Contraceptive Technology Reports: A Transdermal Delivery System Examined: Ethinyl Estradiol and Norelgestromin for Contraception

Author: David F. Archer, MD, Director, Clinical Research Center, The Jones Institute for Reproductive Medicine, The Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk.

Peer reviewer: Kirtly Parker Jones, MD, Professor, Vice Chair for Educational Affairs, Department of OB/GYN, University of Utah Health Sciences Center, Salt Lake City.


The most common form of contraception used by women is an oral tablet consisting of an estrogen and a progestin. The oral contraceptive, which consists of various doses of ethinyl estradiol and a progestational agent, is widely used by women throughout the world. There have been few, if any, attempts to develop new and innovative methods of hormonal contraception in recent years. There has been an increasing interest in delivering hormonal contraceptives using implantable, injectable, transvaginal, or transdermal routes. Each of these approaches has advantages and disadvantages. Perhaps the major advantage of an injectable, implantable, and even a transdermal delivery system is the lowered motivation required by the consumer when using the product. It should be noted that injectable and implantable contraceptive methods require a health care provider. Transdermal contraception only requires a motivated consumer for its use. The frequency of required consumer action with other contraceptive methods varies from daily, monthly, and quarterly to every five years. In comparison, the transdermal system requires consumer action once a week. Clinical trial data indicate that compliance, meaning perfect use of the method, was 88%-91% with the transdermal system.1

Compliance, as measured by appropriate use of the transdermal contraceptive, was better than an oral contraceptive, specifically in younger women between ages 18 and 28.1 Compliance improves with age and, of course, this is due to multiple factors involved in the individual’s life and lifestyle.

The transdermal contraceptive delivery system now available contains ethinyl estradiol and norelgestromin (Ortho Evra/Evra, Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ). This is the only transdermal hormonal method currently available for contraception.

Pharmacokinetics and Pharmacodynamic Profile

The delivery of progestins across the skin has been fraught with difficulty. The problem has been finding an appropriate formulation to deliver sufficient quantities of the progestin required for an effective contraceptive.2 Norethindrone acetate is available as a hormone replacement therapy delivery system, but it has not been developed as a contraceptive.3 Levonorgestrel has been found to be capable of being delivered across the skin in concentrations that could be contraceptive.2, 4-11 At the present time, no transdermal system delivering levonorgestrel or norethindrone acetate used for contraception is commercially available in the United States, although there is clinical development of these steroids.12

The pharmacokinetic profile of the transdermal ethinyl estradiol /norelgestromin (EE/NEGL) shows comparable area under the curve concentrations of both steroids to that achieved for these hormones with an oral contraceptive, Ortho-Cyclen (Ortho-McNeil Pharmaceutical Co., Raritan, NJ).13

The advantage in the delivery of the transdermal hormone is the relatively stable serum blood levels that are obtained for ethinyl estradiol and norelgestromin.14-16 This is different than the rise and fall that is seen with the use of an oral preparation.13

The current dose of the transdermal EE/NEGL delivers 20 mcg per day of ethinyl estradiol and 150 mcg per day of norelgestromin, which is a concentration well within the established reference range for both hormones used as contraception.13

Application of the contraceptive transdermal system (TDS) to the arms, lower abdomen, lower back, or thighs shows slight variability in the overall pharmacokinetic profile. However, the variability is not sufficiently different to be outside of the contraceptively efficacious range.13

The use of the transdermal approach for the delivery of contraceptive steroids is unique and avoids the gastrointestinal absorption and first pass effect of the liver. There has been concern over the interaction between oral antibiotics and oral contraceptive steroids, which implies a gastrointestinal alteration in metabolism and a hepatic induction of enzymes.17 No change in the pharmacokinetic profile of either ethinyl estradiol or norelgestromin delivered transdermally was found with the concomitant use of oral tetracycline.13

Contraceptive Efficacy

There have been three clinical trials that have evaluated the contraceptive efficacy of the TDS containing EE/NEGL for contraception.18-20

These studies have been combined into one analysis recently reported in Fertility and Sterility, which demonstrates a perfect-use failure rate through 13 cycles of 0.8% (95% confidence interval, 0.3-1.3%).21 The corresponding Pearl index from these three studies was 0.88 (95% confidence interval, 0.44-1.33), which is comparable to that of oral contraceptives in the U.S. marketplace.21

There was a small subgroup of women whose body weight was greater than 198 pounds who appear to have an increased risk of pregnancy while using the TDS for contraception.21 This subgroup was apparent in only one of the three clinical trials.21 Counseling and clinical judgment should be involved in the decision as to whether to use the transdermal contraceptive for an individual weighing more than 200 pounds (> 90 kg).

The occurrence of breakthrough bleeding was reduced with time for women using an oral contraceptive or the TDS contraceptive.21 It should be noted, that at all time intervals, there was less incidence of breakthrough bleeding or breakthrough bleeding and spotting with the TDS contraception as compared to the oral contraceptive.21 This may indeed reflect the consistency of the administration of the hormone by the transdermal route without the fluctuations that are seen with oral administration as evidenced in the pharmacokinetic profile.13

Contraceptive efficacy is associated with consumer compliance. There was a trend, although not statistically significant, for the pregnancies to occur in the younger women where the compliance was not as consistent as with older women.1 Certainly, there is always the potential of a method failure, but many of the pregnancies that do occur in clinical trials appear to be participant failure rather than the method itself.

Side Effects

During this study, 74% of the participants completed all 13 cycles of treatment in all three studies.21 Common side effects were those associated with standard oral contraceptives. The major reasons for discontinuation of the TDS were adverse events in 12% of the participants, the individual’s choice or personal reasons in 7%, and lost to follow-up in 4% of the women.21

One of the issues of efficacy in terms of a contraceptive TDS would be the ability of the system to consistently adhere to the skin. Disruption of the interface between the transdermal system and the skin results in a lower flux of the hormone across the skin. Skin adherence was studied in women using the transdermal system in warm humid climates and undergoing a variety of physical activities.22 In these studies, the individuals were asked to use a sauna, use a whirlpool, exercise, or immerse in cool water for 15-20 minutes to document the adhesive profile of the contraceptive TDS.22 It was found that only 1.8% of the patches required replacement because of complete detachment. Further, only 2.9% of the patches had to be replaced because of partial detachment, and it appeared that the adhesive properties of the patch improved with time or reapplication.22

The contraceptive TDS (Evra/Ortho Evra) comes in one size: a 20-cm square patch. Although lower patch sizes have been shown to have dose proportionality with the delivery of the hormones, the most contraceptively efficacious system is with this larger size that, generally speaking, is applied to the lower abdomen or the buttocks.13 It has been shown that the buttocks was the sight of application for consumers in more than 50% of the applications. However, the arms, legs, and other parts of the torso, excluding the breast, have been used for application of the transdermal contraceptive.13 (See Table 1, "Transdermal Contraceptive System Overview," below.)


In summary, the new contraceptive delivery system involving the transdermal delivery of ethinyl estradiol and the progestin norelgestromin (Ortho Evra) is now commercially available on the U.S. marketplace. This contraceptive TDS is highly effective, with a Pearl index and an overall pregnancy rate that is comparable to that found with oral contraceptives. The compliance with the method was high in contrast to oral contraceptive users, which should improve the overall contraceptive efficacy. Loss of adhesive through exercise or immersion in water was minimal and should not detract from the use of this method in the future.


1. Archer DF, Bigrigg A, Smallwood GH, et al. Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women. Fertil Steril 2002; 77 Suppl 2:27-31.

2. Chien YW, Chien TY, Bagdon RE, et al. Transdermal dual-controlled delivery of contraceptive drugs: Formulation development, in vitro and in vivo evaluations, and clinical performance. Pharm Res 1989; 6:1,000-1,010.

3. Archer DF, Furst K, Tipping D, et al. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol 1999; 94:498-503.

4. Friend DR. Transdermal delivery of levonorgestrel. Med Res Rev 1991; 11:49-80.

5. Friend DR. Transdermal delivery of contraceptives. Crit Rev Ther Drug Carrier Syst 1990; 7:149-186.

6. Friend DR, Catz P, Heller J, et al. Transdermal delivery of levonorgestrel. V. Preparation of devices and evaluation in vitro. Pharm Res 1989; 6:938-944.

7. Friend DR, Catz P, Phillips S. Transdermal delivery of levonorgestrel. VII. In vivo studies. Contraception 1989; 40:73-80.

8. Friend DR, Catz P, Heller J, et al. Transdermal delivery of levonorgestrel. IV: Evaluation of membranes. J Pharm Sci 1989; 78:477-480.

9. Catz P, Friend DR. In vitro evaluations of transdermal levonorgestrel. Drug Des Deliv 1990; 6:49-60.

10. Vora B, Khopade AJ, Jain NK. Proniosome-based transdermal delivery of levonorgestrel for effective contraception. J Control Release 1998; 54:149-165.

11. Deo MR, Sant VP, Parekh SR, et al. Proliposome-based transdermal delivery of levonorgestrel. J Biomater Appl 1997; 12:77-88.

12. Sitruk-Ware R. Transdermal application of steroid hormones for contraception. J Steroid Biochem Mol Biol 1995; 53:247-251.

13. Abrams LS, Skee D, Natarajan J, et al. Pharmacokinetic overview of Ortho Evra/Evra. Fertil Steril 2002; 77 Suppl 2:3-12.

14. Abrams LS, Skee DM, Natarajan J, et al. Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception 2001; 64:287-294.

15. Abrams LS, Skee DM, Natarajan J, et al. Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra/Evra) under conditions of heat, humidity, and exercise. J Clin Pharmacol 2001; 41:1,301-1,309.

16. Abrams LS, Skee DM, Wong FA, et al. Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin Pharmacol 2001; 41:1,232-1,237.

17. Archer J, Archer D. Oral Contraceptive Efficacy and Antibiotic Interaction: A Myth Debunked. J A Dermatology Submitted.

18. Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs. an oral contraceptive: A randomized controlled trial. JAMA 2001; 285:2,347-2,354.

19. Smallwood GH, Meador ML, Lenihan JP, et al. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol 2001; 98(5 Pt 1):799-805.

20. Archer D, Hedon B, Helmerhorst F, et al. Comparison of efficacy, cycle control, compliance, and safety in users of a contraceptive patch vs. an oral contraceptive. Int J Gynaecol Obstet 2000; 70(Suppl 1):78.

21. Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: The analysis of pooled data. Fertil Steril 2002; 77 Suppl 2:13-18.

22. Zacur HA, Hedon B, Mansour D, et al. Integrated summary of Ortho Evra/Evra contraceptive patch adhesion in varied climates and conditions. Fertil Steril 2002; 77 Suppl 2:32-35.

Table 1

Transdermal Contraceptive System Overview

This system uses a 28-day (four-week) cycle. A new patch is applied each week for three weeks (21 total days). Week Four is patch-free. Withdrawal bleeding is expected during this time.

Every new patch should be applied on the same day of the week. This day is known as the "Patch Change Day." For example, if the first patch is applied on a Monday, all subsequent patches should be applied on a Monday. Only one patch should be worn at a time.

On the day after Week Four ends, a new four-week cycle is started by applying a new patch. Under no circumstances should there be more than a seven-day patch-free interval between dosing cycles.

If the woman is starting Ortho Evra for the first time, she should wait until the day she begins her menstrual period. Either a First Day start or Sunday start may be chosen. (See below.) The day she applies her first patch will be Day 1. Her "Patch Change Day" will be on this day every week.

For First Day Start: The patient should apply her first patch during the first 24 hours of her menstrual period.

If therapy starts after Day 1 of the menstrual cycle, a nonhormonal backup contraceptive (such as condoms, spermicide, or diaphragm) should be used concurrently for the first seven consecutive days of the first treatment cycle.


• For Sunday start: the woman should apply her first patch on the first Sunday after her menstrual period starts. She must use backup contraception for the first week of her first cycle.

If the menstrual period begins on a Sunday, the first patch should be applied on that day, and no backup contraception is needed.

Where to apply the patch. The patch should be applied to clean, dry, intact healthy skin on the buttock, abdomen, upper outer arm, or upper torso, in a place where it won’t be rubbed by tight clothing. Ortho Evra should not be placed on skin that is red, irritated, or cut, nor should it be placed on the breasts.

To prevent interference with the adhesive properties of Ortho Evra, no makeup, creams, lotions, powders, or other topical products should be applied to the skin area where Ortho Evra patch is or will be placed.

Application of the Ortho Evra Patch

The foil pouch is opened by tearing it along the edge using the fingers. The foil pouch should be peeled part and open flat. A corner of the patch is grasped firmly, and it is gently removed from the foil pouch.

The woman should be instructed to use her fingernail to lift one corner of the patch and peel the patch and the plastic liner off the foil liner. Sometimes patches can stick to the inside of the pouch — the woman should be careful not to accidentally remove the clear liner as she removes the patch. Half of the clear protective liner is to be peeled away. (The woman should avoid touching the sticky surface of the patch.) The sticky surface of the patch is applied to the skin, and the other half of the liner is removed. The woman should press down firmly on the patch with the palm of her hand for 10 seconds, making sure that the edges stick well. She should check her patch every day to make sure it is sticking.

The patch is worn for seven days (one week). On the "Patch Change Day," Day 8, the used patch is removed and a new one is applied immediately. The used patch still contains some active hormones — it should be carefully folded in half so that it sticks to itself before throwing it away.

A new patch is applied for Week Two (Day 8) and again for Week Three (on Day 15), on the usual "Patch Change Day." Patch changes may occur at any time on the Change Day. Each new Ortho Evra patch should be applied to a new spot on the skin to help avoid irritation, although they may be kept within the same anatomic area.

Week Four is patch-free (Day 22 through Day 28), thus completing the four-week contraceptive cycle. Bleeding is expected to begin during this time.

The next four-week cycle is started by applying a new patch on the usual "Patch Change Day," the week after Day 28, no matter when the menstrual period begins or ends.

Under no circumstances should there be more than a seven-day patch-free interval between patch cycles.

Source: Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ. Web:

CME Objectives/Questions

After reading this issue, the CME participant will be able to:

  • identify perfect use of the transdermal contraceptive delivery system (patch) in clinical trials;
  • compare compliance for the patch and oral contraceptives (OCs) for women ages 18-28;
  • contrast the area under the curve for ethinyl estradiol and norelgestromin with the patch and a comparable OC;
  • identify whether serum concentrations of ethinyl estradiol and norelgestromin with the patch were found to change or be unmeasurable during one week of extreme temperature, humidity, and exertion; and
  • compare the method failure of the patch with OCs.

1. Compliance or perfect use of the patch in clinical trials is reported to be:

a. 48%-51%.

b. 68%-71%.

c. 88%-91%

d. none of the above

2. Compliance, measured by perfect use, is better for the patch compared to OCs in women ages 18-28.

a. True

b. False

3. The area under the curve of the serum concentrations for ethinyl estradiol and norelgestromin following use of the patch compared to a comparable OC is:

a. lower.

b. higher.

c. similar.

d. not evaluated.

4. Serum concentrations of ethinyl estradiol and norelgestromin with the transdermal system, during one week of extreme temperature, humidity, and exertion, were found to be:

a. unchanged.

b. increased.

c. decreased.

d. unmeasureable.

5. The perfect-use failure rate of 0.8% with the transdermal contraceptive patch, when compared to OCs, is:

a. better.

b. worse.

c. similar.