|J&J's Other Tylenol Problem: Tylenol-PM|
|May 09, 2010 by Donald Riker, PhD|
With all the notoriety of the J&J quality assurance meltdown Reuters' Susan Heavey reminds us that a flagship component of the Tylenol brand, Tylenol-PM, is under review at FDA. [link] The efficacy of Tylenol-PM (J&J) and Excedrin-PM (Novartis) is still not confirmed to the satisfaction of FDA.
Cheap sleep or hype? The commotion around PM products has been around awhile, at least since the early 1990's. Originally consumers had only two antihistamines available to them, diphenhydramine or doxylamine (Unisom, Chattem/Sanofi), to facilitate sleep; they still do. The concept of combining acetaminophen with antihistamines is a compelling marketing proposition: extend the brand; ladder the benefits; bring new users into the franchise. In the 1980's several researchers hypothesized that anti-histamines were true, rational adjuvants to analgesics, actually increasing pain relief, but sophisticated analysis (using isobolograms) never could completely document the concept.
But is the combination rational? The indication for use assumes that pain interferes with sleep. If so, does pain interfere with falling asleep or maintaining sleep quality? Do all representative users even have pain that interferes with sleep to begin with? Does the severity of pain affect the relief? The clinical design problems are many and start with the actives themselves and statement of a clear objective. Acetaminophen reaches peak plasma levels in 10-60min and has a short half life (2hrs) (fast acting) while diphenhydramine reaches peak plasma levels in 1-4hrs and has a longer and variable half-life (6-10hrs) (slower acting). Sedation studies conducted by me and my co-workers at P&G in the early 1990's [see below] consistently demonstrated that peak sedation after diphenhydramine occurs 3 hours after dosing consistent with peak plasma levels of the drug. Taken together the pharmacokinetics & pharmacodynamics suggest that the more rapidly acting analgesic acetaminophen may be a key component in the drug combination during the period just after dosing and prior to sleep induction. If pain is the problem and the analgesic acts faster than the antihistamine the role of diphenhydramine may be minimal in the first hour after product use. Depending on the power of a factorial clinical design it may be difficult to distinguish the contribution of each active in the first hour when sleep induction is the goal and the desired indication.One simple way for companies to line extend these product is through liquid gels, melts and other dose forms designed to speed dissolution and absorption. Mostly this has been done for both single and combination sleep aids. Although this can help, nevertheless claims to faster action are ultimately limited by the antihistamine's pharmacokinetic parameters and its absolute dose which are invariable or limited by regulation respectively.
The fact is that diphenhydramine, an antihistamine for allergy discovered just after World War II, was never designed to be sleep aid or analgesic. Newer, modern Rx sleep inducing drugs including Ambien (Sanofi), Rozerem (Takeda), Lunesta (Sepracor) and Sonata (King/Wyeth) bear no working resemblance to PM products. They don't work the same way, they are faster acting, and often are designed to disappear after inducing sleep. On the contrary diphenhydramine in all PM products hangs around and can cause next-day drowsiness, or hangover. With a variable half-life averaging about 8hrs it takes nearly 2 days for the drug to completely wash out, unlike acetaminophen, or modern Rx sleep aids.
Clinical trial protocols can be drafted to primarily focus on pain relief, sleep latency, or quality of sleep. So whether the indication itself, or claims deriving there from, can be supported by those recently completed clinical trials will be interesting to learn. While the product concept remains a cogent consumer proposition the scientific thesis and its clinical proof is open to debate. This may be exactly what is on the table at FDA. In addition, the FTC, or various sleep aid competitors, ought to consider whether advertising claims made for these products' efficacy can be supported by available clinical data held by each manufacturer.
This marketing concept's future real present value may yet lie on the Rx---not the OTC side.
Roth, T., Witek, T.J., Merlotti, L., Roehrs, T.A. & Riker, D.K. 1992, "Sedation potential of first generation anti-histamines", Journal of Allergy and Clinical Immunology, vol. 89, no. 1(pt2,#146), 181.
Roth, T., Witek, T.J., Merlotti, L., Roehrs, T.A., Fortier, J. & Riker, D.K. 1993, "Dose related effect of diphenhydramine on daytime sleepiness", Journal of Allergy and Clinical Immunology, vol. 91, no. 1(pt2,#218), 195.
Roth, T., Witek, T.J., Merlotti, L., Roehrs, T.A., Fortier, J. & Riker, D.K. 1992, "Dose related effect of diphenhydramine on daytime sleepiness", Sleep Research, vol. 21, pp. 71.
Witek, T.J., Canestrai, D.A., Miller, R.D., Yang, J.Y. & Riker, D.K., 1992, "The effects of phenindamine tartrate on sleepiness and psychomotor performance", Journal of Allergy and Clinical Immunology, vol. 90, no. 6, pp. 953-961.
Witek, T.J., Canestrari, D.A., Miller, R.D., Yang, J.Y. & Riker, D.K. 1992, "The effects of phenindamine tartrate on sleepiness and psychomotor performance", Journal of Allergy and Clinical Immunology, vol. 89, no. 1(pt2), pp. 181-#147.
[Dr. Riker is a member of the American Society of Pharmacology and Experimental Therapeutics, American Society of Clinical Pharmacology & Therapeutics, and the American Academy of Allergy, Asthma & Immunology. He directed OTC clinical development at RVI/P&G.]
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