Recent Advances in Oral and Transdermal Contraception

US Pharm. 2008;33(9):19-23.

Contraceptive choices currently available in the United States provide safe, reliable, effective, and affordable birth control for virtually any patient. Products come in a variety of forms--tablet, patch, injection, implant, vaginal, and intrauterine. Current oral contraceptive products also contain novel progestins that have altered the scope of benefits and adverse effects.

The availability of new, effective contraceptive products in the last decade has not generated a significant decrease in the rate of unintended pregnancy. About half of all pregnancies in the U.S. are unintended, and more than one in five U.S. pregnancies ends in abortion.¹ A study of more than 10,000 women who requested an abortion found that 46% had not used a contraceptive method during the month they conceived.²

The number-one method of contraception in the U.S. is sterilization.³ Many women who opt for sterilization before the age of 30 later express regret and report choosing sterilization because they didn't know that equally effective reversible options exist.⁴ Combination oral contraceptives (COCs) are the most commonly used reversible form of birth control in the U.S.³ By the third month, the typical user misses three or more pills each cycle.⁵ These data suggest that the contraceptive needs of women are currently unmet (TABLE 1). Health care providers (HCPs) must be knowledgeable about recent advances in birth control methods and able to discuss their pros and cons--including efficacy, adverse effects, and compliance issues--with individual patients.

Recent contraceptive advances discussed in this review include extended-cycle COCs, drospirenone-containing products, the chewable contraceptive pill, and emergency contraceptive options. Concerns about the Ortho Evra transdermal patch and desogestrel-containing products also are discussed.

Extended-Cycle Oral Contraceptives
Extended-cycle products differ from traditional 21/7 COCs by decreasing or eliminating the hormone-free interval (HFI). A variety of dosing schedules are available (TABLE 2). Consecutive days of hormone therapy may extend to 84 or 365 days. In add-back regimens, the HFI is shortened to zero, two, or four days instead of the typical seven-day interval. The remaining days supply a lower dose of hormone than that given during the rest of the cycle.

Reasons for switching to an extended-cycle product include the typical menstrual symptoms experienced during the HFI; improving efficacy in women who forget to restart the pill; and patient preference to decrease the frequency of menstrual-like bleeding. For a number of years, prescribers have utilized continuous administration of monophasic pills to simulate an extended-cycle product. However, patients generally incur additional financial expense with this dosing regimen because insurance companies generally pay for only 13 cycles per year.⁶

Women with dysmenorrhea, premenstrual syndrome, premenstrual dysphoric disorder, or endometriosis prior to starting COCs typically experience exacerbations of these symptoms during the HFI. Decreasing or discontinuing the HFI is likely to reduce or eliminate breast tenderness, headache, bloating, cramping, hypermenorrhea, and the psychological symptoms typical of hormone withdrawal. Patients also experience less menstrual-blood loss with extended-cycle products, thereby decreasing the risk of iron-deficiency anemia. An additional benefit of extended-cycle products may be improved efficacy. A randomized clinical trial found that continuous COC regimens were more effective at preventing follicular development and breakthrough ovulation during the HFI.⁶ These issues are a concern, particularly in patients who have difficulty adhering to the dosing schedule, as low-dose products (20–30 mcg ethinyl estradiol) are the norm.⁷

Extended-cycle products are likely to cause unscheduled bleeding or spotting during active hormone therapy, most commonly during the first few months of therapy. The bleeding and spotting typically improve after several cycles, however. Patients must weigh the convenience of having fewer cycles of scheduled bleeding per year against the possibility of unscheduled bleeding or spotting during the initial stage of therapy.⁸

Studies have compared extended-cycle products with traditional 21/7 products to determine whether patients are more compliant with continuous regimens of a COC. The Coraliance study and many other trials have concluded that extended-cycle products promote compliance and efficacy because patients don't forget to restart the pill after a week-long HFI.⁹

Patients and HCPs have expressed concern that decreasing or eliminating the HFI may be unhealthy and  unnatural. Continuous regimens expose women to two additional months of hormone each year and increase lifetime exposure to estrogen and progestin. Concerns raised by HCPs and patients include unforeseen adverse effects and long-term health problems like endometrial hyperplasia, thrombosis, breast cancer, and future fertility.¹⁰ A definitive answer will not be available until long-term studies of extended-cycle products are completed. To date, no studies supporting these concerns have been published.

The Association of Reproductive Health Professionals (ARHP) commissioned a survey to determine women's views about menstrual cycling and the use of hormonal contraceptives. Almost one-half of survey participants said that they would choose to never have a period, and approximately one-quarter said that they would choose to continue to have monthly cycles.⁶ Another ARHP study found that women would choose extended-cycle products if they were safe, did not affect future fertility, and did not increase adverse effects; cost was also a factor.¹⁰ In the same study, 44% of HCPs believed that menstrual suppression is a good idea and 52% prescribed oral contraceptives for that reason.¹⁰ Among patients and HCPs (7%) who believed that menstruation is physiologically necessary, reasons cited included the importance of confirming that pregnancy did not occur during the previous cycle and the beliefs that menstruation is a natural state and withdrawal bleeding is necessary to cleanse the system.¹⁰

Proponents of extended-cycle contraception note that modern women experience about 450 cycles in their lifetime, compared with only 160 cycles for the pre–Industrial Revolution woman.¹¹ The increased number of cycles for modern women is due to multiple factors, including earlier menarche, later menopause, fewer pregnancies, and less breast-feeding.¹¹ Economically speaking, eliminating menstrual disorders may improve women's work productivity and decrease health care costs. Data collected from 1984 through 1992 found that menstrual disorders were the most commonly reported gynecologic condition.¹² More than 75% of women studied had consulted a doctor about this condition, and nearly 30% had spent one or more days in bed in the previous year.¹² A 2002 study concluded that menstrual bleeding has a significant economic impact for working women, with an estimated annual cost of $1,692 per woman in the workplace.¹³

Desogestrel-Containing Oral Contraceptives
Desogestrel is a third-generation progestin that is found in a number of COCs, including Cyclessa, Ortho-Cept, Mircette, and Desogen. The third-generation products were developed during the 1980s to decrease the androgenic effects, including hirsutism and acne, commonly seen with earlier generations of oral contraceptives. Two meta-analyses published in 2001 concluded that desogestrel-containing oral contraceptives increase the risk of thromboembolism by a factor of 1.7 over products that contain levonorgestrel.^14,15

The FDA requires manufacturers of desogestrel-containing products to include a statement in the Warnings section of COC labeling that these products are associated with a two-fold increase in the risk of venous thromboembolism. According to the FDA, patients at increased risk for thromboembolism should consider switching to a second-generation product.¹⁶ The Public Citizen's Health Research Group (PCHRG) filed a petition with the FDA in February 2007 to remove desogestrel because of the increased risk of developing blood clots.¹⁷ The petition claims that the third-generation products confer no clear advantage over older oral contraceptives that is sufficient to warrant the risks.¹⁷

Drospirenone-Containing Oral Contraceptives
COCs that contain the antimineralocorticoid drospirenone (Yasmin, Yaz; 3 mg drospirenone) as the progestin component may decrease the bloating and water retention that commonly occur with COC use. Drospirenone may cause potassium retention, however, leading to hyperkalemia. While this is not likely to be a problem in most patients, those who are concurrently taking potassium-sparing drugs, including nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, angiotensin II agonists, and potassium chloride, are at increased risk for hyperkalemia.¹⁸ A 2007 study found that 17.6% of women taking a drospirenone-containing product were concurrently taking another potassium-sparing drug; 40% of those aged 35 years and older were taking an interacting combination.¹⁸ In a related study, only 40% of patients who received an interacting combination of drospirenone with a potassium-sparing drug were monitored for hyperkalemia as recommended by product labeling; reasons for noncompliance included physician disagreement with the recommendation, patient factors, and health-plan barriers to testing.¹⁹ Pharmacists can monitor for this interaction and educate patients to help them overcome barriers to having their potassium levels monitored.

Chewable Oral Contraceptive
Femcon Fe contains 35 mcg ethinyl estradiol and 0.4 mg norethindrone in a spearmint-flavored pill that can be swallowed or chewed. The tablet should be followed immediately by a full 8 oz. of liquid. The proposed advantage of this product is ease of administration.²⁰ The seven brown tablets in the HFI contain 75 mg ferrous fumarate.

Use of COCs in Older Women

Perimenopausal women commonly experience hot flashes and dysfunctional uterine bleeding. Hormone replacement therapy can treat vasomotor and menstrual symptoms, but does not prevent ovulation. A patient taking COCs who experiences hot flashes during the HFI may be switched to an extended-cycle product. The use of COCs in older women confers both effective birth control and noncontraceptive benefits like increased bone mineral density and reduced risk of ovarian and endometrial cancer.²¹

Despite the benefits of COC use in older women, significant risks are associated with hormone use. Women over the age of 39 who take COCs have four times the risk of venous thromboembolism (VTE) compared with adolescents. The incidence in these women is 100 cases per 100,000 woman-years; obesity increases the risk.²¹ COC users with a history of hypertension may have an increased risk of heart attack and stroke, and hypertension and smoking act synergistically to increase the risk of stroke and heart attack in COC users.²² Therefore, women over 35 years of age should not take estrogen-containing contraceptives if they smoke or have diabetes, migraines, or hypertension. COC use does not appear to increase the risk of stroke or heart attack in healthy nonsmokers over age 35; oral contraceptives can be continued in these women until age 55.²² Depot medroxyprogesterone acetate or the levonorgestrel intrauterine device (IUD) may be appropriate for women in whom COCs are contraindicated.

Transdermal Contraceptive Patch
The Ortho Evra contraceptive patch, a matrix system containing 6 mg norelgestromin and 0.75 mg ethinyl estradiol, was approved in 2001. Proposed advantages include improved adherence to the regimen and better efficacy if errors of up to two days are made in dosing. This dosing method avoids first-pass metabolism of hormones, gastrointestinal enzymatic degradation, and peaks and troughs in drug levels. It is easy to confirm the presence of the patch, which reassures the user of continued protection. Disadvantages are application-site reactions and decreased efficacy in patients weighing more than 198 lb.²³

The FDA revised the labeling for Ortho Evra in September 2006 and again in January 2008, based on results of an epidemiologic study that found that users of the birth control patch were exposed to 60% more estrogen than users of a typical COC containing 35 mcg estrogen and were twice as likely to develop blood clots.^24,25 A 2007 postmarketing study of women aged 15 to 44 years confirmed earlier studies that women in this age group were at greater risk for VTE.²⁶ Despite the increased overall exposure to estrogen, the peak concentration of estrogen to which women are exposed is about 25% less with Ortho Evra than with typical COCs.²⁴

The FDA recommends that women with risk factors for VTE (TABLE 3) discuss the use of the Ortho Evra patch with their HCP and consider using nonhormonal contraceptive methods instead. Women who are immobilized due to surgery or injury should discontinue the patch while they are recovering from the event.²⁷

PCHRG filed a petition with the FDA in May 2008, requesting withdrawal of Ortho Evra from the market due to safety concerns based on the abovementioned studies.²⁸ PCHRG suggested that the FDA phase out sale of the patch over six months, allowing existing users to obtain refills while switching to another contraceptive.²⁸ Use of the patch has decreased in recent years, most likely due to the reports of risk of thromboembolism. Last year, about 2.7 million prescriptions were written for the patch, down from more than 9.9 million prescriptions in 2004, according to data cited by the petition.²⁸

Emergency Contraception
In August 2006, Plan B was approved for OTC sale to women aged 18 years and older. Plan B contains two tablets of 0.75 mg levonorgestrel. The product labeling states that the tablets are to be taken 12 hours apart starting within 72 hours of unprotected sex. Recent findings suggest that the regimen is equally effective if the tablets are taken as one dose.²⁹ Additional evidence suggests that Plan B may be effective taken up to five days after intercourse; however, this use is not approved.³⁰ Women may purchase Plan B to keep for future use; this concept, called advance provision, is recommended by many HCPs because it eliminates delays in starting therapy. Concerns that widespread availability of Plan B would increase sexual risk-taking behavior have not been borne out in clinical studies.²⁷

COCs may be used for emergency contraception also. Two to five tablets of a COC that contains levonorgestrel as the progestin are used in the Yuzpe regimen, which comprises 100 mcg to 120 mcg ethinyl estradiol combined with 0.5 mg to 0.6 mg levonorgestrel. Plan B is preferred to the Yuzpe regimen because it has fewer adverse effects, particularly nausea and vomiting, that may decrease the regimen's effectiveness.³²

The copper IUD can be used in women who want emergency as well as regular contraception. The proposed mechanism of action is to impair fertilization, alter sperm motility, and impede implantation.³² The IUD may be inserted up to five days after unprotected sex. IUD use is contraindicated in cases of sexual assault where there is a high risk of sexually transmitted disease.³²

Mifepristone, used in the U.S. as an abortifacient since 2000, has been examined for emergency contraception. It has multiple mechanisms of action, depending on when in the menstrual cycle it is administered. A single dose of 10 mg to 50 mg has been shown to be highly effective for preventing pregnancy.³² The dose is effective up to five days after unprotected sex. Impediments to the drug's use are that the only dose available in the U.S. is a 200-mg tablet; prescriber availability is limited to physicians who have registered with the FDA to obtain access; and the drug is likely to delay the onset of menstrual bleeding versus other methods of emergency contraception.²⁹

Summary
A number of new contraceptive methods have been introduced in the U.S. These methods are safe and effective for contraception. They also decrease adverse effects and confer some noncontraceptive benefits.

REFERENCES
1. Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health. 2006;38:90-96.
2. Jones RK, Darroch JE, Henshaw SK. Contraceptive use among U.S. women having abortions in 2000-2001. Perspect Sex Reprod Health. 2002;34:294-303.
3. Chandra A, Martinez GM, Mosher WD, et al. Fertility, family planning, and reproductive health of U.S. women:data from the 2002 National Survey of Family Growth. Vital Health Stat 23. 2005;25:1-160.
4. Hillis SD, Marchbanks PA, Tylor LR, Peterson HB. Poststerilization regret: findings from the United States Collaborative Review of Sterilization. Obstet Gynecol. 1999;93:889-895.
5. Potter L, Oakley D, de Leon-Wong E, Cañamar R. Measuring compliance among oral contraceptive users. Fam Plann Perspect. 1996;28:154-158.
6. AHRPClinical Proceedings. Extended and Continuous Use of Contraceptives to Reduce Menstruation. Washington, DC: Association of Reproductive Health Professionals; 2004.
7. Birtch RL, Olatunbosun OA, Pierson RA. Ovarian follicular dynamics during conventional vs. continuous oral contraceptive use. Contraception. 2006;73:235-243.
8. Portman D. Altering the hormone-free interval with extend­ ed-cycle contraception. Female Patient. 2006 (suppl):1-4.
9. Aubeny E, Buhler M, Colau JC, et al. The Coraliance study: non-compliant behavior. Results after a 6-month follow-up of patients on oral contraceptives. Eur J Contracept Reprod Health Care. 2004;9:267-277.
10. Andrist LC, Arias RD, Nucatola D, et al. Women's and providers' attitudes toward menstrual suppression with extend­ ed use of oral contraceptives. Contraception. 2004;70:359-363.
11. Eaton SB, Pike MC, Short RV, et al. Women's reproductive cancers in evolutionary context. Q Rev Biol.1994;69:353-367.
12. Kjerulff KH, Erickson BA, Langenberg PW. Chronic gynecological conditions reported by US women: findings from the National Health Interview Survey, 1984 to 1992. Am J Public Health. 1996;86:195-199.
13. Côté I, Jacobs P, Cumming D. Work loss associated with increased menstrual loss in the United States. Obstet Gynecol. 2002;100:683-687.
14. Hennessy S, Berlin JA, Kinman JL, et al. Risk of venous thromboembolism from oral contraceptives containing gestodene and desogestrel versus levonorgestrel: a meta-analysis and formal sensitivity analysis. Contraception. 2001;64:125-133.
15. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ. 2001;323:131-134.
16. Desogen (desogestrel and ethinyl estradiol) package insert. Roseland, NJ: Organon USA Inc; August 2007.
17. Public Citizen Health Research Group. Petition to the FDA to Ban Third Generation Oral Contraceptives Containing Desogestrel due to Increased Risk of Venous Thrombosis (HRG Publication #1799). www.citizen.org/publications/release.cfm?ID=7503. Accessed May 20, 2008.
18. McAdams M, Staffa JA, Dal Pan GJ. The concomitant prescribing of ethinyl estradiol/drospirenone and potentially interacting drugs. Contraception. 2007;76:278-281.
19. Mona Eng P, Seeger JD, Loughlin J, et al. Serum potassium monitoring for users of ethinyl estradiol/drospirenone taking medications predisposing to hyperkalemia: physician compliance and survey of knowledge and attitudes. Contraception. 2007;75:101-107.
20. Femcon Fe site. More to chew on. www.femconfe.com/more.jsp. Accessed May 15, 2008.
21. Kaunitz AM. Clinical practice. Hormonal contraception in women of older reproductive age. NEJM. 2008;358:1262-1270.
22. ACOG practice bulletin. No. 73: use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol. 2006;107:1453-1472.
23. 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-S18.
24. Ortho Evra (norelgestromin/ethinyl estradiol transdermal system) package insert. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; March 2008.
25. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol. 2007;109:339-346.
26. ClinicalTrials.gov. Relative risks for non-fatal venous thromboembolism, ischemic stroke and myocardial infarction in users of ORTHO EVRA (norelgestromin and ethinyl estradiol contraceptive patch) compared to levonorgestrel-containing oral contraceptives. www.clinicaltrials.gov/ct2/show/NCT00511784. Accessed July 31, 2008.
27. FDA News. FDA approves update to label on birth control patch. www.fda.gov/bbs/topics/NEWS/2008/NEW01781.html. Accessed May 15, 2008.
28. Public Citizen Health Research Group. Petition to the FDA to Ban Ortho-Evra (HRG Publication #1840). www.citizen.org/publications/release.cfm?ID=7582. Accessed May 15, 2008.
29. von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet. 2002;360:1803-1810.
30. Rodrigues I, Grou F, Joly J. Effectiveness of emergency contraceptive pills between 72 and 120 hours after unprotected sexual intercourse. Am J Obstet Gynecol. 2001;184:531-537.
31. Walsh TL, Frezieres RG. Patterns of emergency contraception use by age and ethnicity from a randomized trial comparing advance provision and information only. Contraception. 2006;74:110-117.
32. LaValleur J. Emergency contraception. Obstet Gynecol Clin North Am. 2000;27:817-839.
33. Jain J, Jakimiuk AJ, Bode FR, et al. Contraceptive efficacy and safety of DMPA-SC. Contraception. 2004;70:269-275.

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