Transdermal hormonal contraception: benefits and risks

Clinical Opinion

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GENERAL GYNECOLOGY

Transdermal hormonal contraception: benefits and risks Ronald T. Burkman, MD

T

ransdermal drug delivery has a number of advantages (Table 1).1-6 Transdermal delivery systems provide continuous administration of drug through the skin, which maintains constant plasma drug levels and avoids the peaks and troughs that are seen with oral administration.1-3 Losses of bioavailability because of first-pass hepatic metabolism and enzymatic degradation in the gastrointestinal tract that are seen with oral drug administration are avoided, which makes it possible to use lower doses of drug to achieve the therapeutic effect.5,7 Continuous delivery of drug may reduce systemic side effects, particularly side effects that are associated with high plasma levels.1,2,5 The multiday dosing that is made possible by the sustained delivery of drugs with short halflives, which would require frequent dosing if given orally, improves patient compliance.1,2 Other advantages of transdermal patches include a nonoral route of administration for patients who are unable to take oral medications and the immediate cessation of drug administration with removal of the patch.1 Unfortunately, the number of drugs that can be delivered by passive diffusion from a patch is limited by the barrier properties of the skin. At the present time, only low molecular weight substances with the correct balance of lipophilic and hydrophilic properties can From the Department of Obstetrics and Gynecology, Baystate Medical Center, Springfield, MA. Received Dec. 1, 2006; accepted Apr. 18, 2007. Reprints: Ronald T. Burkman, MD, Chairman, Department of Obstetrics and Gynecology, Baystate Medical Center, 759 Chestnut St, Springfield, MA 01199; [email protected] Financial interest and/or other relationship with Ortho-McNeil Inc, Raritan, NJ. 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.04.027

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Transdermal drug delivery systems have been available in the United States for ⬎20 years. Since the introduction of the first transdermal patch (scopolamine) for the treatment of motion sickness, ⬎35 transdermal patch products have been approved by the US Food and Drug Administration for a variety of indications that include hormone replacement therapy, nicotine replacement therapy, chronic pain (fentanyl), angina (nitroglycerin), hypertension (clonidine), and more recently, overactive bladder (oxybutynin), and contraception (ethinyl estradiol/norelgestromin). Clinical data demonstrated the efficacy and safety of the contraceptive patch; however, concerns regarding estrogen levels and reports of venous thromboembolism led to the development of 2 epidemiologic studies and, subsequently, revised product labeling. Despite this, the contraceptive patch may be an appropriate option for some patients. Key words: contraceptive patch, hormonal contraception, transdermal delivery Cite this article as: Burkman R. Transdermal hormonal contraception: benefits and risks. Am J Obstet Gynecol 2007;197:134.e1-134.e6.

be delivered effectively through the skin, although chemical permeation enhancers and other technologies are under investigation.1-3,8,9 The drug molecule itself has to be potent, because the patch size limits the amount that can be delivered.1,9 Although there was a high incidence of local skin reactions and problems of adhesion with the first generation of patches that used a reservoir system, the newer matrix systems have reduced these problems substantially.6,7 It is important to recognize that, once a matrix patch is fully detached, it cannot be taped back on. Because the contraceptive hormones are an integral part of the adhesive system, the ability of the patch to deliver appropriate concentrations of hormones is lost when the patch is detached fully.

T RANSDERMAL H ORMONAL C ONTRACEPTION The first transdermal contraceptive patch, a matrix system that contained a combination of 6.0 mg norelgestromin (formerly called 17-deacetylnorgestimate) and 0.75 mg ethinyl estradiol (EE; ORTHO EVRA; Ortho Women’s Health & Urology, Raritan, NJ) was approved by the Food and Drug Administration in November 2001.

American Journal of Obstetrics & Gynecology AUGUST 2007

Norelgestromin is the primary active metabolite of norgestimate, which is a progestin that has been used in combination with EE as an oral contraceptive (OC) since 1986.10 One patch is applied once weekly for 3 consecutive weeks, followed by a patch-free week. During the 7-day wear period, the patch delivers constant, continuous levels of hormones and avoids the peaks and troughs seen with OCs (Figure 1).11,12 The patch is more forgiving of dosing errors than an OC. Even if a scheduled patch change is missed for 2 days during weeks 2 and 3 of a 4-week cycle, clinical efficacy is maintained, and backup contraception is not needed.12 The transdermal delivery of norelgestromin and EE avoids the enzymatic degradation in the gastrointestinal tract and possible first-pass metabolism in the liver that occurs with oral administration.13 In a study that involved 5 premenopausal and 9 postmenopausal women that compared oral with vaginal administration of EE, a first-pass effect was not demonstrated.14 However, little data exist about the transdermal route and other contraceptive steroids that are relative to this issue.

P RESCRIBING I NFORMATION U PDATE The manufacturer of the ORTHO EVRA patch, together with the Food and Drug

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TABLE 1

Advantages and disadvantages of transdermal drug delivery systems1-6 Advantage

Disadvantage

Continuous, sustained release of drug

Only small, lipophilic drugs can be delivered currently through the skin*

..............................................................................................................................................................................................................................................

Avoids peak and trough drug levels

Drug molecule must be potent because patch size limits amount that can be delivered

..............................................................................................................................................................................................................................................

Longer, multiday dosing interval

Not suitable for high drug doses

Avoids first-pass hepatic metabolism and enzymatic degradation by gastrointestinal tract

Adhesion may vary with patch type and environmental conditions

Less frequent dosing improves patient compliance

Skin irritation and hypersensitivity reactions may occur

..............................................................................................................................................................................................................................................

..............................................................................................................................................................................................................................................

..............................................................................................................................................................................................................................................

Alternate route for patients who are unable to take oral medications

..............................................................................................................................................................................................................................................

Drug administration stops with patch removal

..............................................................................................................................................................................................................................................

Dose delivery unaffected by vomiting or diarrhea† ..............................................................................................................................................................................................................................................

* Chemical permeation enhancers may permit transdermal delivery of a wider variety of drugs.8 †

Clinical Opinion

erage concentration at steady state for ethinyl estradiol (EE) are approximately 60% higher in women using ORTHO EVRA compared with women using an OC containing EE 35 mcg. In contrast, peak concentrations for EE are approximately 25% lower in women using ORTHO EVRA. Inter-subject variability results in increased exposure to EE in some women using either ORTHO EVRA or OCs. However, inter-subject variability in women using ORTHO EVRA is higher. It is not known whether there are changes in the risk of serious adverse events based on the differences in pharmacokinetic profiles of EE in women using ORTHO EVRA compared with women using OCs containing 35 ␮g of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism.”11

ORTHO EVRA PI.

E PIDEMIOLOGIC S TUDIES Administration, has amended the prescribing information on the basis of pharmokinetic data and results from 2 separate epidemiologic studies that were designed to evaluate the risk of experiencing serious adverse events when using this method of hormonal contracep-

tion. The revised product labeling now includes the following bolded warning: “The pharmacokinetic (PK) profile for the ORTHO EVRA patch is different from the PK profile for OCs in that it has higher steady state concentrations and lower peak concentrations. AUC and av-

FIGURE 1

Mean serum concentration-time profiles of EE: OC and ORTHO EVRA11 Once-daily administration of an oral contraceptive for 2 cycles or application of ORTHO EVRA for 2 cycles to the buttock in healthy female volunteers ORTHO EVRA - Application to the Buttock Oral Contraceptive (NGM 250 µg/ EE 35 µg) Oral Contraceptive (NGM 250 µg/ EE 35 µg) - Estimated Steady State Data Based on Day 21

140 130 120

EE Concentration (pg/mL)

110 100 90 80 70 60 50 40 30

Oral contraceptive: Cycle 2, days 15-21, ORTHO EVRA: Cycle 2, week 3

20 10 0 0

24

48

72

96

120

144

168

192

216

240

Time (h)

Once daily administration of an OC for 2 cycles or application of ORTHO EVRA for 2 cycles to the buttock in healthy female volunteers. Reprinted from the ORTHO EVRA package insert with permission from Ortho Women’s Health & Urology, a Division of Ortho-McNeil Pharmaceuticals, Inc.

Results from 2 separate case control epidemiologic studies that evaluated the risk of venous thromboembolism (VTE) and heart attack and stroke in contraceptive patch users compared with women who used an norgestimate OC that contained 35-␮g EE have been reported recently.15,16 Jick et al15 provided results on the risk of nonfatal VTE in a nested case-control study using data from PharMetrics (Watertown, MA), a US-based company that collects information about insurance claims that are paid by managed care plans. The main outcome measures for this study were odds ratios and incidence rates that compared the risk of nonfatal VTE in new users of either the transdermal contraceptive patch or norgestimate OCs that contained 35-␮g EE. Sixty-eight cases of VTE were identified in women aged 15-44 years (n ⫽ 31 for the patch; n ⫽ 37 for the OCs); 266 control subjects (women without VTE) were matched by year of birth and index date of the case. The odds ratio for the comparison of the patch with the OC was 0.9 (95% CI, 0.5-1.6). 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 for users of norgestimate-containing OCs (95% CI,

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Clinical Opinion

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29.4-57.6). In that analysis, these findings provide evidence that the risk of nonfatal VTE in transdermal contraceptive patch users is similar to that for users of OCs that contain 35 ␮g of EE and norgestimate. A second epidemiologic study was conducted by i3 Drug Safety, an Ingenix company, with insurance claims information from the Ingenix database and medical record verification of study outcomes.16 The objective of this study was to evaluate the combined risk of heart attack and stroke in users of the contraceptive patch compared with users of norgestimate-containing OCs with 35 ␮g EE. The other objective of the study was to evaluate separately the risk of heart attack, stroke, and VTE in the same women. For VTE, there were 61 total cases, of which 22 women were contraceptive patch users and 39 women were users of norgestimate-containing OCs; 57 control subjects and 186 control subjects were matched in each treatment group, respectively. The odds ratio for VTE that compared current users of the patch with current users of OCs was 2.42 (95% CI, 1.07-5.46).16 The estimated incidence of VTE per 100,000 womenyears was 40.8 for contraceptive patch users and 18.3 for users of the norgestimate-containing OC. Although these data differ from the published study by Jick et al,15 it should be noted that VTE is a relatively rare event and has been reported as a potential risk of all hormonal contraceptive therapy. Further, the level of difference in VTE risk that was reported in the i3 Drug Safety study is similar to that reported in studies that compared desogestrel-containing OCs with levonorgestrel-containing OCs. Finally, it should be noted for comparison that, in several studies, the absolute risk of symptomatic VTE in pregnancy ranges from 50 to 300 events per 100,000 pregnancies.17 For many women, the patch remains a safe and effective method when used according to its label. However, as is the case with all forms of hormonal contraception, the patch may not be suitable for all women. It is important that clinicians and patients have a detailed discussion to determine whether the patch is an 134.e3

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appropriate method for that particular woman.

TABLE 2

E FFICACY : T RANSDERMAL C ONTRACEPTIVE P ATCH

Decile

Body weight Pregnancies range (kg) (n)

1

⬍52

1

2

52-⬍55

2

3

55-⬍58

0

4

58-⬍60

0

5

60-⬍63

2

6

63-⬍66

0

7

66-⬍69

1

8

69-⬍74

0

9

74-⬍80

2

10

ⱖ80

7

In terms of contraceptive efficacy, overall and method failure Pearl indices for the transdermal contraceptive patch are comparable with those of 2 OC formulations.18,19 However, a post hoc analysis of pooled data across 3 pivotal phase III clinical trials showed that the transdermal contraceptive patch may be less effective in women with a body weight of ⱖ198 lbs (ⱖ90 kg) than in women with lower body weights.20 There was a significant association between baseline bodyweight and pregnancy (P ⬍ .001). As shown in Table 2, 5 of the 15 on-treatment pregnancies occurred in the subgroup of women with a baseline body weight of ⱖ90 kg (ⱖ198 lb; ⬍3% of the study population).20 Among women who weighed ⬍90 kg at baseline, there was no association between body weight and pregnancy; pregnancies were distributed evenly across body weight deciles. There was no association between age or race and pregnancy (P ⫽ .134 and P ⫽ .352, respectively).

C YCLE C ONTROL V S OCS The rates of breakthrough bleeding (BTB) in patch users in clinical trials were low and similar to those seen with OCs. When compared with a triphasic OC that contained levonorgestrel 50/75/ 125 ␮g and EE 30/40/30 ␮g (Triphasil), the incidence of BTB with the patch was not significantly different in any of the 13 cycles of use (Figure 2). In the same study, BTB/BTS was significantly higher for the patch vs the OC in cycles 1 and 2 but did not differ significantly in subsequent cycles.19 With regard to pooled cycle control data, the contraceptive patch demonstrated a low incidence of BTB and BTB/BTS; in the comparative trials, there was no statistically significant difference between the contraceptive patch and OC groups in the incidence of BTB at any cycle.20

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Distribution of pregnancies by baseline bodyweight deciles

........................................................................................................... ........................................................................................................... ........................................................................................................... ........................................................................................................... ........................................................................................................... ........................................................................................................... ........................................................................................................... ........................................................................................................... ........................................................................................................... ...........................................................................................................

Subset 10a 80-84

1

Subset 10b 85-89

1

Subset 10c ⱖ90

5

........................................................................................................... ........................................................................................................... ...........................................................................................................

Adapted from 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):S13-8.

S AFETY AND T OLERABILITY With the exception of application site reactions, which are unique to patch wear, the patch is well tolerated and has a profile of adverse events that is similar to that of OCs. In a comparative study with a triphasic OC that contained levonorgestrel 50/75/125 ␮g and EE 30/40/30 ␮g (Triphasil), the most frequent adverse events in each treatment group were headache and nausea (Table 3).21 Breast symptoms, which included breast discomfort, engorgement, and pain, occurred in significantly more patch users than OC users during cycles 1 and 2 only (P ⬍ .001) and, with continued patch use, decreased to none during cycle 13.21 The incidence of dysmenorrhea also was significantly greater in patch users than in OC users (13.3% vs 9.6%; P ⫽ .04).21 None of the individual adverse events that are listed in Table 3, with the exception of application site reactions, led to discontinuation of the patch by ⱖ2% of users. Application site reactions, most of which were mild or moderate in severity, were reported by 20% of patch users but led to discontinuation of use in only 2.6%.21

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5% of their baseline body weight after 9 cycles of use (87.0% vs 81.8%).21

FIGURE 2 16

Compliance by age group : phase III European trial* 100

P ATCH A DHESION

98

OC (n=643)

Patch (n=846)

Compliance (%)

96 94 92 90 88 86

OC comparator = Mercilon® (desogestrel 150 mcg and 20 mcg EE)

84 82 80

Clinical Opinion

< 25

25 - 34

> 34

Age (years)

* Open-label, randomized, multicenter clinical trial. Reprinted from Urdl W, Apter D, Alperstein A, Koll P, Schönian S, Bringer J, et al. Contraceptive efficacy, compliance, and beyond: Factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J of Obstet Gynecol Reprod Bio 2005;121:202-10. With permission from Elsevier.

Users of the patch generally experience minimal changes in body weight. A pooled analysis of data from 3 clinical trials found that only 2.2% of women who used the patch for up to 13 cycles had a weight gain of ⬎10%, and 1.4% of the women had a weight loss of ⬎10%.21 In the comparative trial of the patch and levonorgestrel 50/75/125 ␮g and EE 30/ 40/30 ␮g, the mean increase in body

weight was 0.41 kg in both treatment groups; the distribution of users who gained or lost weight or remained within 5% of baseline weight during the trial was comparable in the 2 groups.19,21 When compared with a placebo patch, the effect of the contraceptive patch on weight gain was comparable; however, a slightly higher percentage of women who used the active patch were within

TABLE 3

Most common adverse events in the comparative study of the patch vs an OC Overall incidence (%) Adverse event

Patch (n ⴝ 812)

OC (n ⴝ 605)

Headache

21.9

22.1

.95

Nausea

20.4

18.3

.34

Application site reaction

20.2

NA

Breast symptoms*

18.8

6.1

⬍.001

Upper respiratory tract infection

13.3

17.9

.02

Dysmenorrhea

13.3

9.6

.04

Abdominal pain

8.1

8.4

.85

P value

.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

NA

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Adapted from 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(suppl 2):S19-26. With permission from the American Society for Reproductive Medicine. * Include breast discomfort, engorgement, and pain.

A 3-period crossover exercise study was conducted in which 30 women applied the contraceptive patch to the abdomen and participated in supervised activities that included showers, sunbathing, strenuous exercise, sauna, whirlpool, treadmill, and swimming; the study showed that adhesive reliability was maintained for 7 days, even under these conditions. Only 1.1% of patches completely detached. In clinical trials, only 1.8% of patches were replaced because they fell off, and 2.9% were replaced because of partial detachment. Even among participants who were enrolled at centers in warm, humid climates (ie, Florida, Louisiana, Georgia), rates of complete or partial detachment were only 1.7% and 2.6%, respectively.22

C OMPLIANCE VS OCS Women of all ages in the clinical trials were able to use the patch more consistently and correctly than the comparative OC.23 In the trial that compared the patch and levonorgestrel 50/75/125 ␮g and EE 30/40/30 ␮g for up to 13 cycles, the percentage of total cycles with reported perfect use was significantly greater in patch users than OC users (88.7% vs 79.2%; P ⬍ .001).19 Among those women who were ⬍20 years old, the percentage of cycles with perfect use was 67.7% for OC users compared with 87.8% for patch users.23 Thus, the patch potentially may decrease contraceptive failures that are associated with incorrect use; in a large population, patch users may experience fewer unintended pregnancies than OC users.19,24 More recently, in a multinational comparative trial, Urdl et al18 found that, overall, patch users had significantly more cycles with perfect compliance than OC users (P ⬍ .001). Similar to the North American studies, compliance in the multinational trial was higher for the patch group across all age groups. In an effort to improve acceptability and stimulate continuation rates (and thus improve compliance) of OCs, an

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FIGURE 3

Comparative data: subjects with breakthrough bleeding

17

(%)* Patch TRI LNG (%)*

50

% of Subjects

40 30 20 10 3.7

4.2

2.9

4.5

2.7 3.0

0 1

3

C

6 l

3.1 1.3

9

0.0

2.4

13

* Percentage of subjects experiencing breakthrough bleeding that required more than 1 pad or tampon on any day. Reprinted from 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 2001;285:2347-54. With permission from the American Medical Association.

approach called “Quick Start” was studied in which women would take their first pill while in the clinician’s office.25 Traditionally, women have been instructed to begin OC use with the next menstrual cycle on day 1 “first day start” or the first Sunday after onset of menses “Sunday start.” Researchers are now looking at the Quick Start approach for other methods of contraception, including the transdermal patch. One group has published results of 60 women who were assigned randomly to initiate use of the contraceptive patch by the Quick Start approach (group 1; n ⫽ 30 women) or on the first day of their next menses (group 2; n ⫽ 30 women). Telephone follow-up was done at 6 weeks to ensure the initiation of the second cycle, and a single follow-up visit was scheduled after the third patch cycle. Continuation rates for groups 1 and 2 were 97% and 93%, respectively, into the second cycle (P ⫽ 1.0), and 93% and 90%, respectively, into the third cycle (P ⫽ 1.0). Approximately one-half of the subjects planned to continue using the patch after the trial.26 Quick Start may be an approach to assist clinicians with counseling and may help women who elect to use the patch to do so more correctly and consistently. 134.e5

E XTENDED U SE W ITH THE C ONTRACEPTIVE P ATCH Traditionally, combined hormonal contraceptives have been administered with the use of a 21-day active hormone cycle, followed by 7 days of placebo (the hormone-free period). To delay or prevent menses, the number of days of active hormones is extended. Delaying menses is an acceptable practice, and some women prefer extended regimens over the traditional 21-day regimens. Extended use with the contraceptive patch was studied to compare bleeding profiles and satisfaction with patch wearers who used the conventional 21 days of active therapy with 1 patch-free week. Healthy, regularly menstruating women (n ⫽ 239) were assigned randomly (2:1 ratio) to receive the transdermal patch in an extended regimen (weekly application for 12 consecutive weeks, 1 patch-free week, and 3 more consecutive weekly applications; n ⫽ 158 women) or the cyclic regimen (4 consecutive cycles of 3 weekly applications and 1 patch-free week; n ⫽ 81 women). Bleeding data were recorded daily, and women also completed satisfaction questionnaires. Participants in both treatment groups and the investigators provided overall assessments of both regimens. Extended use of the transder-

American Journal of Obstetrics & Gynecology AUGUST 2007

mal contraceptive patch resulted in fewer median bleeding days (6 compared with 14 days; P ⬍ .001), bleeding episodes (1 compared with 3 episodes; P ⬍ .001), and bleeding or spotting episodes (2 compared with 3 episodes; P ⬍ .001) compared with cyclic use during days 1-84; median numbers of bleeding or spotting days were similar between regimens (14 compared with 16 days; P ⫽ .407) during the same period. Extended use delayed median time to first bleeding to 54 days compared with 25 days with cyclic use (P ⬍ .001); women were highly satisfied with both regimens.27

P ATIENT S ATISFACTION : T RANSDERMAL C ONTRACEPTION Women who use the transdermal contraceptive patch have higher ratings than OC users when questioned regarding emotional and physical well-being and improvements in premenstrual symptoms. In a large, randomized, open-label comparative trial that was conducted in Europe and South Africa, women who used the transdermal patch for either 6 or 13 cycles rated emotional well-being either somewhat or much better at the last cycle than did women who used an OC that contained 150 ␮g desogestrel/20 ␮g EE (30.7% vs 24.1%; P ⬍ .01).18 Physical well-being also was rated either much or somewhat better by 31.7% of the women who used the patch, compared with 21% of the women who used the OC (P ⬍ .001). Premenstrual symptoms were rated somewhat or much better by 35.4% of patch users, compared with 28.6% of OC users (P ⬍ .01). Improvement in premenstrual symptoms was related significantly to emotional and physical well-being. These factors, in turn, were weakly correlated with overall ratings of satisfaction, which were higher in patch users than in OC users (approximately 60% vs 55%) and significantly so among women ⬎34 years old (approximately 66% vs 55%; P ⬍ .05). The high level of satisfaction and improvements in emotional and physical well-being and premenstrual symptoms that were reported by users of the transdermal contraceptive patch in this trial may also have contributed to the significantly better compliance that was seen

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www.AJOG.org with the patch compared with the OC (P ⬍ .001; Figure 3).18 Women used the transdermal contraceptive patch correctly in 96.5% of total cycles, compared with 90.6% of total cycles of correct use of the OC. Dosing errors of 1 and 2 days occurred in 6.0% and 2.0% of total cycles, respectively, of OC use compared with only 1.6% and 0.5% of total cycles, respectively, of patch use. The improved compliance that was seen with the transdermal contraceptive patch may lead to fewer unintended pregnancies, which will benefit both patients and the healthcare system.19,24

C OMMENT Transdermal contraception has provided an important new therapeutic option for many women. Drugs that are administered by transdermal patches have longer, multiday dosing intervals, compared with orally administered drugs that must be taken at least once daily. The longer dosing intervals with transdermal drug delivery have been shown to improve patient compliance with a number of therapies. Since its introduction, the transdermal contraceptive patch has been used by ⬎5 million women. Recent epidemiologic studies (1 study showed an increased risk of VTE with the patch, and the other study showed no increased risk vs OCs) and a subsequent label update have provided additional information regarding the risk of serious adverse events with ORTHO EVRA compared with OCs. Therefore, for those patients who consider using the patch, it is important that a dialogue take place with the clinician to determine whether it is an appropriate method for that particular woman. Women who are predisposed to blood clots, heart attack, or stroke or who have cancer are not candidates for the contraceptive patch. The possible increased risk of such events should be discussed before use of the patch is initiated. For the women who are appropriate candidates, the patch remains a safe and effective method of contraception. Clin-

ical trials have shown that a significantly greater percentage of women used the patch more consistently and correctly than did those women who used OCs. Thus, the transdermal contraceptive patch offers an alternative for women who seek a hormonal contraceptive that may be easier to use and perhaps be more suitable for today’s active lifestyles. f REFERENCES 1. Potts RO, Lobo RA. Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist. Obstet Gynecol 2005; 105:953-61. 2. Gordon RD, Peterson TA. 4 Myths about transdermal drug delivery. Drug delivery technology. Last accessed: May 16, 2005. Available at: http://www.drugdeliverytech.com/cgi-bin/ articles.cgi?idArticle⫽143. 3. Brown L, Langer R. Transdermal delivery of drugs. Ann Rev Med 1988;39:221-9. 4. Merkle HP. Transdermal delivery systems. Methods Find Exp Clin Pharmacol 1989; 11:135-53. 5. Samisoe G. Transdermal hormone therapy: gels and patches. Climacteric 2004;7:347-56. 6. Stevenson JC. Optimising delivery systems for HRT. Maturitas 1999;33:S31-8. 7. Munoz A. OESCLIM®: an advanced delivery system for HRT. Maturitas 1999;33:S39-47. 8. Hampton T. Breaking barriers in transdermal drug delivery. JAMA 2005;293:2083. 9. Scheindlin S. Transdermal drug delivery: past, present, future. Mol Interv 2004;4:308-12. 10. Lippman JS, Shangold GA. A review of post-marketing safety and surveillance data for oral contraceptives containing norgestimate and ethinyl estradiol. Int J Fertil 1997;42:230-9. 11. Ortho Evra® (norelgestromin/ethinyl estradiol transdermal system). Product labeling. Raritan (NJ): Ortho-McNeil Pharmaceutical, Inc; 2006. 12. Abrams LS, Skee D, Natarajan J, Wong FA. Pharmacokinetic overview of Ortho Evra™/ Evra™. Fertil Steril 2002;77(suppl 2):S3-12. 13. Creasy GW, Abrams LS, Fisher AC. Transdermal contraception. Semin Reprod Med 2001;19:373-80. 14. Goebelsmann U, Mashchak CA, Mishell DR. Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol. Am J Obstet Gynecol 1985;151:868-77. 15. 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 ␮g of ethinyl estradiol. Contraception 2006;73:223-8.

Clinical Opinion

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