US Pharm. 2006;31(9):39-48.

Each year, nearly 2% of U.S. women of repro­ ductive age have an induced abortion.1 This sobering statistic reminds all health care professionals that too often, our patients at risk for unintended pregnancy either fail to use effective birth control or use effective methods incorrectly. With the goal of helping pharmacists facilitate contraceptive success for their patients, this review provides an update regarding hormonal and intrauterine contraceptives and details newer methods, including the progestin-releasing intrauterine system, the contraceptive patch and ring, and extended-regimen oral contraceptives as well as emergency oral contraception.

Combined Hormone Contraceptives
Developed more than four decades ago and representing one of the best-studied prescription medications, oral contraceptives (OCs) combining estrogen and progestin continue to be the most popular reversible contraceptive used by women in the U.S.2 OC use is safe for most women and is associated with numerous noncontraceptive benefits (Table 1). Although OCs represent a highly effective birth control method when they are used correctly, inconsistent or incorrect use (e.g., skipping as few as two to three consecutive days of use) accounts for a surprisingly high annual failure rate of 8%.3,4 This high failure rate underscores the clinical value of hormonal and intrauterine contraceptives that do not require the users' daily attention.

Although the "pill" is not new, many new approaches to initiating and taking OC tablets have recently been developed. An innovative "quick start" approach to OC initiation involves in-office ingestion of the first OC tablet immediately after a negative pregnancy test, regardless of the patient's menstrual status. With this method, patients have immediate exposure to combined hormonal contraceptives (CHCs) and do not need to wait for their next menstrual period to begin or a "Sunday start." A pilot study has suggested that this approach to OC initiation is safe and results in higher rates of OC use than do conventional pill initiation strategies. Patients who use the quick-start approach initiate OC using an in-office sample pack but must fill their OC prescription in a timely manner to ensure continued efficacy.5

The vast majority of traditional OC regimens have used a 28-day plan with 21 days of combined active pills followed by a seven-day hormone-free interval (HFI). A seven-day HFI results in clearance of exogenous estrogen and progestin two to three days after completion of active pills. This allows for several hormone-free days during which levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) rise and follicular growth occurs with increased risk of ovulation if active pills are not started on time (referred to as escape ovulation).6 Shortening the HFI or adding low-dose estrogen during the usual placebo interval may decrease the risk of escape ovulation and further improve contraceptive efficacy.7 Previously, the only OC (Mircette) that attempted to shorten the HFI substituted low-dose estrogen (10 mcg ethinyl estradiol) for five of the seven usual placebo pills.8

In recent years, the trend toward reduction or elimination of the traditional seven-day HFI or placebo interval has resulted in the introduction of several new OC products (Table 2). Two new 28-day OC products, YAZ (3 mg drospirenone/20 mcg ethinyl estradiol)and Loestrin 24 FE (1 mg norethindrone/20 mcg ethinyl estradiol), were recently approved. Each provides 24, rather than 21, days of active combined hormones, followed by four days of placebo tablets, thus shortening the HFI.

The drosperinone-containing product (YAZ) has also been evaluated in women with premenstrual dysphoric disorder who desire pregnancy prevention. Response, defined as a 50% improvement in daily mood and in physical and behavioral scores, was reported in significantly more patients who received treatment in a placebo-controlled study.9 Yet another OC product under development administers combined OCs continuously without a pill-free interval for one year.

Extended OC regimens, which reduce the number of withdrawal bleeding episodes per year, have also become available and continue to increase in popularity. The first approved product to use this approach was Seasonale (levonorgestrel 150 mcg/ethinyl estradiol 30 mcg), which extended active combined OC use to 84 days (12 weeks), followed by one hormone-free week.10 Women interested in this "four periods a year" approach to OCs need to be aware that breakthrough bleeding and spotting (BTB/S) is more common during the initial active pill intervals than that seen with conventional 28-day regimens. However, over time, unscheduled BTB/S declines substantially.10





In May 2006, a 91-day-regimen OC, Seasonique, was approved. This regimen is the first to completely eliminate the HFI by utilizing seven days of low-dose estrogen (10 mcg ethinyl estradiol) during the pill-free interval.11 While not evaluated in head-to-head studies, bleeding data from clinical trials of the 91-day regimens with and without low-dose estrogen during the HFI have been subjectively compared (Figure 1).10,11 In each of the studies, the incidence of BTB/S was similar in the initial cycle, as would be expected given the use of equivalent formulations (levonorgestrel 150 mcg/ethinyl estradiol 30 mcg) during days 1 to 84. While the percentage of patients reporting BTB/S decreased, the decrease was greater in the patients who used low-dose estrogen during the HFI. The data for Seasonique showed a median of less than one day of bleeding per patient month in extended cycles 2 through 4.11





It should be noted that women taking extended-regimen CHCs, regardless of formulation or duration of extension, will have a greater annualized exposure to estrogen compared to women administered 28-day regimens. To date, there have been no reports of additional health risks associated with this exposure.





Approved for contraceptive use in 1992, depot medroxyprogesterone acetate (DMPA or Depo-Provera IM) contraceptive injections provide reversible long-acting birth control that is as effective as sterilization. In the 12 years since its introduction, DMPA has been to a large degree responsible for declining rates of unintended pregnancies and abortions among U.S. women, particularly teens.12 With more than three decades of experience with use abroad, an extensive and reassuring safety track record has accumulated for DMPA.12 In addition, use of DMPA is associated with noncontraceptive health benefits ( Table 3). However, in late 2004, the FDA added a black box warning to DMPA's package labeling regarding loss of bone mineral density (BMD) in women using the product. Because use of DMPA suppresses ovarian estradiol production, BMD declines during DMPA use. Fortunately, BMD is regained rapidly after discontinuation of DMPA, and studies of BMD in women and adolescents who had discontinued use of the product showed no BMD deficit compared to women who have never used DMPA.5 DMPA use has not been linked to the occurrence of osteoporosis or fractures. Accordingly (and notwithstanding the black box), concerns regarding BMD should not limit prescription or continuation of DMPA. Furthermore, ordering dual x-ray absorptiometry testing in healthy young women receiving DMPA is not appropriate.13 When DMPA is being used or considered in women with specific risk factors for low BMD (e.g., slender athletes, perimenopausal smokers), use of supplemental estrogen (e.g., oral conjugates equine estrogen 0.625 mg daily or equivalent doses of other oral/transdermal estrogen) is appropriate.13



A new low-dose subcutaneous formulation of DMPA, depo-subQprovera104 is now available.14 Medroxyprogesterone acetate injectable suspension (DMPA-SC) administered once every three months provides a 30% lower total dose than traditional DMPA IM (150-mg injection). In clinical studies, it suppressed ovulation for more than 13 weeks in all subjects regardless of body mass index, with no pregnancies reported in more than 16,000 woman cycles of use.5,14 Although not evaluated in a head-to-head study, the incidence of bleeding and amenorrhea reported with DMPA-SC appeared to be similar to that reported with DMPA.

Since 2000, two alternative estrogen-progestin CHC methods and one intrauterine contraceptive have been introduced in the U.S. (Table 4). Approved in 2002, the contraceptive patch, Ortho-Evra (transdermal norelgestromin/ethinyl estradiol patch), is applied once weekly for three weeks; subsequently, withdrawal bleeding is anticipated during a patch-free week. In a randomized clinical trial, the contraceptive efficacy of the patch was comparable to that of oral contraception.5 Application site reactions, breast discomfort, and dysmenorrhea were each significantly more common in women treated with the patch. This may, in part, be explained by a significantly higher overall estrogen exposure.15 In a randomized, open-label pharmacokinetic study, mean area under the time versus concentration curve 0–24 hours for the patch was 1.6 times higher than reported for combination OC therapy containing 30 mcg ethinyl estradiol (p <0.05). Although this observation led to the FDA adding a warning to the prescribing information for the contraceptive patch, available published epidemiologic data indicates that the risk of venous thromboembolism in users of the patch is similar to that in women using combination OCs.16,17

Contraceptive efficacy with the patch may be compromised in heavier women (>90 kg/198 lbs). In clinical trials, women weighing at least 198 pounds had a statistically significantly higher rate of pregnancy than the population of lower-weight women.16





Also introduced in the U.S. in 2002, NuvaRing (etonogestrel/ethinyl estradiol vaginal ring) is worn for three weeks, followed by one ring-free week during which withdrawal bleeding occurs. In comparative clinical trials, rates of breakthrough bleeding and spotting were lower with the ring than with OCs.5 More than three quarters of users indicated that they did not note discomfort related to the ring in general or during sexual relations.

Studies have also been conducted on extended use of Ortho Evra and Nuva Ring.18,19 In the study of the patch, patients randomized to the 91-day cycle reported fewer bleeding days but more spotting days during active therapy and significantly longer menstrual cycles (6.9 days compared to 5.2 days; p <.001) than did women in the 28-day–cycle group.18 In the vaginal ring extended-regimen study, women randomized to the shorter extended regimen (49 days) experienced less bleeding and/or spotting than did women who received the 91-day or 364-day regimens.19

Intrauterine Contraception

Widely used worldwide, intrauterine devices (IUDs) offer women convenient, reversible birth control as effective as surgical sterilization. In the mid-1970s, IUDs accounted for nearly 10% of birth control methods use by U.S. women;5 however, today only 1% of U.S. women use IUDs. This decline can be largely attributed to concerns among clinicians and women regarding the link between IUDs and salpingitis and tubal infertility; in particular, the morbidity and litigation associated with the flawed Dalkon Shield has alarmed many people. A high-quality systematic review found that if any increase in the risk of salpingitis is associated with IUD use, it is small and appears confined to the first 20 days to one month post-insertion and falls thereafter.20 Risk is also higher among women with multiple sexual partners. Likewise, use of an IUD is not associated with a subsequent increased risk of tubal infertility.20,21 Knowledge of these risks and their management may encourage clinicians to recommend use of IUDs more broadly.

Two IUDs are currently marketed in the US: Mirena (Table 5) and ParaGard. The copper IUD (ParaGard), introduced in 1988 and approved for up to 10 years of use, is a good choice for women who cannot or prefer not to use hormonal contraception. Because use of the copper IUD can increase menstrual flow and cramps, it is appropriate for women who have no excess menstrual flow or cramps at baseline. In the fall of 2005, the FDA revised prescribing information for the copper IUD.22 Nulliparous women (i.e., those who have never been pregnant), as well as women with a history of pelvic inflammatory disease are now considered appropriate candidates; however, women at current high risk for sexually transmitted infection remain poor candidates. The IUD may be inserted immediately post-partum or after the second month post-partum and is safe for use during lactation.



The levonorgestrel-releasing intrauterine system (IUS; Mirena), introduced in 2000 and approved for up to five years of use, reduces menstrual flow and is therefore appropriate for women who can use a progestin-based method and desire long-term contraception. In addition to use as a contraceptive method, it has also been used in the management of heavy menstrual bleeding and may be a more cost-effective alternative to hysterectomy.23 However, women interested in using the levonorgestrel-releasing IUS should be aware of that initial irregular spotting or bleeding is common after insertion of this device. Hormonal side effects, including acne and ovarian cysts, also occur in some users. Noncontraceptive benefits associated with use of the levonorgestrel-releasing IUS are detailed in Table 5.

Emergency Contraception
The use of emergency (post-coital) contraception (EC) is estimated to have averted more than 51,000 induced abortions in 2000.1 The only dedicated EC formulation available in the U.S. is the progestin-only formulation (Plan B), which consists of two levonorgestrel 0.75-mg tablets.

Progestin-only EC is more effective and causes less nausea and emesis than combination EC.24 Prescribing information for Plan B indicates one tablet should be taken within 72 hours of unprotected intercourse, followed by a second tablet 12 hours later.25 However, taking the two tablets together may be as effective in preventing pregnancy as dividing the dose.24 Optimally, Plan B should be taken as soon as possible or within 72 hours of unprotected intercourse; however, there is evidence that Plan B retains its efficacy in pregnancy prevention when it is taken up to five days after unprotected intercourse.24

In August, the FDA announced that Plan B has been approved for OTC use in women ages 18 and older. The product will remain available by prescription only for women ages 17 and younger. Duramed, Plan B's manufacturer and a Barr subsidiary, has agreed to provide consumers and health care professionals with labeling and education on the product, as well as a hotline that provides answers to questions on Plan B. Plan B will be available OTC only in locations staffed by licensed health care professionals and stocked behind the counter, because it cannot be dispensed without proof of age.

Pharmacists have a critical role in providing access to EC, most importantly by maintaining an inventory of Plan B. Pharmacists can provide women with information about the efficacy and possible side effects of EC, as well as the need to obtain follow-up care if menses do not occur as expected.

Use of Hormonal Contraception and Risk of Breast Cancer
Since the July 2002 publication of findings from the Women's Health Initiative (WHI), which found an increased breast cancer risk with use of menopausal combination hormone therapy, concerns that use of combination hormonal contraception might also increase this risk have been heightened. Many health care professionals are not aware of the Women's CARE study, a large study sponsored by the CDC and NIH that examined breast cancer risk associated with use of hormonal contraceptives.26 Initial findings, published in August 2002, indicated that regardless of length of OC therapy and age or family history, use of OCs was not associated with an elevated breast cancer risk.5,26 A more recent publication from this same study found that neither use of DMPA nor progestin-only implants is linked with an increase in breast cancer risk. 27

Conclusion
Given the number and range of new contraceptive options, it is clear that birth control has expanded well beyond the pill.5 Pharmacists knowledgeable about older hormonal and intrauterine contraceptives and new longer-acting and emergency contraceptives can have an important role by counseling their patients and positively impacting public health by minimizing unintended pregnancy and induced abortion.

Acknowledgement: The author acknowledges the invaluable assistance of Kathryn M. Martin, PharmD, Ms. Georgette Andreason, and Ms. Pam Neumann.

References
1. 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.
2. National Center for Health Statistics. Primary contraceptive methods among women aged 15–44 years--United States, 2002. JAMA. 2005;293:2208.
3. Petitti DB. Combination estrogen-progestin oral contraceptives. N Engl J Med. 2003;349:1443-1450.
4. Trussel J. Contraceptive failure in the United States. Contraception . 2004;70:89-96.
5. Kaunitz AM. Beyond the pill: new data and options in hormonal and intrauterine contraception. Am J Obstet Gynecol. 2005;192:998-1004.
6. Baerwald AR, Olatunbosun OA, Peirson RA. Ovarian follicular development is initiated during the hormone-free interval of oral contraceptive use. Contraception. 2004;70:371-377.
7. Mishell DR. Rationale for decreasing the number of days of the hormone-free interval with use of low-dose oral contraceptive formulations. Contraception . 2005;71:304-305.
8. Mircette Study Group. An open-label, multicenter, noncomparative safety and efficacy study of Mircette, a low-dose estrogen-progestin-oral contraceptive. Am J Obstet Gynecol. 1998;179:S2-S8.
9. Yonkers KA, Brown C, Pearlstein RB, et al. Efficacy of a new low-dose oral
contraceptive with drosperinone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;105:492-501.
10. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.
11. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended regimen oral contraceptive using continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.
12. Westhoff C. Depot-medroxyprogesterone acetate injection (Depo-Provera®); a highly effective contraceptive option with proven long-term safety. Contraception. 2003;68:75-87.
13. Kaunitz AM. Depo-Provera's black box: Time to reconsider? Editorial. Contraception. 2005;72:165-167.
14. Jain J, Jakimiuk AJ, Bode FR, et al. Contraceptive efficacy and safety of DMPA-SC. Contraception. 2004;70:269-275.
15. van den Heuvel MW, van Bragt AJM, Alnabawy AKM, Kaptein MCJ. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2004;72:168-174.
16. Ortho Evra [prescribing information]. Ortho-McNeil Pharmaceuticals, Raritan, NJ. Available at: www.orthoevra.com/active/janus/en_US/assets/common/company/pi/orthoevra.pdf#zoom=100. Accessed June 7, 2006.
17. Jick SS, Kaye JA, Russman 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;73:223-238. Epub 2006 Jan 26.
18. Stewart FH, Kaunitz AM, Laguardia KD, et al. Extender use of transdermal norelgestromin/ethinyl estradiol: a randomized trial. Obstet Gynecol. 2005;105:1389-1396.
19. Miller L, Verhoeven CH, Hout JL. Extended regimens of the contraceptive vaginal ring: a randomized trial. Obstet Gynecol. 2005;106:473-482.
20. Grimes DA. Intrauterine device and upper-genital-tract infection. Lancet . 2000;356:1013-1019.
21. Hubacher D, Lara-Ricalde R, Taylor DJ, et al. Use of copper intrauterine devices and the risk of infertility among nulligravid women. New Eng J Med . 2001;345:561-567.
22. ParaGard T380A Intrauterine Copper Contraceptive [prescribing information]. Duramed Pharmaceuticals, Woodcliff Lake, NJ. Available at: www.paragard.com/paragard/custom_images/Prescribing-Info.pdf. Accessed June 8, 2006.
23. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005; 19(4):CD002126.
24.Westhoff C. Emergency Contraception. N Engl J Med 2003; 349:1830-1835.
25. Plan B [prescribing information]. Duramed Pharmaceuticals, Pomona, NY. Available at: www.go2planb.com/PDF/PlanBPI.pdf. Accessed June 8, 2006.
26. Marchbanks PA, McDonald JA, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346: 2025-2032.
27. Strom BL, Berlin JA, Weber AL, et al. Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contraception. 2004;69:353-360.

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