July 1992. The product, comprised of 18 white daytime tablets and six blue nighttime tabs, arrived in stores in early September with an average retail price of $ 4.56.

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