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Ortho (Ethinyl Estradiol) - Description and Clinical Pharmacology



ORTHO EVRA® is a combination transdermal contraceptive patch with a contact surface area of 20 cm2. It contains 6.00 mg norelgestromin and 0.75 mg ethinyl estradiol (EE), and releases 150 micrograms of norelgestromin and 20 micrograms of EE to the bloodstream per 24 hours.

ORTHO EVRA® is a thin, matrix-type transdermal contraceptive patch consisting of three layers. The backing layer is composed of a beige flexible film consisting of a low-density pigmented polyethylene outer layer and a polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and lauryl lactate as inactive components. The active components in this layer are the hormones, norelgestromin and ethinyl estradiol. The third layer is the release liner, which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle adhesive layer.

The outside of the backing layer is heat-stamped "ORTHO EVRA® 150/20."

The structural formulas of the components are:

Molecular weight, norelgestromin: 327.47

Molecular weight, ethinyl estradiol: 296.41

Chemical name for norelgestromin: 18, 19-dinorpregn-4-en-20-yn-3-one, 13-ethyl- 17-hydroxy-, 3-oxime, (17(alpha))

Chemical name for ethinyl estradiol: 19-Norpregna-1, 3, 5 (10)-trien-20-yne-3, 17-diol, (17(alpha))



Norelgestromin is the active progestin largely responsible for the progestational activity that occurs in women following application of ORTHO EVRA®. Norelgestromin is also the primary active metabolite produced following oral administration of norgestimate (NGM), the progestin component of the oral contraceptive products ORTHO-CYCLEN® and ORTHO TRI-CYCLEN®.

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor and human sex hormone-binding globulin (SHBG) binding studies, as well as studies in animals and humans, have shown that both norgestimate and norelgestromin exhibit high progestational activity with minimal intrinsic androgenicity90-93. Transdermally-administered norelgestromin, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in SHBG, resulting in lower levels of free testosterone in serum compared to baseline.

Pharmacokinetic studies with ORTHO EVRA® demonstrated consistent elimination kinetics for norelgestromin and EE with half-life values of approximately 28 hours and 17 hours, respectively. One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that FSH, LH, and Estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy.



Following application of ORTHO EVRA®, both norelgestromin and EE rapidly appear in the serum, reach a plateau by approximately 48 hours, and are maintained at an approximate steady-state throughout the wear period. CSS concentrations for norelgestromin and EE during one week of patch wear are approximately 0.6-0.8 ng/ml and 40-50 pg/ml, respectively, and are generally consistent from all studies and application sites. These CSS concentrations are within the reference ranges for norelgestromin (0.6 to 1.2 ng/ml) and EE (25 to 75 pg/ml) established based upon the Cave concentrations observed with subjects taking ORTHO-CYCLEN®.

Daily absorption of norelgestromin and EE from ORTHO EVRA® was determined by comparison to an intravenous infusion of norelgestromin and EE. The results indicated that the average dose of norelgestromin and EE absorbed into the systemic circulation is 150 mcg/day and 20 mcg/day, respectively.

The absorption of norelgestromin and EE following application of ORTHO EVRA® to the abdomen, buttock, upper outer arm and upper torso (excluding breast) was evaluated in a cross-over design study. The results of this study indicated that CSS and AUC for the buttock, upper arm and torso for each analyte were equivalent. While CSS values for the abdomen were within reference ranges for EE 35 mcg/NGM 250 mcg oral contraceptive users, exposure to the drugs was lower and strict bioequivalence requirements for AUC were not met in this study. However, in a separate parallel group multiple application pharmacokinetic study, CSS and AUC for the buttock and abdomen were not statistically different. Therefore, all four sites may be considered therapeutically equivalent.

The absorption of norelgestromin and EE following application of ORTHO EVRA® was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for norelgestromin there were no significant treatment effects on CSS or AUC when compared to normal wear. For EE, slight increases were observed due to sauna, whirlpool and treadmill, however, the CSS values following these treatments were within the reference range. There was no significant effect of cold water on these parameters.

In multiple dose studies, CSS and AUC for norelgestromin and EE were found to increase slightly over time when compared to Week 1 of Cycle 1. In a three-cycle study, these pharmacokinetic parameters reached steady-state conditions during all three weeks of Cycle 3. (See Table 1, Figures 1 and 2).

Table 1: Mean (SD) Pharmacokinetic Parameters of Norelgestromin and EE Following 3 Consecutive Cycles of ORTHO EVRA® Wear on the Buttock
Analyte Parameter Cycle 1
Week 1
Cycle 3
Week 1
Cycle 3
Week 2
Cycle 3
Week 3
Norelgestromin Css a 0.70 (0.28) 0.70 (0.29) 0.80 (0.23) 0.70 (0.32)
AUC0-168 b 107 (44.2) 105 (45.5) 132 (57.1) 120 (52.8)
t ½ c nc nc nc 32.1 (12.9)
EE Css d 46.4 (17.9) 47.6 (17.3) 59.0 (25.1) 49.6 (27.0)
AUC0-168 e 6796 (2673) 7160 (2893) 10054 (4205) 8840 (5176)
t ½ c nc nc nc 21.0 (9.07)
a ng/mL
b ng·h/mL
c h
d pg/mL
e pg·h/mL
nc = not calculated

Results from a study of consecutive ORTHO EVRA® wear for 7 days and 10 days indicated that serum concentrations of norelgestromin and EE dropped slightly during the first 6 hours after the patch replacement, still stayed within the reference range and recovered within 12 hours. Target Css of norelgestromin and EE were maintained during 2 days of extended wear of ORTHO EVRA®.


Since ORTHO EVRA® 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.


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.


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.


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 EVRA®. 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 EVRA® 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.


No formal studies were conducted with ORTHO EVRA® 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).


The metabolism of hormonal contraceptives may be influenced by various drugs. Of potential clinical importance are drugs that cause the induction of enzymes that are responsible for the degradation of estrogens and progestins, and drugs that interrupt entero-hepatic recirculation of estrogen (e.g. certain antibiotics) 72.

The proposed mechanism of interaction of antibiotics is different from that of liver enzyme-inducing drugs. Literature suggests possible interactions with the concomitant use of hormonal contraceptives and ampicillin or tetracycline. In a pharmacokinetic drug interaction study, oral administration of tetracycline HCl, 500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRA® did not significantly affect the pharmacokinetics of norelgestromin or EE.

The major target for enzyme inducers is the hepatic microsomal estrogen-2-hydroxylase (cytochrome P450 3A4) 99. See also PRECAUTIONS, Drug Interactions.


In the clinical trials with ORTHO EVRA®, approximately 2% of the cumulative number of patches completely detached. The proportion of subjects with at least 1 patch that completely detached ranged from 2% to 6%, with a reduction from Cycle 1 (6%) to Cycle 13 (2%). For instructions on how to manage detachment of patches, refer to the DOSAGE AND ADMINISTRATION section.

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