Transdermal delivery of combined hormonal contraception: a review of the current literature

Abstract

The transdermal patch provides an effective and convenient option for hormonal contraception. The patch currently on the US market contains 150 µg norelgestromin and 35 µg ethinylestradiol (EE). The 20 cm² patch is applied once weekly for 3 weeks, followed by a patch-free week, for a 21–7 cycle. Typical failure rates are similar to that of combined oral contraceptives (COCs). Transdermal delivery results in less peaks and troughs of estrogen, but a higher total estrogen exposure compared with COCs. Though studies show mixed results, the risk of developing venous thromboembolism (VTE) is about twice as high with the patch as with COCs; however, the absolute risk of VTE remains low. The side effect profile is similar to that of COCs, with slightly higher rates of breast tenderness plus a unique adverse effect of application site reactions. Two new patches have been developed, one containing gestodene and EE in Europe and another containing levonorgestrel and EE. Overall, the patch provides an alternative to COCs for women who want autonomy and the benefit of not needing to take a pill daily, with similar efficacy and tolerability.

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International Journal of Women’s Health 2017:9 315–321
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REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/IJWH.S102306
Transdermal delivery of combined hormonal
contraception: a review of the current literature
Rosanna M Galzote1
Sally Rafie2
Rachel Teal1
Sheila K Mody1
1Section of Family Planning,
Department of Reproductive
Medicine, University of California,
San Diego, 2Department of Pharmacy,
UC San Diego Health, San Diego,
CA, USA
Abstract: The transdermal patch provides an effective and convenient option for hormonal
contraception. The patch currently on the US market contains 150 µg norelgestromin and 35 µg
ethinylestradiol (EE). The 20 cm2 patch is applied once weekly for 3 weeks, followed by a patch-
free week, for a 21–7 cycle. Typical failure rates are similar to that of combined oral contraceptives
(COCs). Transdermal delivery results in less peaks and troughs of estrogen, but a higher total
estrogen exposure compared with COCs. Though studies show mixed results, the risk of developing
venous thromboembolism (VTE) is about twice as high with the patch as with COCs; however, the
absolute risk of VTE remains low. The side effect profile is similar to that of COCs, with slightly
higher rates of breast tenderness plus a unique adverse effect of application site reactions. Two new
patches have been developed, one containing gestodene and EE in Europe and another containing
levonorgestrel and EE. Overall, the patch provides an alternative to COCs for women who want
autonomy and the benefit of not needing to take a pill daily, with similar efficacy and tolerability.
Keywords: contraceptive patch, Ortho-Evra, transdermal, levonorgestrel patch, gestodene
patch, hormonal patch
Background
Since the development of the oral contraceptive (OC) pill in the 1960s, hormonal
contraception has taken many forms. Combined hormonal contraception (CHC),
referring to methods with both estrogen and progestin, can be delivered orally, trans-
dermally, or transvaginally. Although long-acting reversible contraception (LARC)
has become more popular, there is still a desire from patients to have a contraceptive
method they can control. Additionally, hormonal contraception offers benefits not seen
with some of the LARC methods, including improved cycle control and acne treat-
ment. The transdermal and transvaginal contraceptive options give patient autonomy
and the benefit of not needing to use the method daily.
The first transdermal delivery system developed in the 1980s was a scopolamine
patch. Since then, medications that have been developed in a transdermal form
include nicotine, estradiol for hormone therapy, fentanyl, clonidine, nitroglycerin,
among others. For successful delivery of a medication through a transdermal system,
the molecule must be small and lipophilic to permeate through the skin. Estradiol
and ethinylestradiol (EE) are ideal molecules as therapeutic levels can be delivered
easily, whereas progesterone and progestins require higher therapeutic levels.1 The
first transdermal contraceptive patch on the US market, Ortho Evra™ (Ortho-McNeil-
Janssen Pharmaceuticals Inc., Titusville, NJ, USA), was approved by the US Food
and Drug Administration in November 2001.
A transdermal patch offers a number of benefits compared with OCs. There is less
variability in plasma concentrations of estrogen, which may decrease estrogen-related
Correspondence: Sheila K Mody
Section of Family Planning, Department
of Reproductive Medicine, University of
California, San Diego, 9300 Campus Point
Drive, MC 7433, La Jolla, CA 92037, USA
Tel +1 858 249 1205
Fax +1 858 657 7212
Email smody@ucsd.edu
Journal name: International Journal of Women’s Health
Article Designation: Review
Year: 2017
Volume: 9
Running head verso: Galzote et al
Running head recto: Transdermal delivery of combined hormonal contraceptive
DOI: http://dx.doi.org/10.2147/IJWH.S102306
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side effects that result from high peak estrogen levels, such
as nausea. Though peaks and troughs are minimized, overall
estrogen exposure as measured by the area under the con-
centration curve (AUC) is higher with the Ortho Evra patch
compared with the combined oral contraceptives (COCs).
A second major advantage is that the user only changes the
patch once weekly, as opposed to taking a contraceptive pill
daily, which could result in improved adherence. A pooled
study of 1,785 patch users showed perfect use ranging from
88.1% to 91.0% across different age groups. In this study, age
did not affect adherence. Another study has reported larger
differences across age groups.2 In contrast, perfect use of
COCs ranged from 67.7% to 85.2% and differed significantly
by age, with lowest rates in ,20-year-old females.3
Pharmacology and
pharmacodynamics
The Ortho Evra contraceptive patch is a 20 cm2 adhesive that
releases 35 µg EE and 150 µg norelgestromin (NGMN) per
day.4 NGMN is an active metabolite of norgestimate, the
progestin contained in the OCs Ortho-Cyclen® and Ortho
Tri-Cyclen®.4 During development of this product, three
patch sizes, 10, 15, and 20 cm2, were compared in a study
of 610 subjects. It was found that the 20 cm2 patch achieved
ovulation suppression and cycle control similar to that of
Ortho-Cyclen (6.2% 20 cm2 patch, 7.2% Ortho-Cyclen);
thus, the only size patch available is the 20 cm2.5
Reference ranges were set at 0.6–1.2 ng/mL for
NGMN and 25–75 pg/mL for EE, as a developmental tool
to assess efficacy. The concentrations at steady state are
0.83 ng/mL ±0.21 for NGMN and 56.7 pg/mL for EE, both
of which are within the set reference ranges.4 Compared to
the peaks and troughs seen in serum concentrations with the
pill, the patch maintains a steadier concentration throughout
the day. Serum levels of each stayed within the reference
range for the entirety of the 7-day period in the patch’s first
cycle. Serum levels of NGMN and EE were 20% less if worn
on the abdomen compared with the buttock, thigh, or upper
arm, though at all sites, the concentration remained within
the reference ranges. The mean serum levels of NGMN and
EE also remained within the reference range in conditions of
heat, humidity, exercise, and cool-water immersion.4
One study done in the Netherlands compared mean serum
EE concentrations in subjects using the patch (20 µg EE/day),
COC (30 µg EE/day), and NuvaRing® (Merck & Co.,
Kenilworth, NJ, USA; 15 µg EE/day). Concentration over
time was more variable in COCs compared with the patch and
NuvaRing, as the pill had higher peak concentration (Cmax)
of 4.5 times than that of the patch and 1.6 times than that of
the NuvaRing. The overall exposure to EE, measured by the
mean AUC0–21, was highest for the patch that was 3.4 times
that of NuvaRing and 1.6 times that of COCs.6
The mechanism of action of NGMN and EE involves
1) thickening the cervical mucus to prevent sperm penetra-
tion, 2) decreasing the endometrial receptivity to reduce
likelihood of implantation, and 3) inhibiting ovulation by sup-
pressing gonadotropins, follicle-stimulating hormone (FSH),
and luteinizing hormone (LH).7 Steady state concentration
is reached within 2 weeks of patch use, though pregnancy
prevention is achieved after 1 week. The half-lives of NGMN
and EE are 28.4 and 15.2 hours, respectively. Mean FSH,
LH, and estradiol values return to baseline levels 6 weeks
after discontinuation.7
Efcacy
An initial open-label 73-center study in 2001 reported an
overall failure rate of 0.7% and a method-failure rate of 0.4%
through 13 cycles for transdermal delivery. The Pearl index
(PI), or number of pregnancies per 100 woman-years, was
0.71 for overall failure and 0.59 for method failure.8 Similar
numbers were reflected in one subsequent study of pooled
data from three studies in 3,319 women. Failure rates were
0.8% overall and 0.6% from method failure, corresponding
to PIs of 0.88 and 0.7, respectively.9
In a large epidemiological trial in the UK, patients
prescribed Evra™ had an incidence of 0.34 unintended
pregnancies per 100 women-years. This was higher than
the rate with second-generation COCs of 0.16 and 0.12 for
third-generation COCs, but lower than progestin-only pills at
0.43. This case–control study was limited as it analyzed pre-
scriptions of contraception, though did not assess actual use
of each method.10 Pooled data of 812 Ortho Evra patch users
in the US in a 2004 study showed the impact of compliance
on contraceptive efficacy. With perfect compliance, the PI
was 0.73. Imperfect dosing increased failure rates to a PI of
2.33 in patch users. They also found that overall, there was a
significantly higher proportion of cycles with perfect dosing
in patch use compared to OC use (88.7% vs 79.2%).11
Body weight
There was concern over decreased efficacy of transdermal
patches in women with higher body weights. Pooled data from
three multicenter studies showed significantly increased rates of
unintended pregnancy in women $90 kg. In women ,90 kg,
there was no significant association between body weight
and pregnancy. Hormone levels decreased with higher body

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Transdermal delivery of combined hormonal contraceptive
weight, but analyses showed that only 10%–20% of variability
was attributed to body weight.9
A prospective study of contraceptive failures in 1,523
CHC users with a high sample size of obese and overweight
females did not show body mass index (BMI) to be a signifi-
cant risk factor for unintended pregnancy. Three-year failure
rates did not differ across different BMI categories among
CHC users (BMI ,25: 8.44%, BMI 25–30: 11.05%, and
BMI .30: 8.92%). Failure rates were similar across the three
methods: COC, 5.6%; patch, 4.6%; and vaginal ring, 3.4%
(P=0.22). It is postulated that reduced fertility with increased
BMI explains the similar rates of contraception failure.12
Safety
As with any contraceptive containing estrogen, there is a
slightly increased risk of developing venous thromboem-
bolism (VTE) with the patch relative to women not on
hormonal contraceptives. Given the overall higher exposure
to estrogen with the patch (60% greater AUC) compared
to COCs, there was concern that this could translate to an
increased risk of thromboembolism events compared to
women using pills.13
In a postmarketing case–control study published in 2006
by Jick et al,13 nonfatal VTE risk was compared in Ortho
Evra patch users and users of the norgestimate-35 (NGM-35)
OC, containing norgestimate and 35 µg EE, between 2002
and 2004. They found an overall incidence rate for VTE of
52.8 per 100,000 women-years in patch users and 41.8 per
100,000 women-years in NGM-35 OC users. The odds ratio
(OR) for VTE was 0.9 for contraceptive patch users compared
to NGM-35 users.13 A follow-up postmarketing study that
included cases up to 2007 found a higher OR of 2.0 (95% CI
0.9–4.1) between patch and COC users, but concluded that
the patch does not confer statistically significant excess risk
of VTE compared to NGM-35 COC users.14
Findings of a study by Cole et al15 drew different conclu-
sions. The case–control study using private insurance claims
data found a significantly increased risk of VTE, myocardial
infarction, or ischemic stroke in patch users compared to
users of norgestimate-containing COC with 35 µg EE from
2002 to 2004. There was an incidence ratio of 2.2 (95% CI
1.3–1.8) for VTE, with incidences of 40.8 cases per 100,000
woman-years in patch users, compared to 18.3 per 100,000
in norgestimate-containing COC users.15 A study update by
Dore et al16 had consistent findings. They again found an OR
of 2.0 for VTE compared with users of NGM-35 that was
significant.16 The ORs were 0.6 (95% CI 0.1–3.2) for stroke
and 1.2 (95% CI 0.3–4.7) for acute myocardial infarction
(AMI). The incidence of stroke and AMI was low, making it
difficult to understand the precise risk.16 Due to these concerns
over increased risk of thrombotic events, a black box warn-
ing was released by the US Food and Drug Administration
(FDA) in 2004 for Ortho Evra labeling and updated again
most recently in 2011.
Utilization
In 2013, 1.6% of women aged 15–44 years in the US used the
ring or patch, and 2.6% of women using contraception used
either the ring or patch.17 In a study of focus groups of young
women, negative attitudes toward the patch include distrust
of effectiveness, as they are not familiar with this method
of drug delivery, whereas a pill is more widely accepted as
a reliable route. They feared the patch may fall off and held
concerns about visibility. There was also concern regarding
safety and the increased risk of blood clots in this population.
However, many of the women did agree that the patch was
easier to remember to use compared to pills.18
Tolerability
Adverse effects of the patch are similar to those of COCs. The
most commonly reported complaints and reasons for discontin-
uation are mild-to-moderate in severity and include application
site reactions, nausea, emotional lability, headache, and breast
discomfort.8,19 Weight gain is minimal in patch users, similar to
COC users – 87.8% of patch users stayed within 5% of baseline
body weight.19 Rates of unscheduled, or breakthrough bleed-
ing (BTB) and spotting were low (,10% BTB, ,20% BTB/
spotting) and decreased with continued use.9 Application site
reaction is one adverse event unique to the patch. In a pooled
study of 812 patch users, there was a 17.4% overall incidence
of application site reaction, causing discontinuation in 1.9%.
Most reactions (91.4%) were mild-to-moderate in severity.19
Breast symptoms include breast discomfort, engorgement,
and pain. About one-fifth of patch users experienced breast
symptoms, mostly in the first two cycles. They were mild-to-
moderate in severity in most and decreased over time. Breast
symptoms were treatment limiting in 1.9% of participants in
a pooled study. In a comparative study, breast symptoms were
three times more prevalent in patch users than COC users
(18.8% vs 1.6%), but declined to similar rates after the second
cycle.19 Another concern patients express unique to the patch
is detachment. The detachment rate is 4.7% with 1.8% being
fully detached and 2.9% partially detached. A study shows
that adhesion does not differ in conditions of increased heat
and humidity or with exercise. Patients are advised to replace
patches if they become fully or partially detached.20

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Galzote et al
Patient satisfaction
In a study of continuation and satisfaction at 12 months of
women aged 14–45 years in the Contraceptive CHOICE
Project, continuation rates were lowest for the patch at 49.1%
compared to other contraceptive methods (55.1% for COCs to
87.5% for LNG-IUD). Only 35.1% of women using the patch
reported being very satisfied with the method and 55.7% were
not satisfied.21 The most common reasons for discontinuation
of the patch in women in the CHOICE study were not liking
“side effects” and logistical reasons. Approximately 41% of
patch discontinuers reported side effects.21
In contrast, in a small study of 28 adolescents who
started Ortho Evra in 2002–2003, 68% were very satisfied
and 29% were somewhat satisfied, with 93% stating they
would recommend the method to a friend/relative. Despite
high satisfaction rates, adolescents discontinue the patch at
higher rates than COCs.22 A prospective longitudinal study
comparing adolescent use of contraceptive patch versus pills
in 2011 showed after nine cycles that 38% of patch users
compared to 60% of pill users had continued the method
initiated at enrollment. This is despite both methods hav-
ing similar satisfaction and patch users reporting that their
method improved normal daily activities.23
The 1-year contraceptive continuation has been shown
to be low among adolescents. In a 12-month longitudinal
cohort study of 1,387 women aged 15–24 years, the patch
had the lowest continuation rate at follow-up of only 10.9%
compared to 32.7% in pill initiators. Additionally, the preg-
nancy rate in this study was second highest for patch with a
PI (pregnancies per 100 person-years) of 30.1.24 This low rate
of continuation in young women was consistent with another
study in 2015 of 130 adolescents aged 13–20 years. When
offered intrauterine devices (IUDs), injectable, COC, patch,
and the ring, 13% opted for the patch. Six-month continuation
rates were lowest with the patch and ring at 17%, compared
to 88% with the IUD, 20% with the injectable, and 43% with
COCs. Of the 23 who chose the patch or ring, 11 never initi-
ated, 2 continued, and 10 discontinued.25 It is important to
note that this was a small study and reasons for not initiating
or discontinuing methods were not reported.
Current patch
Many of the aforementioned studies are on the Ortho Evra
patch which has been on the market in the US, but the Evra
patch, used in European countries and Canada, has also been
studied extensively.26 This 20 cm2 adhesive contains 600 µg
EE and 6 mg NGMN, releasing 33.9 µg EE and 203 µg NGMN
per day. Studies show that Evra users have higher satisfaction
and compliance rates than COC users.27,28 Although the relative
risk for any VTE has shown to be 2.0 compared to correspond-
ing COCs,29 the Evra patch did not have the same widespread
VTE scare as the Ortho Evra patch did in the US.
New patches
EE/GSD
A novel transparent patch has been developed by Bayer that
delivers 0.5 mg EE and 2.1 mg gestodene (GSD). GSD is a
progestin contained in many COCs widely used in Europe
for years. It is a favorable drug for transdermal use as it
is has an established efficacy and safety profile, and good
skin absorption allowing for a low dose needed and small
patch size. The dosing of this 11 cm2 patch results in the
same amount of hormone exposure as the 0.02 mg EE and
0.06 mg GSD OC. This dosage was justified in a Phase IIa
study that showed ovulation inhibition is not as effective with
half the dose of estrogen or progestin.30 The EE/GSD patch
has decreased EE exposure measured by the AUC compared
to the EE/NGMN patch.31 Similar to the EE/NGMN patch,
there is a 7-day application period for 3 weeks with 1 week
patch-free (21/7). In a Phase III uncontrolled, open-label
study, the EE/GSD patch had an unadjusted PI of 1.19 and
an adjusted PI of 0.81 for pregnancy due to noncompliance.
Of those originally enrolled, 14.3% discontinued due to an
adverse event. Of those who stayed in the study, compliance
was high with a mean of 97.9% and a median of 100%. At
least one adverse event was reported in 61.7% of subjects,
the most common being headache (9.5%), application site
reaction (8.5%), nasopharyngitis (7.0%), cervical dysplasia
including atypical squamous cells of undetermined signifi-
cance (6.2%), and application site erythema (4.9%). Two of
1,631 women in the study were diagnosed with pulmonary
embolism, over the course of the year of the study.32
Despite the lower EE delivery in the EE/GSD patch,
bleeding patterns were shown to be similar compared to the
EE/NGMN patch in a descriptive study. Withdrawal bleed-
ing was shorter in the EE/GSD patch group in the first seven
cycles with similar intensity. The incidence of breast pain
was slightly lower in EE/GSD users compared to tradition
EE/NGMN patch users, which is expected given the total
lower estrogen exposure.33 When compared to a COC con-
taining 0.02 mg EE and 0.1 mg LNG in a Phase III double-
blind, double-dummy multicenter trial, bleeding cycle and
patterns were comparable.34
EE/LNG (AG200-15)
An investigational contraceptive patch, AG200-15, has been
developed by Agile Therapeutics (Princeton, NJ, USA). This
patch is a 15 cm2 matrix core with a surrounding adhesive

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Transdermal delivery of combined hormonal contraceptive
for a total area of 26 cm2, containing 2.3 mg EE and 2.6 mg
levonorgestrel (LNG). Major differences between this and
the currently marketed NGMN/EE patch are the decreased
AUC of estrogen and the use of LNG, which has been shown
to have lower rates of VTE compared to other progestins.
Like the other patches, each patch was applied to the skin
for 7 days three times per cycle followed by one patch-free
week, for a 21/7 cycle. This dosing provides similar LNG
and EE serum concentrations compared to those of 20 µg
LNG and 30 µg EE pill.35
In a Phase III open-label study including obese and
nonobese women, the PI for the patch was 4.45, compared
to 4.02 for the 100 µg LNG, 20 µg EE pill. Compliance was
determined by a self-reporting diary and verified by LNG
and EE levels. After eliminating pregnancies in women
with undetectable hormone levels, the PIs were 2.82 for
the patch and 3.8 for the pill, which, statistically, were not
significantly different. Of note, PIs in obese and nonobese
patients did not significantly differ at 4.59 and 4.40, respec-
tively. Self-reported compliance in this study was 91.6%
in patch users and 79.8% in nonpatch users. However, the
rates of laboratory-confirmed compliance for cycles 2 and
6 were 9.9% and 11% for the patch and 8.8% and 12.6%
for the pill, which were not significantly different for the
two methods. The discrepancy between self-reported and
laboratory-verified compliance sheds light on prior studies
that used patient diaries to assess compliance and may have
been overestimating rates.36 A second Phase III clinical trial
of the EE/LNG patch is being conducted (NCT02158572),
as the first trial including obese and nonobese women had a
high PI and high noncompliance rates.
Bleeding patterns were similar in the patch and pill groups
with 25.4% and 23.2% of women with unscheduled bleeding
or spotting, respectively. There were similar rates of discon-
tinuation due to bleeding for each method. A total of 21.8%
of patch users experienced a drug-related treatment-emergent
adverse event compared with 16% in the pill group. Most
treatment-emergent adverse events were mild-to-moderate
in severity. The most common adverse events were estro-
gen related, including nausea, headache, increased weight,
and breast tenderness.34 Skin reaction occurred in 3.2% of
patch users, a lower rate than that seen with the traditional
NGMN/EE patch.37 Low detachment rates have been reported
(2.0%–3.7%), with sustained wearability with exercise and
in humid climates.38,39
Conclusion
Transdermal patches provide an effective and convenient
method of hormonal contraception. Its once-weekly application
is appealing for women who want an alternative to daily OCs.
Although this offers a theoretical benefit of higher compli-
ance and lower failure rates, efficacy is in the same range as
oral and transvaginal CHCs.40 Compliance rates are reported
to be higher in patch users compared to pill users; although
most studies use diaries or self-reporting to measure compli-
ance, there may be some inaccuracy. Additionally, compli-
ance and continuation are low in adolescents, so the failure
rate with typical use may be higher in this population.
The side effect profile of the patch is similar to that of com-
bined OCs, which are estrogen-related and mostly mild-to-
moderate in severity. These include nausea, breast tenderness,
emotional lability, and dysmenorrhea. One unique adverse
effect is application site reaction, which occurs in ∼20% of
users and is treatment-limiting in 2%. Adhesion of the patch
remains high in humid climates and with exercise.20
An advantage of the transdermal route is that the levels
of estrogen are steady without the peaks and troughs seen
with OCs, but the AUC of estrogen is higher in patch users.
Given the higher total estrogen exposure, there has been
concern raised over a higher risk of VTE compared to pill
users. Studies are conflicting, but there is evidence that
the patch confers a twofold risk of developing a nonfatal
thromboembolic event compared with OCs. Although the
relative risk is higher for VTE compared to OCs the absolute
risk of VTE remains low. In light of this potential increased
risk, two new patches with lower estrogen exposure based
on AUC and different progestins are under investigation.
One is a smaller, transparent EE/GSD patch being studied
in Europe. The other is the EE/LNG patch in the US that
has not yet received FDA approval. It will be interesting to
see if there is higher uptake, acceptability and continuation
with newer patches.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Potts RO, Lobo RA. Transdermal drug delivery: clinical considerations
for the obstetrician-gynecologist. Obstet Gynecol. 2005;105(5 pt 1):
953–961.
2. Bodner K, Bodner-Adler B, Grünberger W. Evaluation of the contra-
ceptive efficacy, compliance, and satisfaction with the transdermal
contraceptive patch system Evra: a comparison between adolescent and
adult users. Arch Gynecol Obstet. 2011;283(3):525–530.
3. 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(2 suppl ):S27–S31.
4. Abrams LS, Skee D, Natarajan J, Wong FA. Pharmacokinetic overview
of Ortho Evra/Evra. Fertil Steril. 2002;77(2 suppl 2):S3–S12.
5. Dittrich R, Parker L, Rosen JB, et al. Transdermal contraception: evalua-
tion of three transdermal norelgestromin/ethinyl estradiol doses in a ran-
domized, multicenter, dose-response study. Am J Obstet Gynecol. 2002;
186(1):15–20.

International Journal of Women’s Health 2017:9
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
320
Galzote et al
6. van del Heuvel MW, van Bragt AJ, Alnabawy AL, Kaptein MC.
Comparison of ethinylestradiol pharmacokinetics in three hormonal
contraceptive formulations: the vaginal ring, the transdermal patch and
an oral contraceptive. Contraception. 2005;72(3):168–174.
7. Ortho Evra® (norelgestromin/ethinyl estradiol transdermal system)
[package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2012.
8. Smallwood GH, Meador ML, Lenihan JP Jr, et al. Efficacy and safety
of a transdermal contraceptive system. Obstet Gynecol. 2001;98(5 pt 1):
799–805.
9. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC,
Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/
Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;
77(2 suppl 2):S13–S18.
10. Jick SS, Habgerg KW, Kaye JA, Jick H. The risk of unintended
pregnancies in users of the contraceptive patch compared to users of
oral contraceptives in the UK General Practice Research Database.
Contraception. 2008;80(2):142–151.
11. Archer DF, Cullins V, Creasy GW, Fisher AC. The impact of improved
compliance with a weekly contraceptive transdermal system (Ortho
Evra) on contraceptive efficacy. Contraception. 2004;69(3):189–195.
12. McNicholas C, Zhao Q, Secura G, Allsworth JE, Madden T, Peipert JF.
Contraceptive failures in overweight and obese combined hormonal
contraceptive users. Obstet Gynecol. 2013;121(3):585–592.
13. Jick SS, Kaye JA, Russman S, Jick H. Risk of nonfatal venous throm-
boembolism in women using a contraceptive transdermal patch and oral
contraceptives containing norgestimate and 35 µg of ethinyl estradiol.
Contraception. 2006;73(3):223–228.
14. Jick SS, Hagberg KW, Hernandez RK, Kaye JA. Postmarketing study of
Ortho Evra and levonorgestrel oral contraceptives containing hormonal
contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal
venous thromboembolism. Contraception. 2010;81(1):16–21.
15. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembo-
lism, myocardial infarction, and stroke among transdermal contraceptive
system users. Obstet Gynecol. 2007;109(2 pt 1):339–346.
16. Dore DD, Norman H, Loughlin J, Seeger JD. Extended case-control
study results on thromboembolic outcomes among transdermal contra-
ceptive users. Contraception. 2010;81(5):408–413.
17. Daniels K, Daugherty J, Jones J, Mosher W. Current contraceptive use
and variation by selected characteristics among women aged 15–44:
United States, 2011–2013. Natl Health Stat Report. 2015;86:1–14.
18. Raine TR, Epstein LB, Harper CC, Brown BA, Boyer CB. Attitudes
toward the vaginal ring and transdermal patch among adolescents and
young women. J Adolesc Health. 2009;45(3):262–267.
19. Sibai BM, Odlind V, Meador ML, Shangold GA, Fisher AC, Creasy GW.
A comparative and pooled analysis of the safety and tolerability of the
contraceptive patch (Ortho Evra/Evra). Fertil Steril. 2002;77(2 suppl 2):
S19–S26.
20. Zacur HA, Hedon B, Mansour D, Shangold GA, Fisher AC, Creasy GW.
Integrated summary of Ortho Evra/Evra contraceptive patch adhesion
in varied climates and conditions. Fertil Steril. 2002;77(2 suppl 2):
S32–S35.
21. Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfac-
tion of reversible contraception. Obstet Gynecol. 2011;119(5):
1105–1113.
22. Harel Z, Riggs S, Vaz R, et al. Adolescents’ experience with the com-
bined estrogen and progestin transdermal contraceptive method Ortho
Evra. J Pediatr Adolesc Gynecol. 2005;18(2):85–90.
23. Sucato GS, Land SR, Murray PJ, et al. Adolescents’ experiences
using the contraceptive patch versus pills. J Pediatr Adolesc Gynecol.
2011;24(4):197–203.
24. Raine TR, Foster-Rosales A, Upadhyay UD, et al. One-year
contraceptive continuation and pregnancy in adolescent girls and women
initiating hormonal contraceptives. Obstet Gynecol. 2011;117(2 pt 1):
363–371.
25. Maslyanskaya S, Coupey SM, Chhabra R, Khan UI. Predictors of
early discontinuation of effective contraception by teens at high risk
of pregnancy. J Pediatr Adolesc Gynecol. 2016;29(3):269–275.
26. Electronic Medicines Compendium; DataPharm Ltd. Janssen-
Cilag Ltd. Evra transdermal patch: Pharmacodynamic properties.
Available from: https://www.medicines.org.uk/emc/medicine/
12124#PHARMACODYNAMIC_PROPS. Accessed April 3, 2017.
27. Crosignani PG, Nappi C, Ronsini S, et al. Satisfaction and compliance
in hormonal contraception: the result of a multicenter clinical study on
women’s experience with the ethinylestradiol/norelgestromin contra-
ceptive patch in Italy. BMC Womens Health. 2009;9:18.
28. Jakimiuk AJ, Crosignani PG, Chernev T, et al. High levels of women’s
satisfaction and compliance with transdermal contraception: results
from a European multinational, 6-month study. Gynecol Endocrinol.
2011;27(10):849–856.
29. Øjvind L, Nielsen LH, Skovlund CW, Løkkegaard E. Venous throm-
bosis in users of non-oral hormonal contraception: follow-up study,
Denmark 2001–2010. BMJ. 2012;344:e2990.
30. Waellnitz K, Duijkers I, Klipping C, et al. A two-centre, open label,
randomised study of ovulation inhibition with three transdermal contra-
ceptive patches, each containing different amounts of ethinyl estradiol
and gestodene in healthy, young women. J Obstet Gynaecol. 2016;
36(1):106–113.
31. Hofmann B, Reinecke I, Schuett B, Merz M, Zurth C. Pharmacokinetic
overview of ethinyl estradiol dose and bioavailability using two trans-
dermal contraceptive systems and a standard combined oral contracep-
tive. Int J Clin Pharmacol Ther. 2014;52(12):1059–1070.
32. 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):1518–1525.
33. Gruber D, Skřivánek A, Serrani M, Lanius V, Merz M. A comparison of
bleeding patterns and cycle control using two transdermal contraceptive
systems: a multicenter, open-label, randomized study. Contraception.
2015;91(2):105–112.
34. Merz M, Kroll R, Lynen R, Bangerter K. Bleeding pattern and cycle
control of a low-dose transdermal contraceptive patch compared with a
combined oral contraceptive: a randomized study. Contraception. 2015;
91(2):113–120.
35. Kaunitz AM, Portman D, Westhoff CL, et al. Low-dose levonorgestrel
and ethinyl estradiol patch and pill: a randomized control trial. Obstet
Gynecol. 2014;123(2 pt 1):295–303.
36. Kaunitz AM, Portman D, Westhoff CL, Archer DF, Mishell DR Jr,
Foegh M. Self-reported and verified compliance in a phase 3 clinical
trial of a novel low-dose contraceptive patch and pill. Contraception.
2015;91(3):204–210.
37. Kaunitz AM, Archer DF, Mishell DR Jr, Foegh M. Safety and toler-
ability of a new low-dose contraceptive patch in obese and nonobese
women. Am J Obstet Gynecol. 2015;212(3):318.e1–318.e8.
38. Archer DF, Stanczyk FZ, Rubin A, Foegh M. Pharmacokinetics and
adhesion of the Agile transdermal contraceptive patch (AG200-15)
during daily exposure to external conditions of heat, humidity and
exercise. Contraception. 2013;87(2):212–219.
39. Kaunitz AM, Portman D, Westhoff CL, Mishell DR Jr, Archer DF,
Foegh M. New contraceptive patch wearability assessed by investiga-
tors and participants in a randomized phase 3 study. Contraception.
2015;91(3):211–216.
40. Trussell J. Contraceptive failure in the United States. Contraception.
2011;83(5):397–404.

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