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Figure 4: Mean (SD) EE Serum Concentrations (pg/mL) Following Application of ORTHO EVRAŽ to Abdomen for 7 Days and 10 Days (Dotted horizontal lines indicate reference range. Solid vertical arrows indicate actual time of patch removal. Dotted vertical arrow indicates theoretical time of patch removal under normal use.) Metabolism Since ORTHO EVRAŽ is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of norelgestromin and EE that would be expected with oral administration is avoided. Hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. Text Continues Below
Distribution Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is extensively bound to serum albumin. Elimination Following removal of patches, the elimination kinetics of norelgestromin and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of norelgestromin and EE are eliminated by renal and fecal pathways. Special Populations Effects of Age, Body Weight, Body Surface Area and Race: The effects of age, body weight, body surface area and race on the pharmacokinetics of norelgestromin and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of ORTHO EVRAŽ. For both norelgestromin and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only a small fraction (10-25%) of the overall variability in the pharmacokinetics of norelgestromin and EE following application of ORTHO EVRAŽ may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks. Renal and Hepatic Impairment No formal studies were conducted with ORTHO EVRAŽ to evaluate the pharmacokinetics, safety, and efficacy in women with renal or hepatic impairment. Steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).
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