What's New in Transdermal Contraception: Today's Patch
From a worldwide perspective, the need for contraception will continue to grow due to demographic realities; by 2050 an estimated 26 billion new couples will require contraception.1 Currently 40% of all pregnancies worldwide occur to women who absolutely did not want to conceive at the time they did. Pairing that figure with the current material mortality numbers of over 250,000 deaths each year yields the tragic fact that over 100,000 young women die each year because they could not or did not prevent a pregnancy they did not want to have. Women with unintended pregnancies have higher rates of preterm delivery, and premature rupture of membranes.2
In the United States, increased use of IUDs and implants has reduced the unintended pregnancy rate, but still 45% of pregnancies are unintended at a time when maternal mortality ratios and the numbers of women suffering severe maternal morbidity are increasing.3,4,5,6 Unintended pregnancies occur in every age group; 80% of adolescent pregnancies are unintended and nearly half of pregnancies to women over 40 are unintended.7 Almost half of the US unintended pregnancies can be attributed to nonuse of contraception by sexually active couples, but half is due to contraceptive failure, which also often involves user error. Better understanding of the factors underlying poor use of contraception can help reduce this tragedy. Women (and clinicians) may still harbor misperception about the risks of contraception or may not appreciate the health risks of pregnancy.8 Financial and administration barriers to women’s access to contraception need to be overcome. Resources within the medical team need to be available to provide timely options. And new options that make it easier or more pleasant for couples to use contraception are needed.
Contraceptive implants and intrauterine devices (both hormonal and copper) have provided the most effective, reversible pregnancy protection that is also so convenient that some have described it as “forgettable.” But many women are apprehensive about losing control over their fertility. The price of that control, however, is diligence. Oral contraceptive pills offer top tier contraceptive efficacy if they are taken correctly and consistently. Daily pill taking requirements can be challenging at multiple levels – from having adequate supplies on hand to remembering to take a pill each day. Statistics show this is not easily accomplished. In one large study, it was found that fewer than 30% of women obtained their pill supplies from pharmacies on time for one year.9 Logistic barriers are even more important to interruption of pill use than are side effects.10 Other studies have shown that even if supplies were available, over 50% of established pill users miss at least 3 pills a pack.11
To break down many practice-based access barriers, comprehensive evidence-based guidelines have been published in recent years. The first was the US Medical Eligibility Criteria from the CDC which was most recently updated in 2016. The US MEC rates the safety of each of the different contraceptive methods for women with a range of medical conditions to enable individualized counselling.12 The second was the US Selected Practice for Contraceptive Use, which was also updated in 2016.13 This document pared down the numbers of examinations and laboratory tests needed for family planning and separated those services from what is integral to well-women care. It also promoted reproductive life planning and quick start of contraceptives. Reproductive life planning helps women identify their reproductive goals (how many children do they want and when) in order to determine which immediate contraceptive methods would best meet their needs. Quick start (AKA same day start) encourages immediate method initiation as long as the clinician can be reasonably certain that the woman is not pregnant. Patient-centered counseling has built upon the lessons learned from the CHOICE contraceptive project that women should be offered their contraceptive options in order of efficacy in typical use.14 Added to that approach is the need to highlight the noncontraceptive benefits that might be important to the individual woman and the attributable risks/side effects of each of these methods.
Are you a good pill taker?
For user-controlled methods, how often did you forget to use the method?
Are there any methods you have heard about and would like to try?
How important is spontaneity of use?
Is protection form STIs important considering your life situation?
Is cost an issue? Does your health insurance plan cover any contraceptive method?
Do you want scheduled bleeding?
To address the challenges posed by daily administration, combined hormonal contraceptives have been made available in transdermal patches that last for 7 days and vaginal contraceptive rings that provide pregnancy protection for a month. Transdermal patches are particularly appropriate for women who want scheduled monthly bleeding and are more amenable to externally visible methods than they are to intravaginally placed methods. Each patch contains a fixed amount of estrogen (ethinyl estradiol (EE)) and a progestin that is absorbed through the skin directly into systemic circulation bypassing the first pass effect seen with oral contraceptives.
Women need to be instructed on how to use patches. One patch can be placed anywhere on the woman’s torso except her breasts (lower abdomen, buttocks, back); some patches can be put on the upper arm. After one patch has been in place for 7 days, the next one is placed in a different area of the skin. After 3 consecutive weekly patches, women have a patch-free week during which their scheduled bleeding starts.
Women considering the patch also need to understand what risks and side effects they potentially may face with its use. Most of those risks are related to use of exogenous estrogen and are generally similar to those risks posed by combination oral contraceptives: thromboembolism (both venous and arterial), melasma, bleeding changes and elevation in blood pressure. In addition, women should understand the side effects uniquely related to patch use, including skin irritation and how to manage patch detachment.
In the United States, the history of the first contraceptive patch was one of the most dramatic examples of the boom and bust pattern so frequently seen in contraception.15 The Ortho Evra patch was introduced in May 2002 and enjoyed a meteorite rise in popularity. Women were attracted by the convenient once-a-week dosing while clinicians were impressed with the steady state hormonal levels that avoided peaks and troughs seen with daily pill ingestion and with the higher levels of correct and consistent use reported by patch vs pill users in the clinical trials. By November 2002, the patch was the second most frequently prescribed combined hormonal contraceptive product. Post hoc analysis showed that women with higher weights had higher failure rates, so labeling changes were introduced suggesting that patch use in women weighing more than 70 kg might not be appropriate candidates. A year or so later, concerns about potentially higher risks for venous thrombosis with the patch were first raised. Although the transdermal route avoided hepatic first pass effects on coagulation factors, two features of the Ortho-Eva patch lent biological plausibility to the potential for its increased venous thromboembolism. The first was that the total 24-hour estrogen exposure (area-under-the-curve) was 60% higher with patch than it was with the comparator 30 mcg oral contraceptive. The second was that the progestin used in the Ortho Evra patch was an active metabolite of a third-generation progestin, norgestimate; third generation progestins had been associated with potentially higher VTE risk than the more androgenic second-generation progestin, levonorgestrel. Labeling changes indicated that some (but not all) epidimediologic studies found higher VTE risk with this patch. Sales of Ortho Evra plunged and all promotional activities were halted. In 2015 a generic formulation (Xulane) was introduced and had completely replaced Ortho Evra by 2016.
The fall of the Ortho Evra patch created an opportunity for newer formulations of transdermal products if they could avoid the concerns that were raised with the first-generation patch. Two investigational patches have been developed; each of them has lowered the dose of estrogen absorbed and one has replaced a third-generation progestin with a second-generation progestin.
The first of these is a patch with 0.55mg ethinyl estradiol and 2.1mg gestodene called Apleek® (Bayer AG, Berlin, Germany). The total 24-hour estrogen exposure with this patch is similar to a 19-23mg EE-containing oral contraceptive;16 by comparison the original EE/NGT patch had steady state EE that was 2.0-2.7 times higher.16 A Phase III 13-cycle clinical trial conducted with 1,631 subjects in 7 European and Latin American sites reported a Pearl Index of 1.19 pregnancies per 100 women-years. Correcting for pregnancies that resulted from noncompliance, the Pearl Index with correct and consistent use was 0.81 pregnancies per 100 woman-years.17 Compliance was good; 97.9% of women placed all of their patches as directed. Complete detachment was reported in 5.7% of patches; complete or partial detachment occurred at least once to 15.3% of subjects; application site irritation was reported by 8.5% of subjects. Unscheduled bleeding declined from 11.4% of subjects in cycle 1 to 6.5% in cycle 12. Two cases of pulmonary embolism occurred.17 It should be noted this method has been available in Europe since 2014; it is not known if and when product approval will be sought in the United States.
The second patch called Twirla® (Agile Therapeutics, Princeton, NJ) is composed of 2.3mg ethinyl estradiol and 2.6 mg levonorgestrel. The calculated daily estrogen dose is similar to a COC containing 30mcg EE pill, half the estimated daily EE dose seen with the Ortho Evra patch.18,19 Three Phase III clinical trials have studied patch efficacy, safety, patient compliance and bleeding patterns. In a comparative trial of the patch versus oral contraceptives with 20mcg EE/100mcg levonorgestrel, 1,504 women were enrolled: 30% were obese; 40% represented racial/ethnic minorities; 55% were new users of hormonal contraception. The total pregnancy rates (Pearl index) for the patch was 4.45 per 100 woman-years and for the pill was 4.02 per 100 women-years. With correct and consistent use those rates were 2.82 and 3.60.20,21
The latest Phase III trial was required by the FDA before it would consider any approval. This study was a single arm, more traditional study design, but that also greatly expanded subject eligibility to include women more reflective of today’s women in the United States. Over 2,000 subjects were studied; no upper limits were placed on BMI or age as long as the woman had monthly menses. Only 39.4% had BMI <25 kg/m2; the highest BMI was 63 kg/m2. The study was prospectively designed to study the relationship between BMI and pregnancy rates. Total pregnancy rates among women under age 36 ranged from 3.05 per 100 women-years for normal weight women to 6.42 for women with BMI >30 kg/m2. Serious adverse events occurred in 1.97% of patients: cholelithiasis (n=4); deep vein thrombosis (n=3), pulmonary embolism (n=3), depression (n=3), gastroenteritis (n=2), cholecystitis (n=2), and ectopic pregnancy (n=2). Hormonally-related side effects were reported at unusually low levels; nausea (4.1%), headache (3.6%), mood swings (2.8%), mastalgia (1.9%).22 Bleeding patterns were quite acceptable; 2.2% of women discontinued the study due to bleeding or spotting problems.23
Transdermal contraception has been available in the United States for 15 years. It was a very popular method when it was first introduced, but that popularity fell due to issues around safety, raised by relative high estrogen exposure and use of a third-generation progestin. Two new transdermal patches have been developed. One is available in Europe (Apleek) with low levels ethinyl estradiol and a third-generation progestin. The second patch with lower levels of EE and a second-generation progestin (Twirla) has just completed a Phase 3 clinical trial in the United States much more representative of modern US women. The potential availability of a new patch that address the concerns raised by the first-generation patch holds promise that transdermal contraceptive can return as a first-line, mainstream option for women seeking the features of combined hormonal contraception with added convenience of once-a-week administration.
- Sitruk-Ware R. Contraception: an international perspective. Contraception. 2006;73(3):215-22.
- Mohllajee AP, Curtis KM, Morrow B, Marchbanks PA. Pregnancy intention and its relationship to birth and maternal outcomes. Obstet Gynecol. 2007;109(3):678-86.
- Finer LB, Zolna MR. Declines in Unintended Pregnancy in the United States, 2008-2011. N Engl J Med. 2016;374(9):843-52.
- MacDorman MF, Declercq E, Thoma ME. Trends in Maternal Mortality by Sociodemographic Characteristics and Cause of Death in 27 States and the District of Columbia. Obstet Gynecol. 2017;129(5):811-818.
- Molina RL, Pace LE. A Renewed Focus on Maternal Health in the United States. N Engl J Med. 2017;377(18):1705-1707.
- Creanga AA, Bateman BT, Kuklina EV, Callaghan WM. Racial and ethnic disparities in severe maternal morbidity: a multistate analysis, 2008-2010. Am J Obstet Gynecol. 2014;210(5):435.e1-8.
- Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception. 2011;84(5):478-85.
- Nelson AL, Rezvan A. A pilot study of women's knowledge of pregnancy health risks: implications for contraception. Contraception. 2012;85(1):78-82.
- Nelson AL, Westhoff C, Schnare SM. Real-world patterns of prescription refills for branded hormonal contraceptives: a reflection of contraceptive discontinuation. Obstet Gynecol. 2008;112(4):782-7.
- Westhoff CL, Heartwell S, Edwards S, Zieman M, Stuart G, Cwiak C, Davis A, Robilotto T, Cushman L, Kalmuss D. Oral contraceptive discontinuation: do side effects matter? Am J Obstet Gynecol. 2007;196(4):412.e1-6.
- Potter L, Oakley D, de Leon-Wong E, Cañamar R. Measuring compliance among oral contraceptive users. Fam Plann Perspect. 1996;28(4):154-8.
- U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. https://www.cdc.gov/reproductivehealth/contraception/pdf/summary-chart-us-medical-eligibility-criteria_508tagged.pdf. Last accessed Nov. 26, 2017.
- CDC U.S. Selected Practice Recommendations for Contraceptive Use, 2016. https://www.cdc.gov/mmwr/volumes/65/rr/rr6504a1.htm. Last accessed Nov. 26, 2017.
- Madden T, Mullersman JL, Omvig KJ, Secura GM, Peipert JF. Structured contraceptive counseling provided by the Contraceptive CHOICE Project. Contraception. 2013;88(2):243-9.
- Boonstra H, Duran V, Northington Gamble V, Blumenthal P, Dominguez L, Pies C. The "boom and bust phenomenon": the hopes, dreams, and broken promises of the contraceptive revolution. Contraception. 2000;61(1):9-25.
- Hofmann B, Reinecke I, Schuett B, Merz M, Zurth C. Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive. Int J Clin Pharmacol Ther. 2014;52(12):1059-70.
- Wiegratz I, Bassol S, Weisberg E, Mellinger U, Merz M. Effect of a low-dose contraceptive patch on efficacy, bleeding pattern, and safety: a 1-year, multicenter, open-label, uncontrolled study. Reprod Sci. 2014;21(12):1518-25.
- Archer D et al. Results from teh pharmacokinetic profile of AG200-15 poster presented at the ACOG Annual Clinical and Scientific meeting. April 30-May 4, 2011.
- Sriprasert I, Stanczyk FZ, Archer DF. Ethinyl estradiol and levonorgestrel in a transdermal contraceptive delivery system. Expert Opin Pharmacother. 2015;16(12):1901-9.
- Kaunitz AM, Portman D, Westhoff CL, Archer DF, Mishell DR Jr, Rubin A, Foegh M. Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial. Obstet Gynecol. 2014;123(2 Pt 1):295-303.
- Kaunitz AM, Archer DF, Mishell DR Jr, Foegh M. Safety and tolerability of a new low-dose contraceptive patch in obese and nonobese women. Am J Obstet Gynecol. 2015;212(3):318.e1-8.
- Nelson AL, Kaunitz AM, Kroll R, et al. Results from the SECURE Trial presented at ACOG Annual Clinical and Scientific meeting May 6-9, 2017.
- Nelson AL, Kaunitz, AM, Kroll R, et al. Bleeding and spotting results from the SECURE Trial: a Phase 3 study of the AG200-15 investigational transdermal contraceptive patch. Presented at the North American Forum on Family Planning. Atlanta, GA Oct. 14-17, 2017.C