This chapter should be cited as follows:
Burkman, R, Glob. libr. women's med.,
(ISSN: 1756-2228) 2014; DOI 10.3843/GLOWM.10395
This chapter was last updated:
April 2014

Transdermal Contraception

Ronald T. Burkman, MD
Professor, Department of Obstetrics and Gynecology, Tufts University School of Medicine, Division of General Obstetrics and Gynecology, Baystate Medical Center, Springfield, Massachusetts, USA

INTRODUCTION

For the first time since the 1960s, several new contraceptive methods have been introduced into clinical practice in the United States as well as overseas. This chapter focuses on one of these new methods, the transdermal contraceptive patch. In some ways, this particular system mimics an oral contraceptive by delivering a combination of estrogen and progestin to the user. A major difference is that the dosing frequency is usually weekly for 3 of 4 weeks as opposed to daily pill-taking with oral contraceptives, although there are limited data that continuous weekly use is both efficacious and tolerated by many women.1, 2

PHARMACOLOGY

The transdermal contraceptive patch is 20 cm roughly the size of a matchbook.1 The patch consists of a matrix in three layers: an outer polyester protective layer that is light tan, a middle layer containing an adhesive and the contraceptive steroids, and an inner clear polyester liner that is removed prior to application to the skin. The transdermal patch contains a total of 6.0 mg of norelgestromin and 0.75 mg of ethinyl estradiol. Norelgestromin, also known as 17-deacetylnorgestimate, is the active metabolite of norgestimate, which is the progestin contained in certain oral contraceptives. Ethinyl estradiol is the estrogen component of most oral contraceptives. The transdermal contraceptive patch is designed to deliver 150 μg of norelgestromin and 20 μg of ethinyl estradiol daily for a 7-day period. After 7 days, the patch is removed and a new one is applied to another skin site. Three consecutive 7-day patches are applied in a typical cycle followed by a 7-day patch-free period to allow withdrawal bleeding. Application sites that have been determined to be therapeutically equivalent in clinical trials include the buttocks, lower abdomen, upper outer arm, and upper torso except for the breasts.3

Fig. 1 contrasts the contraceptive steroid absorption characteristics of the transdermal patch and an oral contraceptive.4 As shown in the left half of the figure (Fig. 1A), both of the contraceptive steroids reach the reference range within 24–48 hours after skin application. The reference range represents the range of serum concentrations of both steroids in which ovulation is usually suppressed. After removal of the transdermal patch after 7 days of use, serum steroid levels fall to nondetectable levels within 24 hours. In contrast, the right half of the figure (Fig. 1B) demonstrates the typical dose–response curves seen with oral administration of a contraceptive. As shown, the transdermal contraceptive system maintains relatively steady-state serum concentrations of steroids without the characteristic peaks and troughs of an oral contraceptive. Although the usual duration of use of each patch is 7 days, its ability to maintain serum concentrations of the steroids in the desirable reference range has also been evaluated for more extended use. In this study, serum concentrations remained in the reference range when a patch was left on for more than 7 days. The data indicated that the efficacy of the transdermal contraceptive patch would be maintained even if a scheduled change was missed for as long as 2 full days.

 

Fig. 1. Mean serum concentrations of ethinyl estradiol (EE) and norelgestromin over time for (A) a transdermal contraceptive patch and (B) an oral contraceptive (Abrams LS, Skee D, Natarajan J, Wong FA: Pharmacokinetic overview of ORTHO EVRA™/EVRA™. Fertil Steril 2002;77:S62.)

EFFICACY

The efficacy of the transdermal contraceptive patch has been evaluated in three clinical trials: a noncomparative trial5 and two randomized clinical trials1, 6 comparing the patch to an oral contraceptive. As shown in Table 1, the typical use and method use (perfect compliance with the dosing schedule) pregnancy rates were both less than one pregnancy per 100 woman-years. These rates are comparable to pregnancy rates achieved with current oral contraceptives. Furthermore, the similarity between the typical and method use rates suggests that women in the three trials were able to use the method correctly without difficulty. This finding is supported by an analysis of self-reported rates of 'perfect' compliance of patch users versus oral contraceptive users.7 The data indicate that users of the transdermal contraceptive patch achieved perfect compliance in 88% of cycles compared to about 78% of cycles for oral contraceptive users. The rate of perfect compliance did not vary by age for patch users, while oral contraceptive users who were in younger age groups had lower perfect compliance rates. For example, for oral contraceptive users less than 20 years and aged 20–24 years, the compliance rates were 68% and 74%, respectively. Thus, the comparative trials indicate that women of all age groups can use the transdermal system successfully. Other possible predictors of contraceptive failure with the transdermal contraceptive patch have also been evaluated. In addition to age, race also did not predict a likelihood of failure with this method.8 However, baseline body weight was associated with risk of pregnancy. Among the 15 pregnancies in the three clinical trials, five occurred among 83 women who weighed 90 kg (198 pounds) or more. This represented less than 3% of the overall study sample. In contrast, the other 10 pregnancies were relatively evenly distributed across the range of weights below 90 kg in the study group. This finding is not unique to this method; women using the Norplant implant system weighing more than 160 pounds had higher contraceptive failure rates beginning at about 3 years of use.9  Furthermore, there is evidence among oral contraceptive users that higher body weight carries an increased risk of contraceptive failure.10

Table 1. Efficacy of the transdermal contraceptive patcha

Study

Cycles

Pregnancies

Pregnancies with perfect useb

Pregnancies with typical usec

Noncomparative trial5

10,994

 6

0.59

0.71

Oral contraceptive, comparative trial6

  5921

 4

0.66

0.88

Oral contraceptive, comparative trial1

  5240

 5

0.99

1.24

Combined total

22,155

15

0.70

0.88

a Pregnancies per 100 women-years
b Failure (pregnancy) when taking correctly
c Perfect use failure plus user failure
(Burkman RT: The transdermal contraceptive patch: A new approach to hormonal contraception. Int J Fertil 2002;47:72)

 

Indications

For women desiring a nonpermanent contraceptive method who have no contraindications to the use of estrogen or progestin-containing contraceptive methods.

 

Contraindications

The contraindications are similar to those for other methods containing both estrogen and progestin such as combination oral contraceptives and the vaginal ring. These include, but are not limited to, prior or increased risk for thromboembolism, uncontrolled hypertension or diabetes, vascular disease or prior stroke, ischemic heart disease, liver disease, and tumors which are estrogen dependent.11 Also, use in postpartum women should be delayed until 21–42 days after delivery, depending on the presence or absence of risk factors, owing to an increased risk of venous thromboembolism.12 In addition, women with sensitive skin or dermatologic disorders may not be suitable candidates for this method.

USE

Women can initiate the patch at any time in their cycle as long as pregnancy is reasonably excluded.  If initiation occurs more than 5 days after onset of menses, a back-up method should be used for the first 7 days of patch use.13

The patch can be applied to the abdomen, buttocks, upper torso except breasts, and upper arms.  The patch is changed weekly for 3 weeks followed by 1 week which is patch free.14 The same site should not be used when patches are changed.  Occlusive dressings and lotions should not be used where the patch is applied.  In the randomized clinical trial which examined extended use of the patch, the satisfaction rates comparing extended to usual use were over 87% in both groups.2 Further, the extended use groups had fewer bleeding days but higher rates of headache and breast discomfort. 

With delay in patch changes, there are different approaches to use depending upon when the delay occurs.14 With delay of the start date beyond the scheduled date with the first patch, application of the patch becomes the new start date.  Further, back-up contraception such as condoms should be used for the next 7 days. If changing the second or third patch occurs within 48 hours of the scheduled date, the subsequent change dates remain the same and no additional precautions need to be taken.  The rationale for this approach is based on the patch maintaining adequate blood levels of the contraceptive hormones for up to 9 days after application.  If the application of a new patch occurs later than 48 hours, back-up contraception should be used for the 7 days after patch application and the date the patch is applied becomes the new change date.  Delay in removing the third patch carries little risk as long as the first patch in the next cycle is applied on the usual start date.

If a patch becomes fully or partially detached for less than 24 hours, it can be re-applied if the adhesive still works or a new patch can be used with no change in change dates.  Tape or similar approaches should not be used to apply a patch that has lost its adhesive properties.  If detachment exceeds 24 hours, a new patch should be applied, back-up contraception should be used for 7 days, and the date of application becomes the new change date. It should be noted that detachment is rare even when patches are used in warm or humid climates or by physically active people.15

SIDE-EFFECTS

In the three published clinical trials involving the transdermal contraceptive patch, the serious adverse events potentially attributable to use of this system include: two cases of nonfatal pulmonary embolism (one case involved a woman wearing the patch until the day of abdominal surgery); one case of menorrhagia; one case of arm pain, paraesthesia and hypesthesia; one case of migraine headache; one case of cholecysitits; and one case of carcinoma in situ of the cervix.16

Table 2 lists the most frequently reported side-effects other than unscheduled bleeding in the clinical trials with the transdermal patch. Within the trials comparing the patch to an oral contraceptive, the frequency of these side-effects was similar except that patch users had application site reactions, more breast symptoms (only during the first two cycles), and more dysmenorrhea.16 Relative to breast symptoms, approximately 85% of women experiencing them described them as mild to moderate, and the frequency of the symptoms markedly declined with continued use of the method.

Table 2. Most common side effects1, 5, 6

Side effect

Overall incidence (%)

Treatment-limiting event (%)

Breast symptoms

22.0

  1.9

Headache

21.1

  1.1

Application site reactions

17.4

  1.9

Nausea

16.8

  1.7

Upper respiratory tract infection

10.1

<1.0

Dysmenorrhea

10.1

<1.0

(Sibai BM, Odlind V, Meador ML, et al: A comparative and pooled analysis of the safety and tolerability of the contraceptive patch (ORTHO EVRA™/EVRA™). Fertil Steril 2002;77:S22.)

 

The pattern of breakthrough bleeding (bleeding requiring more than one pad or tampon daily) and spotting with the transdermal contraceptive patch is similar to that demonstrated in oral contraceptive trials. As indicated in Table 3, by approximately 6 months, the frequency of such bleeding declines substantially and remains stable.

 

Table 3. Breakthrough bleeding and breakthrough bleeding/spotting by cycle

  Comparative trial2
 

Noncomparative trial4 patch

(n = 1664) (%)

Transdermal contraceptive patch

(n = 812) (%)

Oral contraceptivea

(n = 605) (%)

Breakthrough bleeding

 Cycle 1

 3.7

 3.7

 4.2

 Cycle 3

 3.7

 2.9

 4.5

 Cycle 6

 2.5

 2.7

 3.0

 Cycle 9

 1.5

 1.3

 3.1

 Cycle 13

 1.7

 0.0

 2.4

Breakthrough bleeding and/or spotting

 Cycle 1

17.5

18.3

11.4

 Cycle 3

11.1

10.0

 8.8

 Cycle 6

 7.3

 9.5

 7.1

 Cycle 9

 6.5

 6.7

 4.6

 Cycle 13

 9.2

 5.5

 7.1


aTriphasic preparation with levonorgestrel as progestin.
(Burkman RT: The transdermal contraceptive patch: a new approach to hormonal contraception. Int J Fertil 2002;47:73.)

 

Based on data from a placebo-controlled, randomized clinical trial over 9 months, there is no evidence that use of the patch influences body weight.16 Mean body weight increased from baseline by less than 2 pounds for both the contraceptive patch and placebo groups with 80% of users in both groups within 5% of their starting weights by the end of 9 months.

MAJOR RISKS

As is true of all estrogen-containing contraceptive methods, venous thromboembolism is the commonest serious side-effect associated with patch use, although less commonly users with risk factors can also experience stroke and myocardial infarction. The risk of venous thromboembolism among patch users may be slightly higher than the risk among oral contraceptive users. This may be owing to the finding that the overall concentration of ethinyl estradiol, the estrogen used in the currently available patch, is 60% higher when measured as 'area under the curve' (see Fig. 1A).17, 18 However, it is important to recognize the absolute risk of this complication is far less than what women experience in pregnancy or postpartum.

One of the first investigations related to this issue was a nested case–control study which was completed in 2006 using a claims database of a large managed-care organization.19 Cases were women aged 15–44 years who were current users of the patch or an oral contraceptive containing 35 µg of ethinyl estradiol and norgestimate and who had a first-time recorded claim (index date) for a clinically diagnosed deep vein thrombosis (DVT) or pulmonary embolus (PE) and who received an anticoagulant. Up to four women who did not have a diagnosis of venous thromboembolism (VTE) were matched to each case by year of birth and the index date of the case. The final study population consisted of 68 cases of VTE and 266 controls. The unadjusted matched odds ratio for VTE for the patch versus OC was 0.9 (95% CI 0.5–1.6). There was no change in OR after adjusting for duration of exposure or switching from another hormonal contraceptive. The overall incidence rate for VTE was 52.8 per 100,000 women-years (95% CI 35.8–74.9) among patch users and 41.8 per 100,000 women-years (95% CI 29.4–57.6) for users of norgestimate-containing OCs. Adjusted for age, VTE incidence rate ratio (IRR) for current use of the patch versus OC was 1.1 (95% CI 0.7–1.8), with no effect modification by age. 

Another nested case–control study was conducted by i3 Drug Safety also using an insurance claims database.20, The design was similar to that described above except there was verification of cases through medical record review.  For VTE, there were 61 total cases, 22 among patch users and 39 among the OC users; 57 controls and 186 controls were matched in each treatment group, respectively. The OR for VTE comparing current users of the patch and OCs was 2.42 (95% CI 1.07–5.46). The estimated incidence of venous thromboembolism per 100,000 women-years was 40.8 for contraceptive patch users and 18.3 for users of the norgestimate-containing oral contraceptive.

A similar case–control study was conducted by another group of investigators also using an insurance claims database.  However, like the i3 Drug Safety study, there was medical record verification of the outcomes.21 The OR for VTE among patch users compared to current OC users was 2.2 (95% CI 1.2–4.0). There were no significant differences for either stroke or myocardial infarction between the two groups. 

A US Food and Drug Administration study examined a variety of cardiovascular and vascular events in a cohort representing over 67,000 women-years of use of the progestin norelgestromin in the patch and combined oral contraceptives.22 Although there was an overall increased risk of VTE among users of the patch compared to users of an oral contraceptive containing the same progestin (OR 1.55, 95% CI 1.17–2.07), the risk disappeared when only new users were analysed.

These studies have limitations owing to their design. For example, the nested case–control design utilizes restricted databases, limiting access to all potential confounders. In some studies, there was no information on body weight, family history of VTE or smoking (known to be risk factors for VTE) or on compliance with the method. The databases include only short-term use of the methods. Furthermore, the studies may suffer from both reporting bias and nondifferential misclassification. Although the odds ratios differ in these studies, it should be noted that VTE is a relatively rare event and is a potential risk with all combination hormonal contraceptive therapy. Further, the level of difference in VTE risk reported in the i3 drug safety study is similar to that reported in studies comparing desogestrel-containing oral contraceptives to levonorgestrel-containing oral contraceptives. 

Putting these risks in perspective, the risk of VTE among reproductive women not using combined hormonal contraception is about 50–100 events per 100,000 women-years23 and the risk in pregnancy and postpartum is about 200 events per 1000,000 woman-years.24, 25 Although the use of combined hormonal contraception increases the baseline absolute risk of VTE, it is still less than the rate in pregnancy and overall is still a rare event.

NEW DEVELOPMENTS

A new transdermal patch which contains 2.6 mg of levonorgestrel and 2.3 mg of ethinyl estradiol within a matrix core is undergoing investigation.26, 27 Compared to the currently available norelgestomin patch, there are some phamacokinetic differences.  In a cross-over study of 32 subjects comparing use of the new patch with use of an oral contraceptive containing 30 µg of ethinyl estradiol and 250 µg of norgestimate, the area under the curve for ethinyl estradiol was significantly higher in the oral contraceptive group in the first week of use although there were no differences between the two preparations in areas under the curve in week three.26 Similar to data with the current patch, oral contraceptive users had peak concentrations of ethinyl estradiol roughly three times those experienced with patch use.  As is true with most pharmacokinetic data, it is unclear how such findings alter risk of estrogen-dependent sequelae such as venous thromboembolism. 

A randomized clinical trial has been completed comparing 1129 users of this new patch with 375 users of an oral contraceptive containing 20 µg of ethinyl estradiol and 100 µg of levonorgestrel over a 13 cycle time period.27 Over one-half of the women in the study were new users of hormonal contraception, 40% were of racial or ethnic minorities and 30% were obese. The contraceptive efficacy in the first six cycles as measured via Pearl Indices for all patch users versus all OC users was 4.45 and 4.02, respectively. These rates are similar to recent typical use rates measured in other studies.28 When the efficacy analysis was confined to compliant users, the Pearl Indices for patch versus OC users were 2.82 and 3.80, respectively. There was one case of subclavian vein thrombosis in a user of the patch.  However, it should be recognized that this study lacked the statistical power to adequately assess risk of  VTE for users of this new patch. Thus, it remains unknown whether this new patch compared to the currently available patch will carry less risk of the complication.  Finally, side-effects such as unscheduled bleeding, headache and weight gain were relatively uncommon and were comparable in the patch and OC groups.    

SPECIFIC MANAGEMENT ISSUES

Contraceptive counseling will need to be adapted to meet the attributes of this new contraceptive delivery system. Women without contraindications to oral contraceptive use constitute the initial set of potential users. However, as noted previously, women with a history of significant skin allergy or exfoliative dermatologic disorders may not be ideal candidates. Obese women also need to be counseled about the potential for reduced efficacy. Reminder systems to ensure appropriate weekly changing of the patch, using a different site for the next application, and avoiding use of lotions or occlusive dressings will need to be used.

An obvious important attribute of any transdermal delivery system is its ability to remain adherent during the course of the dosing schedule. In the various trials, 1.8% of transdermal patches required replacement for complete detachment and 2.9% became partially detached.15 Replacement rates were similar when data obtained from women living in warm, humid climates were reviewed compared to those living in more temporate climates. In a separate study, 30 women were subjected to various environmental conditions over several 7 day time periods during transdermal patch use including normal activity, sauna use, whirlpool bath use, use of a treadmill followed by showering, cool water immersion, as well as a combination of these activities.15 Only one patch became detached during the 87 cycles that were evaluated suggesting that skin adherence is not adversely affected by a vigorous, athletic lifestyle. When patches do become detached, users should attempt to reattach them if possible, without using ancillary adhesives or tape. If detachment is noted to be 24 hours or less, the cycle continues as usual with the patch being changed on the previously determined change day. If detachment has occurred for more than 24 hours, a new patch should be applied, backup contraception should be used for 1 week, and the day that the new patch is applied now becomes the patch change day.

CONCLUSION

The transdermal contraceptive system has an efficacy and side-effect profile similar to that of combination oral contraceptives. A major difference is that the dosing is weekly as compared to daily. Clinical trial data suggest that this dosing frequency improves the ability of women to use this method correctly. Because of its uniqueness, the counseling of users needs to be modified to address issues specific to this system.

 

REFERENCES

1

Audet MC, Moreau M, Koltun WD, Waldbaum AS, Shangold G, Fisher AC, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA : the journal of the American Medical Association. 2001;285(18):2347-54

 

2

Stewart FH, Kaunitz AM, Laguardia KD, Karvois DL, Fisher AC, Friedman AJ. Extended use of transdermal norelgestromin/ethinyl estradiol: a randomized trial. Obstetrics and gynecology. 2005;105(6):1389-96.

 

3

Abrams LS, Skee D, Natarajan J, Wong F, Anderson GD. Pharmacokinetics of a contraceptive patch (EVRA/ORTHO EVRA) containing norelgestromin and ethinyl estradiol at four application sites. Br J Clin Pharmacol. 2002.

 

4

Abrams LS, Skee D, Natarajan J, Wong FA. Pharmacokinetic overview of Ortho Evra/Evra. Fertil Steril. 2002;77(2 Suppl 2):S3-12.

 

5

Smallwood GH, Meador ML, Lenihan JP, Shangold GA, Fisher AC, Creasy GW, et al. Efficacy and safety of a transdermal contraceptive system. Obstetrics and gynecology. 2001;98:799-805.

 

6

Hedon B, Helmerhorst FM, Cronje HS, Shangold G, Fisher AC, Creasy G. Comparison of efficacy, cycle control, compliance, and safety in users of a contraceptive patch vs. an oral contraceptive. International Journal of Obstetrics and Gynecology. 2000;70(1 (Supplement)):78.

 

7

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

 

8

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):S13-8.

 

9

Gu S, Sivin I, Du M, Zhang L, Ying L, Meng F, et al. Effectiveness of Norplant implants through seven years: a large-scale study in China. Contraception. 1995;52(2):99-103

 

10

Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstetrics and gynecology. 2002;99(5):820-7.

 

11

Prevention CfDCa. U.S. Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR. 2010;59(May 28, 2010):1-86.

 

12

Prevention CfDCa. Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: Revised Recommendations for the Use of Contraceptive Methods During the Postpartum Period. MMWR. 2011;60(June 8, 2011):1-10.

 

13

Prevention CfDCa. U.S. Selected Practice Recommendations for Contaceptive Use, 2013. MMWR. 2013;62(June 14, 2013):1-60.

 

14

Ortho Evra (norelgestromin/ethinyl estradiol transdermal system). Product labeling. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc.; Revised March 2008.

 

15

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 Suppl 2:32-5.

 

16

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):S19-26.

 

17

van den Heuvel MW, van Bragt AJ, Alnabawy AK, 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):168-74.

 

18

Devineni D, Skee D, Vaccaro N, Massarella J, Janssens L, LaGuardia KD, et al. Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive. Journal of clinical pharmacology. 2007;47(4):497-509.

 

19

Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73(3):223-8.

 

20

Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstetrics and gynecology. 2007;109(2 Pt 1):339-46.

 

21

Dore DD, Norman H, Loughlin J, Seeger JD. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception. 2010;81(5):408-13.

 

22

Epidemiology FOoSa. Combined Hormonal Contraceptives (CHCs) and the Risk of Cardiovascular Disease Endpoints. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf (accessed on March 3, 2014). 2011.

 

23

Heinemann LA, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception. 2007;75(5):328-36.

 

24

Gynecologists ACoOa. Thromboembolism in pregnancy. Washington, D.C.: ACOG, 2000.

 

25

Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ, 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Annals of internal medicine. 2005;143(10):697-706.

 

26

Archer DF, Stanczyk FZ, Rubin A, Foegh M. Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial. Contraception. 2012;85(6):595-601.

 

27

Kaunitz AM, Portman D, Westhoff CL, Archer DF, Mishell DR, Jr., Rubin A, et al. Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial. Obstetrics and gynecology. 2014;123(2 Pt 1):295-303.

 

28

Trussell J, Portman D. The creeping pearl: why has the rate of contraceptive failure increased in clinical trials of combined hormonal contraceptive pills? Contraception. 2013;88(5):604-10.