Ronald T. Burkman
Table Of Contents
Ronald T. Burkman, MD
RISKS AND SIDE EFFECTS
SPECIFIC MANAGEMENT ISSUES
For the first time since the 1960s, several new contraceptive methods are being 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 weekly for 3 of 4 weeks as opposed to daily pill-taking with oral contraceptives. An obvious question is whether there is a real need for this method given the widespread use of oral contraceptives, particularly in the United States.
Data from surveys of contraceptive practices clearly lend support to the need for such new approaches. For example, the most recent National Survey of Family Growth indicated that among women in the 15- to 44-year-old age group approximately 5% or 3 million total were not using contraception and were at risk of unintended pregnancy.1,2 Among the 5.4 million pregnancies occurring in women of this age group, approximately one half were unintended. Of equal significance was the finding that 53% of women experiencing an unintended pregnancy were using contraception. These findings suggest there still is a need to improve the ability of women to obtain contraception, select a method appropriate for them, and use the selected contraceptive method correctly. Another analysis from the survey indicates that inconsistent use of contraception is a significant contributor to unintended pregnancy.3 Among oral contraceptive users, 16% of women indicated they missed three or more pills within a 3-month time period. Factors associated with inconsistent use included Hispanic and black ethnicity, new users, low-income status, and having had a prior unintended pregnancy. Although there was a trend for teenage women to have a greater likelihood of inconsistent use compared to other age groups, the differences among various age groups were not statistically significant. In one of the largest studies performed in the United States, 1657 oral contraceptive users nationwide were surveyed at 2 and 6 months after initiating or switching to the use of a new oral contraceptive preparation.4,5 Failure to take one’s pill at the same time every day and not fully understanding the package insert information was associated with missing two or more pills per cycle. Overall, in this study 47% of oral contraceptive users reported missing one or more pills during a cycle and 22% missed two or more. Side effects were the most important reason women stopped taking oral contraceptives in this study. Thirty-seven percent of women stopped for this reason; this percentage rises to 46% when physicians’ recommendation to discontinue, presumably for some side effect, is included in the total. Somewhat disconcerting was the finding that among study participants who elected to discontinue oral contraceptives but did not wish to become pregnant, 19% adopted no method, approximately 60% selected a less effective method (e.g., barrier method, spermicides, or withdrawal), and 42% discontinued without first contacting their heath care provider. Patient recollection of missing oral contraceptive pills is also a problem. In a study of 103 students who kept a pill-taking diary and who also were provided with an electronic pill pack to record when pills were removed from the pack, the electronic pack recorded missed pills at rates two to three times higher than the subjects recorded in their diaries.6 Such problems of recollection obviously can contribute to reduced efficacy, because doubling-up strategies cannot be adopted if one does not remember that an oral contraceptive pill has been missed that day. In summary, compliance or adherence to a method appears to be an important contributor to contraceptive failure. The introduction of new methods such as the transdermal contraceptive patch that are effective and safe should assist in addressing unplanned or unintended pregnancy. In addition, because the contraceptive patch has a weekly dosing schedule and can readily be seen at its application site, adherence to or compliance with the correct use of the method should be enhanced. This chapter describes the basic characteristics of the transdermal contraceptive system, the pharmacokinetics, efficacy, side-effect profile, as well as provides data related to compliance or adherence. In addition specific issues relating to the use of this method are also discussed.
The transdermal contraceptive patch is 20 cm2, roughly the size of a matchbook.7 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 of time. 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.8
Figure 1 contrasts the contraceptive steroid absorption characteristics of the transdermal patch and an oral contraceptive. As shown in the left half of the figure, both of the contraceptive steroids reach the reference range within 24 to 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 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 seven 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.
The efficacy of the transdermal contraceptive patch has been evaluated in three clinical trials: a noncomparative trial9 and two randomized clinical trials7,10 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 1 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.11 The data indicates 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 ages 20 to 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.12 However, baseline body weight was associated with risk of pregnancy. Among the 15 pregnancies in the three clinical trials, 5 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.13 Furthermore, there is evidence among oral contraceptive users that higher body weight carries an increased risk of contraceptive failure.14
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 47:72, 2002)
|RISKS AND 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.15
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 were similar except that patch users had application site reactions, more breast symptoms (only during the first two cycles), and more dysmenorrhea.15 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.
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.
aOC, oral contraceptive (triphasic preparation with levonorgestrel as progestin).
Patch, transdermal contraceptive patch.
(Burkman RT: The transdermal contraceptive patch: a new approach to hormonal contraception. Int J Fertil 47:73 2002)
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.15 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.
|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, 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.16 Replacement rates were similar when data obtained from women living in warm, humid climates was reviewed. In a separate study, 30 women were subjected to various 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.16 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.
Failure to change the transdermal contraceptive patch at the appropriate time also is an issue that needs to be addressed with patients. When a new patch cycle is delayed beyond the scheduled start day, users should be instructed to apply a patch as soon as they remember and use backup contraception for at least 1 week. Furthermore, the day they apply the patch becomes the new patch change day. If a user forgets to change the first or second patch on time, the care provider will need to know various strategies to help users get back on schedule and avoid an unplanned pregnancy. There is a 2-day period of continued release of adequate contraceptive steroid levels when the patch is left on for two extra days. If a user changes the patch within this window, the patch change day remains the same and there is no need for backup contraception. Failure to replace a patch after this 2-day time period increases the risk for contraceptive failure. Therefore, users will need to use backup contraception, or in some instances emergency contraception, if this occurs. In addition, the day she remembers to apply the patch becomes the new change day. Forgetting to remove the third patch on time carries less risk. One should instruct the user to remove it when she remembers and tell her that the change day is not altered. Finally, if one wishes to switch to a new patch change day, this should be done during the last week of a cycle when patches are not usually used.
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 suggests 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.
7. Audet MC, Moreau M, Koltun WD, et al: Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: A randomized controlled trial. JAMA 285:2347, 2001
8. Abrams LS, Skee D, Natarajan J, Wong F, et al: Pharmacokinetics of a contraceptive patch (EVRA/ORTHO EVRA) containing norelgestromin and ethinyl estradiol at four application sites. Br J Clin Pharmacol 53:141, 2002
10. Hedon B, Helmerhorst FM, Cronje HS, et al: Comparison of efficacy, cycle control, compliance, and safety in users of a contraceptive patch vs. an oral contraceptive Int J Obstet Gynecol 70:78, 2000
11. 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 77:27, 2002
12. 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 77:S13, 2002
16. Zacur HA, Hedon B, Mansour D, et al: Integrated summary of Ortho Evra/Evra contraceptive patch adhesion in varied climates and conditions. Fertil Steril 77:32, 2002