Extended Regimens?The New Standard for OCs?

Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.

An estimated 10 million women in the United States and 100 million women worldwide use combination oral contraceptives (OCs).¹ Designed to simulate the 28 days of the natural menstrual cycle, most OCs use 21 days of active pills and 7 days of placebo pills known as a hormone-free interval (HFI). In recent years, the FDA has approved formulations of OCs that change the HFI by reducing the number of hormone-free days for each cycle, increasing the time period between HFIs, supplementing the HFI with low-dose estrogen, or a combination of these strategies.^2-7 The result is fewer and/or shorter hormone withdrawal periods.

Studies evaluating the reduction or elimination of the 7-day HFI have documented both the safety and efficacy of extended OC regimens.^8-13 Sulak et al conducted a study to evaluate the timing, frequency, and severity of hormone-related symptoms (eg, pain, headache, bloating, etc) reported by women taking OCs.¹⁴ The results of the study concluded that the symptoms women experienced during the 7-day HFI were significantly worse when compared with the 21 days of active pills.

The new OCs, which change the HFI, may decrease the incidence of hormone fluctuations experienced by women using OCs, reduce withdrawal bleeding, and maximize ovarian follicular suppression.^14-18 Willis et al reported that decreasing the typical 7-day HFI may provide greater pituitary?ovarian inhibition, thus decreasing the risk of escape ovulation and formation of ovarian cysts, as well as symptoms associated with hormone withdrawal.¹⁷

Pharmacists should be prepared to provide women with the information necessary to enable them to make informed decisions about the new OC options. Many women may not be aware that, while taking OCs, the bleeding they experience is due to withdrawal of hormones during the HFI and is not a natural menstrual period. During each natural cycle, a woman?s body is preparing for a potential pregnancy?ovulation occurs and the uterine lining builds up. When pregnancy does not occur, hormone levels drop and the lining of the uterus sheds. During an OC cycle, ovulation is prevented and build-up of the uterine lining is minimized. Just as in a natural cycle when hormones are withdrawn, the uterine lining sheds.

What Do Women Want?

Today, due to later childbearing and fewer children per family, women in industrialized societies experience 3 times as many menstrual periods over their lifetime as their ancestors,¹⁹ and interest in menstrual suppression is growing among women. In a survey reported in 2004, Andrist et al reported that, although 78% of women surveyed had never heard of menstrual suppression with OCs, 59% would be interested in having fewer menstrual periods, and 33% would elect to never have a menstrual period.²⁰ Glasier et al reported that more than 50% of women disliked having a menstrual cycle, and 33% to 50% would consider using an OC that would temporarily halt menstruation.²¹ In another survey, den Tokelaar et al reported that, among females aged 15 to 34 years, an estimated 24% to 35% preferred to have a menstrual cycle 4 times annually, and 3% to 4% would prefer one cycle annually.²² In this survey, women younger than 40 preferred to menstruate no more than 4 times a year, whereas 50.6% of women between the ages of 45 and 49 preferred to eliminate periods completely.

Menstrual Suppression

Due to the emergence of extended-regimen OCs, the subject of menstrual suppression has been an issue of debate for many health care professionals. Menstrual adjustments have been used for years, however, to suppress medical conditions that are exacerbated by menstruation and the cyclical variations of the female hormones.²³ Since the 1970s, researchers have studied the use of OCs to decrease menstrual bleeding, and the findings show that monthly menstruation is not medically necessary, nor is menstrual suppression harmful.^15,16

A number of OC products that extend the cycle or alter the HFI are available (Table). The first regimen to alter the HFI was Mircette, which replaced placebo pills on days 24 to 28 of each cycle with low-dose estrogen (10 mcg) tablets.⁸ The first approved extended regimen, Seasonale, uses a 91-day regimen (84 days of active pills followed by 7 days of placebo).² Seasonique also uses a 91-day regimen, with the addition of 7 days of low-dose estrogen during the HFI.³ Although the 2 regimens have not been compared in a head-to-head trial, the addition of 7 days of low-dose estrogen to the HFI appears to decrease the average length of scheduled bleeding.^9,10 In addition to Mircette, two 28-day regimens that shorten the HFI are available. Loestrin 24 Fe and YAZ each use 24 days of active therapy followed by 4 days of placebo.^5,6 The only continuous use product currently available is Lybrel, which uses active combination therapy daily.⁷

*Inert ingredient with no intended therapeutic effect. Adapted from references 2-13.

Extended-regimen OCs may result in unscheduled bleeding and/or spotting during the early stages of therapy, which tend to decrease as therapy continues.^9-13 The continuous use of OCs without any break has been shown to incrementally induce amenorrhea in about 60% of women taking a continuous regimen for 1 year.¹³ Women using any OC should be informed of the potential for episodes of breakthrough bleeding and spotting during initial months of use and that these episodes should decrease or subside over time. Women experiencing prolonged breakthrough bleeding and spotting or any episodes of heavy bleeding should be advised to contact their gynecologist immediately.

Pharmacists should encourage women seeking advice about contraception to discuss the various options available with their gynecologists to determine if they are an appropriate candidate for extended or continuous use OCs. When counseling women who have been prescribed these agents, pharmacists must screen for possible drug interactions and contraindications and discuss the warning signs of serious adverse events associated with all OCs, such as thrombosis. If possible, provide a patient education printout on the proper use of OCs. It also is important to remind patients that OCs may prevent pregnancy, but they do not protect against the transmission of sexually transmitted diseases, including HIV.

References

• Hatcher RA, Nelson A. Combined Hormonal Contraceptive Methods. In Hatcher RA, ed. Contraceptive Technology, 18th rev ed. New York, NY: Ardent Media; 2004:391-460.
• Seasonale Prescribing Information. www.seasonale.com/pdf/Seasonale_prescribing_info.pdf. Accessed May 16, 2008.
• Seasonique Prescribing Information. www.seasonique.com/Files/PrescribingInfo.pdf. Accessed May 16, 2008.
• Mircette Prescribing Information. www.mircette.com/Prescribing_Info.pdf. Accessed May 19, 2008.
• YAZ Prescribing Information. berlex.bayerhealthcare.com/html/products/pi/fhc/YAZ_PI.pdf. Accessed May 16, 2008.
• Loestrin Prescribing Information. www.loestrin24com.com/pdf/pi_loestrin24_fe.pdf. Accessed May 16, 2008.
• Lybrel Prescribing Information. www.wyeth.com/content/showlabeling.asp?id=489. Accessed May 16, 2008.
• The 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.
• Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.
• Anderson, FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.
• Nakajima ST, Archer DF, Ellman H. Efficacy and safety of a new 24-day oral contraceptive regimen of norethindrone acetate 1 mg/ethinyl estradiol 20 micro g (Loestrin 24 Fe). Contraception. 2007;75:16-22.
• Bachmann G, Sulak PJ, Sampson-Landers C, Benda N, Marr J. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drosperinone. Contraception. 2004;70:191-198.
• Archer D, Jensen JT, Johnson JV, Borisute H, Grubb GS, Constantine GD. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 results. Contraception. 2006;74:439-445.
• Sulak P, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.
• Sulak PJ. Continuous oral contraception: changing times. Best PractRes Clin Obstet Gynaecol. 2008;22:355-374.
• Nelson A. Communicating with patients about extended cycle and continuous use of oral contraceptives. J Womens Health. 2007;4:463-470.
• Willis SA, Kuehl TJ, Spiekerman M, Sulak PJ. Greater inhibition of the pituitary-ovarian axis in oral contraceptive regimens with a shortened hormone-free interval. Contraception. 2006;74:100-103.
• Vandever MA, Kuehl TJ, Sulak PJ, et al. Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens. Contraception. 2008;77:162-70.
• Eaton SB, Pike MC, Short RV, et al. Women's reproductive cancers in evolutionary context. Q Rev Biol 1994;69:353-367.
• Andrist LC, Arias RD, Nucatola D, et al. Women's and providers' attitudes toward menstrual suppression with extended use of oral contraceptives. Contraception. 2004;70:359-363.
• Glasier AF, Smith KB, van der SPuy ZM, et al. Amenorrhea associated with contraception-an international study on acceptability. Contraception. 2003;67:1-8.
• den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use. Contraception. 1999;59:357-362.
• What You Need to Know about Menstrual Suppression. The Association of Reproductive Health Professionals Web site. www.arhp.org/factsheets/menstrualsuppression.cfm. Accessed May 16, 2008.