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Transdermal Ethinylestradiol/Norelgestromin

A Review of its Use in Hormonal Contraception

  • Adis Drug Evaluation
  • Published:
Treatments in Endocrinology

En]Summary

Abstract

Ethinylestradiol 20 μg/day plus norelgestromin 150 μg/day have been formulated into a transdermal patch for hormonal contraception. The predominant mechanism of action for transdermal ethinylestradiol/norelgestromin (Ortho Evra™, Evra™) is inhibition of ovulation by suppression of gonadotropins. It suppresses follicular development, induces changes to the endometrium that reduce the probability of implantation, and increases the viscosity of cervical mucus, which may prevent sperm penetration into the uterus.

Two large randomized, nonblind efficacy studies demonstrated that transdermal ethinylestradiol/norelgestromin was as efficacious in preventing pregnancy as oral triphasic ethinylestradiol/levonorgestrel or oral ethinylestradiol/desogestrel. A large, noncomparative study also showed transdermal ethinylestradiol/norelgestromin to have good contraceptive efficacy. Moreover, in the two comparative trials, women using transdermal ethinylestradiol/norelgestromin had higher rates of perfect compliance than women using oral contraception. Age did not affect the rate of perfect compliance in women using the transdermal ethinylestradiol/norelgestromin patch, whereas the rate of compliance reduced with younger age in oral contraceptive users. Pooled results from three efficacy studies found that 1.8% of patches were replaced as a result of complete detachment and 2.9% because of partial detachment. Physical exercise, water immersion, and living in a humid climate did not affect patch adhesion.

Transdermal ethinylestradiol/norelgestromin was generally well tolerated in clinical trials. The most common menstrual disturbances were breakthrough bleeding/spotting and dysmenorrhea. The incidence of discontinuation of treatment because of an adverse event was ≤3.2%, with the most common reason being application-site reactions.

Conclusions: Transdermal ethinylestradiol/norelgestromin offers a well tolerated, effective, reversible, and easy-to-use method of hormonal contraception with an increased likelihood of compliance relative to oral contraceptives.

Pharmacodynamic Properties

The predominant mechanism of action for transdermal ethinylestradiol/norelgestromin is suppression of gonadotropins, resulting in inhibition of ovulation. The estrogenic component, ethinylestradiol, acts mainly by inhibiting development of follicles through reducing the secretion of follicle-stimulating hormone and by reducing the stimulus for the release of luteinizing hormone (LH). The progestin, norelgestromin, is thought to act by suppressing the preovulatory rise of LH. Moreover, with hormonal contraceptive use, there is an increase in the viscosity of cervical mucus, which may prevent sperm penetration into the uterus, and changes are induced in the endometrium that reduce the chances of implantation.

In a randomized, nonblind trial, transdermal ethinylestradiol/norelgestromin 10/75, 15/112.5 or 20/150 μg/day suppressed ovulation in a dose-related fashion. It also suppressed follicular development (measured by maximum mean follicular diameter) in randomized, nonblind trials; at a dosage of 20/150 μg/day, transdermal ethinylestradiol/norelgestromin was at least as effective as oral contraceptives (ethinylestradiol/norgestimate or monophasic or triphasic ethinylestradiol/levonorgestrel). The drug also caused similar changes in cervical mucus and endometrium to those observed with oral triphasic ethinylestradiol/levonorgestrel 30/50, 40/75 and 30/125 μg/day or ethinylestradiol/desogestrel 20/150 μg/day.

Transdermal ethinylestradiol/norelgestromin increased serum lipid levels, other than high-density lipoprotein2 cholesterol levels and calculated low-density lipoprotein cholesterol levels, relative to placebo, but had similar effects on coagulation parameters to oral ethinylestradiol/desogestrel and oral triphasic ethinylestradiol/levonorgestrel.

Pharmacokinetic Properties

After multiple applications of transdermal ethinylestradiol/norelgestromin 20/150 μg/day, mean maximum serum concentrations of 0.096 μg/L of ethinylestradiol and 1.14 μg/L of norelgestromin were reached after 53.5 and 45.8 hours, respectively. Of note, mean and steady-state serum concentrations of ethinylestradiol and norelgestromin remained within the range required for contraceptive efficacy even with extended patch-wear of up to 3 additional days.

Although the transdermal delivery system avoids first-pass metabolism, ethinylestradiol is hydroxylated in the liver to various glucuronide and sulfate metabolites, and norelgestromin is metabolized to norgestrel as well as other hydroxylated and conjugated metabolites. The mean elimination half-lives for ethinylestradiol and norelgestromin are approximately 20 and 29 hours, and the metabolites of both are eliminated in the urine and feces.

The contraceptive efficacy of the transdermal ethinylestradiol/norelgestromin patch, like that of oral contraceptive agents, may be reduced with coadministration of certain drugs, including rifampin (rifampicin), ampicillin, barbiturates, griseofulvin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, hypericum (St John’s Wort) and protease inhibitors.

Clinical Efficacy

In two large randomized, nonblind, multicenter studies, transdermal ethinylestradiol 20 μg/day plus norelgestromin 150 μg/day had contraceptive efficacy similar to that of oral triphasic ethinylestradiol/levonorgestrel (30/50, 40/75, and 30/125 μg/day, for days 1–6, 7–11, and 12–21 of each cycle) and oral ethinylestradiol/desogestrel (20/150μg daily) after 6 or 13 cycles. Cumulative life-table pregnancy rates and Pearl indices for overall and method failure rates did not differ significantly between the transdermal patch and oral contraceptives. Moreover, in a large noncomparative, multicenter study, transdermal ethinylestradiol/norelgestromin showed good contraceptive efficacy as measured by life-table pregnancy rates and Pearl indices. Pooled analysis showed that, of the on-therapy pregnancies (n = 15) that occurred in the three efficacy studies, 33% were in the subset of <3% of participants who had a bodyweight of ≥90kg.

Women using the transdermal ethinylestradiol/norelgestromin patch had significantly (p < 0.001) higher perfect compliance rates (using the drug exactly as instructed) than women using oral contraceptives in randomized trials. Moreover, a significant trend demonstrated reduced compliance with younger age in oral contraceptive users, whereas there was no significant difference in compliance across age groups among the transdermal patch users.

During three efficacy studies in which more than 70 000 patches were used (7-day duration of application), 1.8% were replaced because of complete detachment and 2.9% for partial detachment. Neither living in a humid climate nor physical activity, including exercise, heat, humidity, and water immersion, seemed to affect patch adhesion. Detachment rates declined during the course of the studies, possibly because women became more experienced with application of the patches.

Tolerability

Dysmenorrhea and breakthrough bleeding/spotting were the most common menstrual disturbances observed in women receiving ethinylestradiol/norelgestromin patches in efficacy and dose-finding studies. The incidence of breakthrough bleeding/spotting had reduced to <10% by the sixth cycle of treatment, and was generally similar to the incidence in women receiving oral triphasic ethinylestradiol/levonorgestrel. The incidence of dysmenorrhea with ethinylestradiol/norelgestromin patches was≥10% in randomized, nonblind and noncomparative studies.

Nonmenstrual adverse events occurred with similar incidence among both transdermal patch users and oral contraceptive users, with the exception of application site reaction and breast discomfort, which occurred more frequently in patch users. The incidence of breast discomfort decreased after the first few cycles and by about the third cycle was not significantly different to the incidence in oral contraceptive users. Nausea and headache occurred in ≈20% of women using the ethinylestradiol/norelgestromin patches; however, <2% discontinued treatment as a result of either of these adverse effects. Transdermal ethinylestradiol/norelgestromin had a similar effect on bodyweight as placebo and oral ethinylestradiol/levonorgestrel, with mean increases of <1kg. Treatment-limiting adverse events were low: ≤3.2% of women discontinued transdermal treatment because of an adverse event, with application-site reactions being the most frequent cause.

Dosage and Administration

The ethinylestradiol/norelgestromin 20/150 μg/day transdermal patch is approved in the US and the EU for use in the prevention of pregnancy. The patch should be applied to clean, dry, intact skin of either the abdomen, upper arm, the buttock or upper torso (excluding the breasts). If a woman is using the patch for the first time, she should wait until her menstrual period begins and apply the patch within 24 hours (no backup contraception required). If the patch is applied after the first day of the menstrual cycle (e.g. applying the patch on the first Sunday after menstruation begins is a stated option in US prescribing information), nonhormonal backup is required for the first week of the first cycle. A new patch should be applied every 7 days for the first 3 weeks of each cycle, and each patch should not be worn for more than 7 days.

In the event of a partial or complete detachment (up to 24 hours), reattachment should be attempted or a new patch should be applied immediately. If a patch is detached for more than 24 hours (or duration of detachment is unknown), a new contraceptive cycle should be started immediately and backup contraception used for the next 7 days.

If a woman forgets to apply a patch at the start of the cycle, a patch should be applied as soon as possible and backup contraception should be used for the first week. If a woman forgets to change a patch at the end of the first or second week, the old one should be removed and a new one applied but no backup contraception is necessary if this is done within 48 hours. If it has been longer than 48 hours, a new cycle should be started and backup contraception should be used for 7 days.

The contraindications and warnings that apply to orally administered hormonal contraceptives should also be considered when prescribing the transdermal ethinylestradiol/norelgestromin patch. There appears to be an increased risk of pregnancy in women ≥90kg, compared with individuals of lower bodyweight, who use transdermal ethinylestradiol/norelgestromin.

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Notes

  1. Use of tradenames is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Inc., 860 Town Center Drive, Langhorne, Pennsylvania, 19047, USA

    Karen L. Goa, Gregory T. Warner & Stephanie E. Easthope

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  1. Karen L. Goa
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Correspondence to Stephanie E. Easthope.

Additional information

Various sections of the manuscript reviewed by:

P.D. Darney, Center for Reproductive Health Research and Policy, University of California, San Francisco, California, USA; G.W. Davila, Section of Urogynecology and Reconstructive Pelvic Surgery, Cleveland Clinic Florida, Weston, Florida, USA; C. Davtyan, David Geffen School of Medicine, University of California, Los Angeles, California, USA; J. Evans, Christchurch Women’s Hospital, Christchurch, New Zealand; F. Langdana, Wellington School of Medicine, Wellington, New Zealand; R. Reid, Christchurch School of Medicine, Christchurch, New Zealand; J.S. Sanfilippo, Magee Women’s Hospital, Pittsburgh, Pennsylvania, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ethinylestradiol/norelgestromin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘ethinylestradiol norelgestromin’ and (‘transdermal’ or ‘patch’). EMBASE search terms were ‘transdermal’ and ‘contraception’. AdisBase search terms were (‘ethinylestradiol norelgestromin’ or ‘ethinylestradiol norgestimate’) and (‘transdermal’ or ‘patch’). Searches were last updated 14 Apr 2003.

Selection: Studies in ovulatory females who received ethinylestradiol/norelgestromin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: ethinylestradiol norelgestromin, ethinylestradiol norgestimate, contraception, pharmacodynamics, pharmacokinetics, therapeutic use.

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Goa, K.L., Warner, G.T. & Easthope, S.E. Transdermal Ethinylestradiol/Norelgestromin. Mol Diag Ther 2, 191–206 (2003). https://doi.org/10.2165/00024677-200302030-00005

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