|A New Contraceptive
Option: A Focus on
the Transdermal Contraceptive System
At a commercially supported
symposium held in association with the Annual Meeting of The American Society
for Reproductive Medicine, leading authorities provided an update on issues
relating to contraception. Discussions included rates of unintended pregnancy,
recently available contraceptive choices, and data on a new contraceptive option
the Transdermal Contraceptive System.
This program was supported by an educational grant from Ortho-McNeil Pharmaceutical, Inc.
The Rationale for New Contraceptive Options
Over the past two to three
decades, the world of contraceptive options has expanded greatly, with entirely
new delivery systems as well as significant modifications of existing systems.
But despite the improvements and the general availability of contraception in
the United States, as many as half of all pregnancies are unplanned or unintended.
Approximately one-half or about 3.5 million pregnancies occur by accident each year in the U.S. Of these about half are terminated via elective abortions; the rest proceed to delivery. These statistics paint a grim picture of our modern society, in which, despite many effective options, too many women who wish to avoid pregnancy are either not using contraception, or not using it correctly and consistently.
This apparent anomaly inspires a number of questions, according to Ronald T. Burkman, MD, an obstetrician-gynecologist from Tufts University School of Medicine. For women not using contraception despite not wanting children, the questions are:
Is it a matter of motivation?
Is it the result of a past negative experience with birth control?
As many as 60% of women who become pregnant are using
some form of contraception in the month prior to their unintended pregnancy.
What could be the problem here?
Is it a matter of inability to use the methods correctly?
Do the side effects interfere with compliance?
The high rates of unintended pregnancies suggest that
contraception could still be improved, and research has indicated what properties
of contraceptives are most important to women. According to Dr. Burkman, this
research suggests that women want contraceptives that are:
Have a prolonged duration of action
Are rapidly reversible
Offer privacy of use
Are not associated with amenorrhea
Provide protection against STI (sexually transmitted infection)
New Methods of Contraception
Four new methods of contraception attempt to address the needs of women who find the older options undesirable or difficult to use properly (Table 1).
Each of these offers a longer term of contraception, which research has shown is associated with higher rates of compliance. Commenting on the pluses and minuses of the newer options, Dr. Burkman stated that the newer injectable system combining estrogen and the progestin, MPA, is highly efficacious and is associated with regular monthly cycles. However, he said, It does require a reinjection every 28 days, plus or minus 5 days, [to provide effective contraception after initiation]. Also, the injection must be given by a healthcare professional. On the plus side, and unlike the progestin-only injectables, the return to fertility is quite rapid after it is discontinued.
The new levonorgestrel-releasing IUD (LNG-IUS) offers
excellent efficacy over its 5-year span of use. But it is associated with a
different bleeding pattern from the copper T-380 in that bleeding tends to be
somewhat less predictable in the first few months, and can be heavy.
Like the injectable, it requires insertion and removal by a trained clinician.
The flexible vaginal ring is embedded with the progestin, etonogestrel, which is the major metabolite of desogestrel, plus ethinyl estradiol (EE). It is worn for 3 out of 4 weeks, and is inserted and removed by the user. Pregnancy rates are comparable to those of oral contraceptives. One question that arises with this form of contraception is whether increased weight has an impact on efficacy. This question remains unanswered because, as Dr. Burkman said, Unfortunately, in the clinical trials with roughly 2,200 subjects, only 20 were in a weight category that enabled a study of weight effects. However, cycle control was good in studies with the vaginal ring, and compliance was achieved in 90% of subjects.
Among oral contraceptives, the most promising new entry contains the low androgenic progestin, norgestimate, plus 25 micrograms of estrogen (Ortho Tri-Cyclen® Lo). It has the identical formulation as the best-selling Ortho Tri-Cyclen®, but with 10 mcg less estrogen. In clinical trials, Ortho Tri-Cyclen® Lo had a tolerability profile similar to the 20 mcg pills. Despite this, cycle control did not vary from that of the higher dose 35 mcg sister product.
The new transdermal contraceptive from Ortho-McNeil Pharmaceutical, (Ortho Evra®) features a matrix system with an outer protective layer, a middle layer that contains the contraceptive steroid in the adhesive (from which the hormones disperse), and a peel-back layer that is removed prior to application to the skin. It can be applied to four sites on the body: the abdomen, buttocks, upper torso (except for the breast), and the outer arm. As a weekly contraceptive, one patch is applied each week for three weeks. Withdrawal bleeding occurs during the fourth, patch-free, week.
The patch contains 6.0 mg of norelgestromin (NGMN), a major metabolite of norgestimate (formerly 17-deacetylnorgestimate), and 0.75 mg of ethinyl estradiol (EE). On a daily basis, it delivers 150 mcg of NGMN and 20 mcg of EE. Norelgestromin (norgestimate) was selected because of its long-established safety profile in the U.S. as well as in Europe. It has minimal systemic effects and maintains excellent cycle control. Once the patch is applied, steroid levels rapidly reach the reference range in which ovulation is inhibited and remain within this range for a seven full days. Once the patch is removed, hormone levels drop rapidly to almost undetectable levels within a day or two. Of particular interest with the transdermal system is its smooth pharmacokinetics, a pattern that differs significantly from the pharmacokinetics of oral preparations, which are characterized by striking peaks and troughs of steroid levels (Burkman RT. Int J Fertil Womens Med 2002;47(2):69-76) (Figure 1).
Effects on the patch of physical exercise and sweating and environmental conditions such as humidity were evaluated in a Health Club Study (Abrams, et al. J Clin Pharmacol 2002;41:1301-1309.) This was an open-label, randomized, single-center, 3-period, 6-condition study (Conditions were normal activity, sauna, whirlpool, cool water bath, treadmill, or a combination.). Enrolled healthy women (N = 30) wore the transdermal contraceptive system for 7 days on the abdomen. This was followed by a 4-week washout. In addition to pharmacokinetics and patch adherence, the investigators evaluated how difficult it was to remove the patch in these settings.
Overall results from this study demonstrated that conditions of heat and humidity did not have a substantial effect on pharmacokinetics or adhesiveness of the patch. Among 87 weekly cycles, only one patch became detached. The sum of all pharmacokinetics studies showed that the contraceptive patch delivers constant levels of NGMN and EE and that serum concentrations of NGMN and EE are maintained in the contraceptive reference range for nine days.
Efficacy and safety of the patch were assessed in three studies, each published (Table 2).
Smallwood, et al., in a non-comparator trial, evaluated 10,994 cycles, for an overall Pearl Index of 0.71 and a Method Pearl of 0.59 (Smallwood GH, et al. Obstet Gynecol 2001;98:799-805). Two comparator studies (Audet M et al. JAMA 2001;285:2347-2354. Hedon, et al.) evaluated the efficacy and safety of the patch versus the pill. These data indicate, in addition to high contraceptive efficacy, that women were able to use the method correctly and consistently, an important finding. Said Dr. Burkman: The Overall Pearl, which is the typical use rate, is very good, and is similar to the Perfect Use, or Method rate. This suggests very clearly that compliance in these studies including the ability to use the method correctly was quite good. Self-report data confirmed this finding.
In the Audet study, the patch was compared to a triphasic levonorgestrel OC. These data also show that compliance was significantly better with the patch versus the pill. Once again, said Dr. Burkman, patient reports back up this finding of good compliance. In prior studies with oral contraceptives, compliance has been shown to vary by age group, with teenagers being less compliant as a group than older women. But, according to data on the patch, compliance rates of roughly 90% are obtained, regardless of age.
Adverse events (AEs) were similar to most contraceptive studies, with two exceptions: application site reactions (20%) and breast discomfort (19%). However, both AEs were treatment-limiting in a total of only 2.5% of subjects. Breast discomfort seems to be self-limiting, Dr. Burkman added, appearing in the first few cycles with the patch, after which time it is similar to the degree of discomfort associated with OCs. Breakthrough spotting was slightly higher with the transdermal system than with OCs in the first two cycles; from cycle 3 on they were similar to the OC comparator. Lipid studies have shown similar changes with the transdermal system as those seen with the pill. In general, studies have shown no significant alterations of LDL/HDL cholesterol ratio with the transdermal system, which is not metabolized via the gut. In sum, both the efficacy and safety of the transdermal system were comparable to OCs in clinical studies.
Pregnancy risk in overweight women was a concern in trials
with the patch, as it is with oral contraceptives. When failure rates with the
patch were evaluated in approximately 3,300 test subjects, by weight decile,
there was an even distribution of pregnancies until the last decile, which represented
individuals of roughly >198 pounds. In these patients, there was a higher
failure rate. A retrospective cohort analysis of risk of OC failure also showed
a higher rate of pregnancy in women in the top quartile of weight. In this study
(Holt VL. Obstet Gynecol 2002;99:820-7) individuals over 70.5 kilograms
(>155 pounds) had a 1.6-fold increased risk of pregnancy. This finding has
not led to an additional Precaution or Warning in the Package Inserts. Instead,
clinicians are encouraged to provide counseling for patients whose weight may
suggest that the method may be associated with a slightly lower rate of efficacy.
Applauding the work that has resulted in the design of several novel contraceptive options, Dr. Burkman expressed a hope that the new methods will reduce the rates of unplanned pregnancies. But also, he said, the past has shown that personal preferences can have an impact on compliance, and therefore on rates of unplanned pregnancy. New choices are important in this regard, to allow the clinician and patient to choose a method that best suits the womans lifestyle, and that leads to proper use.
Clinical Management of the Transdermal Contraceptive System
Clinical data indicate and experienced practitioners know that efficacy is no longer a challenge with steroid contraception. Nor is safety. It is, according to Lee P. Shulman, MD, from the University of Illinois at Chicago, to empower women to determine what method they are most likely to use consistently and correctly. Ultimately, Dr. Shulman said of his colleagues in womens healthcare, Our greatest responsibility is to be educators to support our patients in finding what [form of contraception] ultimately is going to be successfully incorporated into their lives.
That education extends to the newest forms of contraceptive systems, such as the transdermal contraceptive patch, which, Dr. Shulman added, is unlike the reservoir patches of the 70s and early 80s, with its new matrix design.
Use of the Transdermal System
The transdermal patch is placed over clean, dry skin of the buttocks, abdomen, upper torso (excluding the breast), or upper outer arm. It should be positioned so that it wont be rubbed by tight clothing, or involved in motion. For example, Dr. Shulman said, It should obviously not be placed in the areas of the scapula or near the neck. Women are advised to rotate the patch positioning such that successive weekly patches are not placed in the exact same location.
Patients may elect to adhere the patch during the first 24 hours of their menstrual period. (If therapy starts after day 1 of the menstrual cycle, a nonhormonal form of contraception should be used for the first 7 consecutive days of the treatment cycle.) A new patch is to be applied on day 8 (week 2), then another new patch should be applied on day 15 (week 3). Week four is patch-free. The next four-week cycle is started the day after day 28, no matter when the menstrual period begins or ends.
The system does not provide a placebo patch, for reasons including the risk of confusing the placebo with the active treatment patch. Also, in clinical trials, participants did not express a need for a placebo patch.
Ortho-McNeil provides detailed instructions for managing partial detachment, although in clinical study in warm, humid climates, the patch detachment rate was as low as 4.7% in over 70,000 patches.
Patient counseling should include information about common side effects, such as breast tenderness and breakthrough bleeding and spotting that occur in the initial few cycles of use with the patch. However, in studies with the patch, only 18% of women reported breast symptoms, and of this number, the symptoms were mild to moderate in more than 80% of the women. In the Audet study, similar rates of breakthrough bleeding and spotting were found between the 35 mcg EE OC and the transdermal system.
FDA labeling for all steroid contraceptives includes language regarding a reduction of contraceptive efficacy when hormonal contraceptives are co-administered with some antibiotics, antifungals, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. Due to the fact that the transdermal system bypasses gut/liver metabolism, it appears to reduce the risk for some drug interactions. For example, studies have shown that there is no interaction between the patch and tetracycline and no reduction in EE levels.
The role of the physician in the contraceptive choice process is first, educational, Dr. Shulman concluded. Patient management, where the choice of contraception is concerned, is rather more like eliciting patient priorities and then reviewing options to enable and facilitate informed patient decision-making. With good counseling, women are more likely to select a method that best suits their individual contraceptive needs. Ideally, the advantages of the new longer-acting contraceptive options, like the patch, will help to meet these needs and go on to help reduce the rates of unplanned pregnancies in this country.
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