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UPDATE HOW DEVELOPMENTS ARE CHANGING PATIENT CARE

Sara Newmann, MD, MPH Fellow in Family Planning, CONTRACEPTION Department of Obstetrics, Gynecology, and Reproductives Sciences, San Francisco General Hospital, A number of refi nements in access to, or use of, University of California–San Francisco deserve our attention Philip D. Darney, MD, MSc Professor and Chief, Department of Obstetrics, Gynecology, and Reproductive Sciences, year ago, the US Food and Drug of its overall effi cacy. We also have an- San Francisco General Hospital, Administration (FDA) granted other year of experience with the levo- University of California–San Francisco over-the-counter (OTC) status for -releasing intrauterine system Dr. Newmann reports no fi nancial A relationship relevant to this article. Plan B, the -only emergen- (Mirena) and its multiple benefi ts be- Dr. Darney receives support from Organon, is a consultant to Organon cy contraceptive. In the past few years, yond contraception, and with extended and Bayer, and is a speaker for Organon we have accumulated data on the general hormonal contraceptive regimens. This and Bayer. impact of improved access to emergency® Dowdenarticle highlights Health what we Media know about contraception (EC), as well as evidence these three forms of contraception. CopyrightFor personal use only Greater access to Plan B leads to increased—and faster—use IN THIS ARTICLE ❙ The many Now that Plan B is available OTC to creases its utilization, but causes it to be benefi ts of the both men and women 18 years and old- used sooner.2–7 Most of the trials conduct- levonorgestrel- er,1 several questions are in order: ed so far have compared advance provi- releasing IUS • What are the effects of this change? sion of EC with counseling about EC or a Page 52 • Does OTC access or provision of the prescription for it. Only one trial has in- drug in advance reduce or cluded a pharmacy-access arm, and it was ❙ 4 continuous OC oral contraceptive use? conducted before FDA approval of OTC • Does it increase the number of sexual status.3 It found that pharmacy access did regimens partners or rate of sexually transmit- not increase use of EC, compared with Page 53 ted disease (STD)? standard access (ie, returning to the clinic • Does it reduce unintended pregnancy? when EC was needed). It is too early to To acquire the drug OTC, an adult tell what effect OTC availability will have must ask the pharmacist for it and show on the usage rate, but data so far support proof of age. Even before the FDA ap- the practice of giving the patient a supply proved OTC status, many clinicians gave of EC rather than just a prescription. patients an advance prescription or actual medication so an appointment would be Increased access to EC does not unnecessary in a time of need. affect regular contraceptive behavior Several randomized trials have found Multiple studies have shown that ad- that advance provision of EC not only in- vance provision of EC has no signifi cant

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For mass reproduction, content licensing and permissions contact Dowden Health Media. UPDATE CONTRACEPTION

… nor does it cause promiscuity Levonorgestrel pills can be or increase the rate of STD Multiple studies have demonstrated taken both at once and as long that advance provision of EC does not as 5 days after intercourse increase the number of sexual partners or rate of STD.3–6 The largest of these rescribing information for levonorgestrel emergency studies compared both pharmacy ac- contraception (EC) recommends ingestion of the fi rst cess without a prescription and advance P0.75-mg tablet within 72 hours (3 days) of a single act provision of EC to standard access. of unprotected intercourse, with the second tablet taken 12 That study included 2,117 sexually ac- 11 hours after the fi rst. However, data show that levonorgestrel tive young women and found no differ- EC can prevent pregnancy up to 5 days after intercourse. In a ence in the rate of STD or number of sex World Health Organization multicenter randomized trial of vari- 3 ous EC regimens, levonorgestrel EC prevented 79% to 84% of partners among the three study groups. expected pregnancies when taken within 1 to 3 days, and 60% Smaller studies comparing advance pro- to 63% when taken 4 to 5 days after intercourse.12 Randomized vision of EC with standard access also trials have also found that taking both 0.75-mg levonorgestrel found no signifi cant difference in these pills simultaneously prevents pregnancy as effectively as taking variables.8,9 them 12 hours apart. Levonorgestrel EC prevents or delays ovulation by inhibit- No evidence of fewer unintended ing the luteinizing hormone surge during the follicular phase.13 pregnancies—yet Secondary mechanisms of contraceptive action include We know that progestin-only EC can thickening of the cervical mucus; decreased pH level, which reduce unintended pregnancy by al- immobilizes sperm; and decreased recovery of sperm from the most 90%.10 However, studies have not uterus.14 yet demonstrated such a decrease in the general population. One reason may effect on the use of regular contraception. be that the two studies that considered Studies have examined the impact of EC unintended pregnancy as a primary out- on both baseline oral contraceptive usage come3,9 were too small to detect a differ- FAST TRACK and condom usage and found no signifi - ence in pregnancy rates, or it may be that cant change in either among women who EC was underutilized by women in the Providing the patient 3–6 with emergency used EC during the study. studies. contraception in advance does not Levonorgestrel intrauterine system increase the number of sexual partners or has benefi ts beyond contraception rate of STD The levonorgestrel intrauterine system LNG-IUS compares favorably (LNG-IUS) has been shown to signifi cant- to endometrial ablation ly decrease blood loss and increase hemo- The LNG-IUS provides nonoperative, lo- globin and serum ferritin levels in women cal, and minimally invasive treatment of with idiopathic menorrhagia.15 The LNG- menorrhagia, producing clinical results IUS reduces blood loss to a greater degree similar to those of different endometrial (as much as 96% after 1 year) than do ablation methods for dysfunctional uterine placebo, nonsteroidal anti-infl ammatory bleeding or menorrhagia. The LNG-IUS is drugs, antifi brinolytic medication, and comparable to endometrial resection in its oral contraceptives.16 In one study,16 the reduction of blood loss, patient satisfac- LNG-IUS was the only treatment that re- tion, rate of amenorrhea, and recurrent duced menstrual bleeding to less than 80 menorrhagia.17 It also is equivalent to mL/day—the upper limit of normal. thermal balloon ablation in its reduction

52 OBG MANAGEMENT • August 2007 of bleeding and increased quality of life considered a fi rst-line therapy for women and hemoglobin level.18,19 And it produces with fi broids who wish to preserve their a higher amenorrhea rate than expectant childbearing potential. management after endometrial resection in women with adenomyosis, and averts Endometrial hyperplasia is reduced the need for further procedures, such as The LNG-IUS can prevent and induce re- hysterectomy and repeat resection.20 gression of endometrial hyperplasia.23,24 In addition, it reduces bleeding and spotting In many women, LNG-IUS renders among women using hormone replace- hysterectomy unnecessary ment therapy.25,26 Studies also suggest it In a controlled trial involving 56 women may be benefi cial in the treatment of stage on a waiting list for hysterectomy, 64% I endometrial cancer, although further re- of those who received the LNG-IUS and search into this effect is needed.27 14% of those in a control group removed themselves from the list at the end of 6 Endometriosis-related pain is eased months because they were satisfi ed with In a randomized trial comparing the symptom control (P<.001).21 In a trial LNG-IUS with a gonadotropin-releas- involving 236 women with menorrhagia ing hormone (GnRH) analogue among randomized to LNG-IUS or hysterecto- women with chronic pelvic pain due to my, the groups had similar quality-of-life endometriosis, both treatments reduced scores at 1 and 5 years of follow-up—and pain and improved psychological well-be- costs associated with the LNG-IUS were ing to the same degree—but the LNG-IUS signifi cantly lower than those associated caused no systemic hypoestrogenic symp- with hysterectomy, even after 50 women toms, unlike the GnRH analogue.28 In a randomized to the LNG-IUS opted for randomized trial comparing the LNG- and underwent hysterectomy.41 IUS with expectant management among women who had undergone laparoscopic Consider the LNG-IUS a fi rst-line resection of endometriosis, women in the therapy for symptomatic fi broids LNG-IUS arm had signifi cantly decreased FAST TRACK The LNG-IUS continuously decreases fi - recurrent dysmenorrhea.29 64% of women who broid and uterine volume and blood loss In addition, the LNG-IUS is effective and increases ferritin levels over time for as long as 5 years, can be used in con- received the LNG-IUS among women with symptomatic fi - junction with systemic , and is an removed themselves broids.22 It should therefore be routinely effective contraceptive. from a waiting list for hysterectomy at the end of 6 months Continuous oral contraceptive regimens: 4 effective options

Oral contraceptives (OCs) can be pre- • reduce the incidence of breakthrough scribed for continuous use to achieve a bleeding number of different goals30: The fi rst two options are highly ef- • decrease the number of placebo days fective and produce shorter and fewer per cycle bleeds, and the last option is especially • reduce the number of placebo weeks appropriate for women troubled by un- or withdrawal weeks per year scheduled bleeding during continuous • eliminate withdrawal weeks from the OC use. All four options decrease men- cycle entirely strual symptoms. CONTINUED www.obgmanagement.com August 2007 • OBG MANAGEMENT 53 UPDATE CONTRACEPTION

Reduce the number of placebo days with no placebo or withdrawal inter- Compared with the standard 28-day regi- val. This option is safe and acceptable men (21 days of active pills followed by 7 to women, according to two small ran- days of placebo), extended regimens sig- domized trials and two prospective trials, nifi cantly reduce ovarian activity and pro- but larger studies are needed to confi rm duce smaller follicles and a lower estrogen these results.37–40 Continuous use for level.31,32 Extended regimens may involve 1 year is associated with less bleeding, fewer days of placebo pills per cycle, or higher rates of amenorrhea, and similar very small amounts of estrogen through- side effects, compared with convention- out the withdrawal week of the regimen. al regimens.37,38 Patient acceptance and These modifi cations may translate into satisfaction also are high,39 with most increased effi cacy. In two randomized tri- women choosing to keep taking the pill als comparing extended regimens with a continuously. Lybrel, an OC designed for standard regimen, the extended regimens this purpose, contains 20 μg of ethinyl es- were highly effective, with a tradiol and 90 μg of levonorgestrel and is of up to 1.29 (1.29 pregnancies for every intended to eliminate menses through 1 100 woman-years of use), and produced year of continuous use. shorter withdrawal bleeds.33,34 Reduce breakthrough bleeding Decrease the number of placebo or For women who experience unscheduled withdrawal weeks bleeding while taking an OC continuous- The FDA approved the fi rst OC to be ly, one option is to stop taking pills when packaged for extended use (Seasonale) breakthrough bleeding occurs and initiate in 2003. Each pack contains 84 active a hormone-free interval. This approach tablets of ethinyl (0.03 mg) and was studied in a randomized trial in levonorgestrel (0.15 mg), followed by which women were scheduled to take an seven placebo pills. This highly effective OC continuously for 168 days.40 Women regimen has a failure rate of 0.60 per 100 who had persistent unscheduled bleeding FAST TRACK woman-years.35 Another extended-use for longer than 7 days were randomized Extended OC OC (Seasonique) contains 7 days of ethi- to a 3-day hormone-free interval or con- nyl estradiol (10 μg) instead of placebo tinuation of the active pills. Those who regimens reduce pills and may, therefore, suppress follicu- continued taking active pills had more ovarian activity and lar development to an even greater degree bleeding over the long term, and a large produce smaller during the withdrawal week.36 percentage found it necessary to institute follicles and a lower Extended cycles can be achieved with a delayed hormone-free interval. estrogen level than any monophasic OC in an off-label man- This option may be particularly use- ner. Simply instruct the patient to take ful for women who experience persistent the standard 28-day one active tablet for 42 consecutive days breakthrough bleeding on a continuous regimen (known as “bicycling”) or for 63 consec- regimen.40 ■ utive days (“tricycling”), followed by 4 to 7 pill-free days. References Unscheduled bleeding with the 63- 1. U.S. Food and Drug Administration. FDA approves over-the-counter access for Plan B for women 18 and day regimen appears to be similar to older; prescription remains required for those 17 and the rate associated with the 21-day regi- under [August 24, 2006]. Available at: http://www.fda. 35 gov/bbs/topics/NEWS/2006/NEW01436.html. Ac- men. An extended-cycle regimen can be cessed July 11, 2007. modifi ed according to how often the user 2. Harper CC, Cheong M, Rocca CH, Darney PD, Raine wants withdrawal bleeding. TR. The effect of increased access to emergency con- traception among young adolescents. Obstet Gyne- col. 2005;106:483–491. Eliminate the withdrawal week 3. Raine TR, Harper CC, Rocca CH, et al. Direct access to through pharmacies and Perhaps the most radical extended-cycle effect on unintended pregnancy and STIs: a random- regimen is continuous use of active pills ized controlled trial. JAMA. 2005;293:54–62. CONTINUED

54 OBG MANAGEMENT • August 2007 UPDATE CONTRACEPTION

4. Raymond EG, Trussell J, Polis CB. Population effect of 24. Perino A, Quartararo P, Catinella E, et al. Treatment of increased access to emergency contraceptive pills: a endometrial hyperplasia with levonorgestrel releasing systematic review. Obstet Gynecol. 2007;109:181–188. intrauterine devices. Acta Eur Fertil. 1987;18:137–140. 5. Walsh TL, Frezieres RG. Patterns of emergency con- 25. Ettinger B, Pressman A, Silver P. Effect of age on rea- traception use by age and ethnicity from a randomized sons for initiation and discontinuation of hormone re- trial comparing advance provision and information placement therapy. Menopause. 1999;6:282–289. only. Contraception. 2006;74:110–117. 26. Andersson K, Mattson LA, Rybo G, Stadberg E. In- 6. Jackson RA, Schwarz EB, Freedman L, Darney PD. trauterine release of levonorgestrel—a new way of Advance supply of emergency contraception. Effect adding in hormone replacement therapy. on use and usual contraception—a randomized trial. Obstet Gynecol. 1992;79:963–967. Obstet Gynecol. 2003;102:8–16. 27. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine 7. Hu X, Cheng L, Hua X, Glasier A. Advanced provision of emergency contraception to postnatal women in treatment of early endometrial cancer. China makes no difference in rates: a random- Am J Obstet Gynecol. 2002;186:651–657. ized controlled trial. Contraception. 2005;72:111–116. 28. Petta CA, Ferriani RA, Abrao MS, et al. Randomized 8. Gold MA, Wolford JE, Smith KA, Parker AM. The ef- clinical trial of a levonorgestrel-releasing intrauterine fects of advance provision of emergency contraception system and a depot GnRH analogue for the treatment on adolescent women’s sexual and contraceptive be- of chronic pelvic pain in women with endometriosis. haviors. J Pediatr Adolesc Gynecol. 2004;17:87–96. Hum Reprod. 2005;20:1993–1998. 9. Raymond EG, Stewart F, Weaver M, Monteith C, Van 29. Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Der Pol B. 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