Bioequivalence of over‐the‐counter (OTC) progesterone cream (PC)

Progesterone cream is an OTC (non‐prescription) product that contains USP Progesterone (P). The exposure (E) of progesterone cream (PC) was compared to an FDA approved oral micronized form of P. Twelve healthy postmenopausal (as determined by elevated FSH and menstrual cycle history) Caucasian females, mean age of 54.6+7.0 yr and mean weight of 77.2+16.6 kg were enrolled. The trial consisted of 2 phases: women received PC (Pro‐gest ® Transitions for Health Inc., Portland, OR) 40 mg twice daily topically for 12 days using rotating sites (phase I) or oral micronized P (Prometrium ® Solvay Pharmaceuticals, Marietta, GA) 200 mg daily for twelve days (phase II) in a randomized, crossover fashion. Dosing was designed to achieve steady‐state concentrations. A washout period of 1 month between phases was used. On day 12 of each phase, whole blood and saliva for P were collected at 0, 2, 4, 6, 8, 10, and 12 hrs after final PC application and at 0,1, 2, 4, 6, 10, 12, and 24 hrs after last ingestion of oral P. Salivary (reflecting free drug) and whole blood progesterone concentrations were measured using LC‐MS‐MS. WinNonlin was used to determine the AUC 0–12 hr for PC (normalized to an 80 mg/24 hr total dose) and AUC 0‐24 hr for oral P using non‐compartmental analysis. A paired t‐test was used to compare AUC 0‐24hr for the 80 mg daily dose of PC to the 200 mg oral P.(See Table) OTC PC at a dose of 40 mg twice daily gives equal exposure to oral P at a dose of 200 mg daily. This is presumably due to the high first pass metabolism of oral P that should not occur with PC. This raises the question of whether OTC PC should be regulated since it may provide significant exposure compared to FDA approved products. Clinical Pharmacology & Therapeutics (2004) 75 , P10–P10; doi: 10.1016/j.clpt.2003.11.036P Form Adjusted AUC(ng‐hr/ml) [mean(90% CI)] p valuePC (Pro‐gest ® ) 17.0 (9.9–24) 0.874 Oral P (Prometrium ® ) 16.2 (8.4–24)