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Executive Summary

PHENYLPROPANOLAMINE INDUCED HYPERTENSION IS "INSIGNIFICANT," according to a study by George Blackburn, MD, PhD, Harvard Medical School, et al., in the June 9 issue of the Journal of the American Medical Society. Thompson Medical partially funded the study and supplied its phenylpropanolamine-containing appetite suppressant Dexatrim. The company submitted the study results to FDA about one year ago. Blackburn's study was also submitted to FDA in a June 1 filing by the Nonprescription Drug Manufacturers Association. In response to FDA's May 4 request to companies for dosing studies on phenylpropanolamine, NDMA submitted a compilation of published and unpublished studies. That compilation of studies was previously given, in conjunction with the Nonprescription Drug Manufacturers Association of Canada, to the Canadian Health Protection Branch. "The prevalence of hypertension in the obese and the widespread use of PPA [phenylpropanolamine] as an appetite suppressant and nasal decongestant are factors that have generated common concern over the use of this sympathomimetic agent," the researchers reported. "Our study has demonstrated a definite effect of PPA on diastolic blood pressure, the magnitude of which, however, is clinically insignificant (< 4 mm Hg)." The clinical trial consisted of a one-day study involving 881 volunteers of various weights from normal to severely obese. Medications containing 75 mg of phenylpropanolamine in a sustained-release formula and 25 mg in an immediate-release form were administered to two groups in a double-blind manner every four hours during a 12-hour test day, while a third control group received placebos. Blood pressure and pulse rates were taken before medication and 10 times during the ensuing 12 hours. "A statistically significant blood pressure and pulse rate effect was observed for the two phenylpropanolamine formulations in the first six hours, but these generally disappeared in the last six hours," the researchers concluded. Mean time for peak diastolic blood pressure was 3.5 hours in patients receiving the sustained release formula and 4.2 hours in those receiving the immediate release formula and placebo. Overall, treatment with phenylpropanolamine was associated with a 2 to 4 mm Hg increasein blood pressure and an increase in the pulse rate of 1 to 8 beats per minute compared with placebo. The researchers found that "subjects with higher baseline diastolic blood pressure as well as subjects in a higher weight class had significantly less blood pressure elevation." "The concern about clinically significant hypertensive effects of phenylpropanolamine . . . is therefore not justified in our study," the researchers stated. While acknowledging the results of other studies showing a link between phenylpropanolamine and hypertension, the researchers hypothesized that they may have involved "a more potent nonracemic isomer not approved for marketing in the United States." In addition, the other studies "were based on small sample sizes and were not confirmed by well controlled studies by other investigators." "It should be emphasized that our findings apply to very short-term administration of phenylpropanolamine in healthy individuals," the researchers stated. "However, more significant long-term pressor effects of similar doses of the phenylpropanolamine are unlikely in view of the short half-life (49 minutes) of this compound." Thompson Medical says that it is currently conducting studies of phenylpropanolamine, including a investigation of the long-term use of the ingredient. Also included in the recent NDMA submission to FDA are three recent studies performed by SmithKline Consumer and Ciba Consumer. SmithKline's multiple dose study shows that a reduction in the pressor response "occurs with successive doses of 100 mg phenylpropanolamine when administered as an acute dose after several placebo days, after b.i.d. 50 mg phenylpropanolamine dosing, and when given as a single daily dose for five days," the document says. SmithKline's ascending dose study found "an increased occurrence of pressor responses becoming significant with single doses [greater than or equal to] 75 mg phenylpropanolamine," which is "at least three times the OTC recommended dose of 25 mg phenylpropanolamine" for nasal decongestants. Ciba conducted a rising dose titration study, which shows that "clinically meaningful increases in blood pressure were not observed at immediate release doses of phenylpropanolamine less than 125 mg -- 3.5 to 5 fold multiples of the maximal immediate release doses in OTC decongestant and weight control products in Canada and the U.S."

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