Contraceptive Technology Reports
A Review of Extended-Cycle Oral Contraception
Author: Richard S. Legro, MD, Professor of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey.
Peer Reviewer: Leslie Miller, MD, Associate Professor, Obstetrics and Gynecology, University of Washington, Seattle.
Overview: Rationale for Extended-Cycle Oral Contraception
Seasonale (Barr Laboratories, Pomona, NY), the first extended-cycle oral contraceptive (12 weeks continuous daily active pill followed by a one-week inactive pill) approved by the Food and Drug Administration (FDA) is expected to become clinically available by the end of this month. This approval represents a bold but precedented step away from the traditional model of 28-day oral contraceptive pill (OC)-induced cycles. The idea of giving the pill for 21 days with a seven-day hiatus (21/7 OC) to allow a withdrawal bleed was based primarily on the historical desire to mimic the natural menstrual cycle. A monthly bleed at that time point was reassuring to patient and physician alike that pregnancy was unlikely, and at that point, the potential teratogenicity of the pill and long-term effects on fertility were unknown. From a political and religious standpoint, a "natural" cycle would be more acceptable to secular and religious authorities who were opposed to contraception that eliminated the monthly withdrawal bleed entirely.1 Although the pill underwent the most extensive scrutiny and clinical trials of any compound up to that date, no dose ranging or dose extension (beyond 21 days) studies were carried out. It was only with time and experience that it was discovered that the higher estrogen doses [the original combinations contained 100-150 mcg ethinyl estradiol (EE)] were associated with a higher risk of thrombotic events, and the dose then was lowered with minimal effects on breakthrough bleeding.2
The clinical use of the OC now has extended beyond contraception to the treatment of several benign gynecologic conditions such as hyperandrogenism (acne and hirsutism), chronic pelvic pain, dysfunctional uterine bleeding, dysmenorrhea, and endo-metriosis;3 prevention of multiple disorders such as anemia, endometrial cancer, ovarian cancer, benign breast disease, and pelvic inflammatory disease;3 and finally personal and professional preference to avoid vaginal bleeding. A strong voice has emerged advocating elimination of the withdrawal-bleeding component completely.4,5
Hormone replacement therapy (HRT) in postmenopausal women has undergone a similar evolution. Bleeding not only is undesirable from a personal preference, but also as a side effect, as unexpected bleeding (frequently termed "breakthrough bleeding") is the single most common reason for discontinuing the 21/7-day OC regimen.6 Other common reasons for discontinuing use include nausea, weight gain, mood changes, breast tenderness, and headaches.6 Thirty-two percent of women starting 21/7-day OC therapy will discontinue their use within six months, largely due to these symptoms.7
A 1996 Dutch survey found that the majority of women in all age groups prefer either a decreased frequency of bleeding to less than once a month or complete elimination of bleeding through the use of oral contraceptives.8 Additionally, the majority of the women surveyed preferred to have less painful, shorter, and less heavy periods, or most desired: complete amenorrhea. In the United States, the Washington, DC-based Association of Reproductive Health Professionals commissioned the Rochester, NY-based Harris Interactive to conduct a telephone survey of U.S. women regarding their preferences on frequency and characteristics of menstrual bleeding.9 Of the 491 women ages 18-49 included in the survey conducted in 2002, 44% stated that they would prefer never to menstruate, and this preference increased to 59% when only those ages 40-49 were analyzed. (Fewer than 30% preferred monthly menses. More than one in four women had missed professional, social, athletic, or family-oriented events because of their period, menstrual cramps, or other menstrual effects. Of the 70% of women who currently or previously used OCs, 15% stated that they had used their OC regimen to delay or stop their period.9
The first large study on the acceptability of an extended 84-day regimen was performed by Loudon and colleagues in 1977.10 There was a certain institutional reluctance to this change as noted in the article: "The doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves."10 However, the women in the study welcomed the reduced number of periods and associated relief from menstrual symptoms. This study of 196 women looked at reducing menstruation to a three-month cycle event (84 active days/seven placebo) which is very similar to the Seasonale schedule, although this study used an 50-mcg ethinyl estradiol/lynestrenol monophasic OC. Breakthrough bleeding decreased with each three-month cycle of use, and no breakthrough bleeding was cited after nine months of use. At the conclusion of the study, many of the patients refused to return to a monthly cycle and preferred the trimonthly regimen. There have subsequently been a number of other studies or extended contraception.11-13
Overview of Seasonale
Seasonale is the first FDA-approved extended-cycle oral contraceptive for the prevention of pregnancy. Seasonale is a 91-day regimen taken daily as 84 active monophasic tablets of 30-mcg EE and 150 mcg levonorgestrel, followed by seven inactive tablets. According to the package insert, in a one-year controlled trial with Seasonale, four pregnancies occurred in women 18-35 years of age during 809 completed 91-day cycles of Seasonale during which no backup contraception was utilized. This represents an overall use-efficacy (typical user efficacy) pregnancy rate of 1.98 per 100 women-years of use. In the published study, sponsored by Barr Laboratories, Seasonale was compared to monthly cycles of Nordette (30 mcg EE/150 mcg levonorgestrel) in a parallel, randomized, multicenter, open label study.14 Pregnancy rates were comparable between the extended-cycle and traditional cycle regimens.
Results on Seasonale were better when compliance was included in the calculation of pregnancy rates. "Compliant use" patients were defined by eliminating all cycles in which a patient skipped two or more consecutive pills, had a pattern of overall noncompliance (< 80% pill-taking), or used or alternate forms of contraception-prohibited medications (that interacted with OC metabolism). Using a life table analysis of treatment failures (i.e. pregnancy) among compliant use patients, the life table point estimate was 0.55 pregnancies per 100 women for Seasonale and 1.45 per 100 women for Nordette. In this study, no formal statistical tests were conducted between treatment groups, and only descriptive statistics were reported.14 Thus, while there may be a theoretical benefit to extended-cycle use in lowering pregnancy rates for women on oral contraception, further and larger studies are necessary to document this benefit.
Bleeding Patterns on Seasonale
The reported bleeding patterns on Seasonale were obtained in a select group of women, and care should be taken in extrapolating to the larger population until more data emerges. The majority in the study had used OCs in the past; less than 10% were new users.14 A large percentage in both groups had used OCs in an extended fashion in the past. Additionally those prior users who had experienced prolonged breakthrough bleeding (> 10 days) while previously on OCs were excluded from participation. More women on Seasonale discontinued the study prematurely for unacceptable bleeding than did women in the 21/7-day regimen (7.7% vs. 1.8%). The authors noted that there was no correlation between "bleeding" reported as an adverse event, "bleeding" reported in an electronic diary the patients kept, and "bleeding" given as a patient-specified reason for study discontinuation. However the percentage of subjects experiencing breakthrough bleeding declined with each successive 91-day extended-cycle, from a median of 12 days per cycle during cycle one to a median of four days during cycle four. (See Figure 1.)
Further an increasing number of women became completely amenorrheic during the expected withdrawal period as the study progressed. The total days of bleeding and/or spotting (withdrawal plus intermenstrual) were similar over one year for Seasonale subjects and subjects on the 21/7-day cycle regimen. However, the extent of bleeding also appears to be less on the extended-cycle regimen. Among patients treated with the extended-cycle regimen, more than half of the overall days were due to spotting and not bleeding. This contributed to a greater percentage of bleeding-only days with the conventional regimen (median 12.2%) compared to the extended-cycle regimen (5.7%). But 58.5% of the extended-cycle users still had breakthrough bleeding during cycle four.
Other Adverse Effects of Seasonale
Reports of headache were lower for extended-cycle regimen patients than for the conventional patients (21% vs. 28%) in the reported trial of Seasonale, though this difference was not reported as statistically significant.14 Other adverse events were comparable across the treatment groups. Specifically, there were no differences in lipid changes between treatment groups, with expected changes in low-density lipoprotein cholesterol and triglycerides reported in both groups. Further, there were "no clinically meaningful changes" in other important parameters between groups including body weight, heart rate, blood pressure, or other physical exam results. (These data were not specifically reported in the paper, and this comment was noted in the discussion section of the paper.) Finally, it is premature to speculate about increased risk for serious adverse events. Although no woman developed endometrial hyperplasia or cancer on Seasonale, one woman in the extended-cycle developed a pulmonary embolus. Contributing factors may have included age (the subject was 39), obesity, and recent air travel.14 Theoretically, a more prolonged exposure (an additional 14 days every 91 days) to synthetic estrogen/progestin in the extended-cycle regimen may increase the risk for deep venous thrombosis and embolus. Further study and use of the medication is needed to address this important safety concern.
Clinical Use of Seasonale
During the study, Seasonale was started in the same fashion as conventional OCs. That is, the first active pill was taken on the first Sunday following the onset of menses. The Seasonale tablet dispenser includes three trays of cards holding 12 weeks of active medication (pink) and on the third tray, one week of inactive pills without hormone (white) for week 13. The package insert recommends using a backup form of contraception (such as condom or spermicide) for the first seven days on the pill. Otherwise the use recommendation is similar to that of conventional low-dose OCs. It is recommended to take the Seasonale pill the same time every day and to double up the pill the next day if an active pill is missed. Further recommendations include to double up on two consecutive days if two days are missed and to use alternate forms of contraception for the next seven days.
As noted above, unexpected bleeding is common with Seasonale. During the first extended cycle, about one in three women will have 20 or more days of unplanned bleeding or spotting. Thus, it is recommended to continue the pill during unscheduled breakthrough bleeding episodes during this first extended cycle, especially since this breakthrough bleeding is likely to decrease in subsequent extended-cycles. Inactive pills should be taken at their scheduled times, especially during the initial cycles. Stopping the active pill, intentionally skipping active pills, or combining active pills during bleeding episodes are empiric treatments that have little data to support their use to treat breakthrough bleeding in extended regimens. Women on Seasonale who have prolonged, unscheduled bleeding should contact their physicians. Such bleeding may be a result of pregnancy, intrauterine abnormalities, or endometritis. These possibilities should be considered and evaluated in such patients, although there is no evidence that these causes are more likely in extended regimen patients.
For those subjects who have no definable cause of bleeding, and it is presumed to be due to the extended-cycle regimen, there is little evidence at present that administering an alternative formulation in an extended-cycle fashion may achieve a better result as there have been no head-to-head comparisons of varying extended-cycle regimens. While other studies using conventional monophasic pills have shown lower bleeding rates on extended therapy, the comparatively small size and single center focus of these studies limit the universality of their conclusions.
One recent randomized study of a 168-day extended regimen vs. a 21/7-day cycle used OCs containing 20 mcg EE/ 100 mcg levonorgestrel but only contained 32 subjects.13 In this study, there were fewer total bleeding days in the extended regimen compared to the conventional (25.9 vs. 34.9 days), but no statistical difference was noted, most likely due to the small sample size.
Another larger randomized study of 79 subjects using the same formulation (20 mcg EE/100 mcg levonorgestrel) in traditional vs. a 336-day continuous OC dosing without any period week found a highly significant decrease in total bleeding days at any time point in the study.15
However, there were no differences in total spotting days between treatment groups, and when the analysis was restricted to cycle days 1 to 21 when the cyclic user is not supposed to have bleeding or spotting, there was an initial increase in spotting in the extended group (at least in the first 84 days of the continuous regimen) compared to the 21/7-day regimen.15
A larger clinical problem may become the substantial number of women who develop amenorrhea on the extended cycle. While the package insert recommends considering the possibility of pregnancy should amenorrhea continue through the inactive pill period, the need for clinical follow-up and/or pregnancy testing should be individualized. Amenorhea could be a desired condition but more reassuring in the setting of continuous use, with an active pill every day.
Patients for Extended-Cycle Regimens
This issue of selecting patients still is being addressed. We can begin with the demographics of women who have participated in extended-regimen studies. They tend to be in their 20s, with a body mass index (BMI) of about 25 (i.e., just at the threshold of being overweight), and most have had prior experience with OCs.13-15 This latter characteristic suggests that there may be a stepwise progression from traditional OC to a desire to try extended regimen OC. In one study reporting educational background, 90% had a college and/or graduate school background, which implies an educated cohort.15
Other studies have suggested that there may be a varying incidence of adverse effects on extended regimen depending on initial BMI, with obese women (BMI > 30) more likely to experience menorrhagia but less likely to experience dysmenorrhea. But this study was a retrospective study and reflected potential selection bias in treatment regimen.16 Thus, body habitus would seem a poor selection criterion at this point.
Another patient group that may benefit are the periodically noncompliant patients at risk for pregnancy, especially those that forget the first pill(s) of a new pack. This transition to the new pack is associated with higher noncompliance rates.17 With fewer transitions on the extended-cycle (four vs. 13 on the 21/7-day cycle), there will be fewer opportunities to forget, and there will be a lower premium on forgetting one to two days of other pills in the middle of the extended cycle (with the exception of probably increased breakthrough bleeding).
The Future of Seasonale
FDA approval of this drug legitimizes the extended-cycle regimen concept, though the same formulation may be available by discarding the inactive pills from a number of available 21/7-day products that are identical with Seasonale. These include Nordette (Monarch Pharmaceuticals; Bristol, TN), Levlen (Berlex Laboratories; Richmond CA), and Levora (Watson Laboratories; Corona, CA). Comparable, if not bioequivalent, products contain the same dose of ethinyl estradiol (EE) as is present in Seasonale (30 mcg) but contain 300 mcg norgestrel, of which 50% is metabolized to levonorgestrel: Lo-Ovral, (Wyeth Pharmaceuticals; Philadelphia) and Low-Ogestrel (Watson Laboratories; Corona, CA).
However, one immediate advantage of Seasonale over the extended use of these other formulations is that an FDA-approved product is more likely to be covered by insurance companies, many of which will not pay for more than 13 21/7-day packs in a calendar year. Thus there may be less out-of-pocket expense for patients if Seasonale is selected. Some, however, have questioned the cost-effectiveness of a trimonthly regimen compared to a 21/7-day regimen for the average patient only seeking contraception when one compares hygiene product cost to OC pill cost.18
The majority of patients in the Seasonale trial rated their overall satisfaction with the extended-cycle OC as good to excellent and stated they would choose to continue with fewer menstrual periods even after the study.14 Patient acceptance will more likely depend on a patient’s desire to reduce the overall number of bleeding days on oral contraception rather than a desire to mimic a natural cycle. OCs by definition are "unnatural" as the ovaries do not secrete supraphysiological amounts of estrogen and progestin 21 days out of 28 and a withdrawal bleed is not necessary for contraception. As with traditional OCs, patients will need to be counseled about the unique benefits and side effects of extended-cycle contraception. There is certainly a misconception that there is endometrial buildup on hormonal contraception that requires a withdrawal bleed to shed on a regular basis. Patients and perhaps a few practitioners will need to be dispelled of this myth. Even after one year of continuous OC use, monitoring of the endometrium with ultrasound and biopsy in a subset of patients showed endometrial atrophy and not proliferation as was noted in cyclic users.15
It appears from the preliminary study that the discontinuation rate may be higher for extended-cycle oral contraception than for the traditional 21/7-day cycle and that this may be due to the initial higher breakthrough bleeding/spotting rates on extended-cycle treatment.15
The reported range of discontinuation for extended-cycle treatment ranges widely in the literature. In 1994, a trimonthly extended-cycle regimen using levonorgestrel and a low-dose estrogen was investigated. Two hundred and three women were enrolled, but only 30% completed the 52-week study. Women cited breakthrough bleeding, breast tenderness, and headaches as the primary reasons for discontinuing.19 However, much lower discontinuation rates have been reported in individual case series, when more intensive counseling may improve compliance.16
Off-Label Uses of Seasonale
As with the traditional OCs, off-label uses eventually may become one of the larger markets for this product. However, here is a word of caution: There are few data about its utility in off-label indications. Table 1, above, summarizes potential areas where an extended-cycle regimen may be theoretically beneficial. They include personal choice, whether it be out of professional obligations, such as the desire to avoid menstruation while on active combat duty, during athletic competitions (female swimmers, etc.), or for unique events (vacation, honeymoon, etc.). However for other indications, proper studies, and preferably FDA-regulated trials, need to be conducted before these can be utilized routinely. Some of these indications, such as a theoretical decreased risk for endometrial and/or ovarian cancer through the more prolonged suppression, probably will not be answered in our academic lifetimes, given the number of women and extended duration that such a study would require.
Studies of menstrual-related symptoms may be more manageable to conduct. These menstrual-related symptoms flare up during the pill-free interval and persist even after extended use of the 21/7-day OC.20 Hyperandrogenism is another fertile area for further study. Several OCs currently have FDA indications for the treatment of acne, and it is reasonable to suppose that an extended-cycle regimen will seek the same indication. What is potentially more intriguing is to compare in a double blind, randomized, placebo control trial the effects of a 21/7-day regimen compared to an extended-cycle regimen on acne. A benefit of extended-cycle regimen would further legitimize the use of an extended-cycle regimen for prolonged ovarian suppression.
Summary
Seasonale is the first FDA-approved extended-cycle oral contraceptive for the prevention of pregnancy. Seasonale is a 91-day regimen taken daily as 84 active tablets of 150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol followed by seven inactive tablets. Seasonale is effective in preventing pregnancy.
Breakthrough bleeding is more common in the initial extended-cycle compared to 21/7-day OC regimens, but bleeding tends to decrease with time. The side effect profile of Seasonale is comparable with a 21/7-day regimen, but further study is needed to comment on rare serious adverse events. The discontinuation rate of Seasonale may be slightly higher than that of the 21/7-day regimen, but this may be overcome with proper counseling and patience. Overall satisfaction with this form of contraception appears high. Further off-label uses of extended-cycle regimens need further investigations before they can be recommended routinely.
References
1. McLaughlin L. The Pill, John Rock, and the Church. Boston: Little, Brown & Co.; 1982.
2. Asbell B. The Birth of the Pill: A Biography of the Drug that Changed the World. New York City: Random House; 1995.
3. Sherif K. Benefits and risks of oral contraceptives. [Review] [22 refs]. Am J Obstet Gynecol 1999; 180(6 Pt 2):S343-348.
4. Kaunitz AM. Menstruation: Choosing whether . . . and when. [Review] [40 refs]. Contraception 2000; 62:277-284.
5. Coutinho EM. Is menstruation obsolete? Oxford, England: Oxford University Press; 1999.
6. Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: A prospective evaluation of frequency and reasons. Am J Obstet Gynecol 1998; 179(3 Pt 1):577-582.
7. Arslanian SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab 2001; 86:66-71.
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.
9. Association of Reproductive Health Professionals. Extended regimen oral contraceptives. Harris Poll, June 14-17, 2002. Available at: www.arhp.org/healthcareproviders/visitingfacultyprograms/extended/nationalsurvey.cfm. Accessed 5/15/03.
10. Loudon NB, Foxwell M, Potts DM, et al. Acceptability of an oral contraceptive that reduces the frequency of menstruation: The tri-cycle pill regimen. BMJ 1977; 2:487-490.
11. Sulak PJ, Cressman BE, Waldrop E, et al. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. [Review] [7 refs]. Obstet Gynecol 1997; 89:179-183.
12. Miller L, Notter KM. Menstrual reduction with extended use of combination oral contraceptive pills: Randomized controlled trial. Obstet Gynecol 2001; 98(5 Pt 1):771-778.
13. Kwiecien M, Edelman A, Nichols MD, et al. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: A randomized trial. Contraception 2003; 67:9-13.
14. Anderson FD, Hait H. A multicenter, randomized study of an extended-cycle oral contraceptive. Contraception 2003; 68:89-96.
15. Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: A randomized trial.[Comment]. Obstet Gynecol 2003; 101:653-661.
16. Sulak PJ, Kuehl TJ, Ortiz M, et al. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol 2002; 186:1,142-1,149.
17. Adams HPJ. Oral contraception noncompliance: The extent of the problem. Adv Contracept 1992; 8(suppl 1):13-20.
18. Schwartz JL, Creinin MD, Pymar HC. The trimonthly combination oral contraceptive regimen: Is it cost-effective? Contraception 1999; 60:263-267.
19. Kovac GT, Rusden J, Evans AA. Trimonthly regimen for oral contraceptives. Br J Fam Plann 1994; 19:274-275.
20. Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 2000; 95:261-266.
CE/CME Objectives/Questions
After reading this article, the reader will be able to:
- Compare the pregnancy rates of extended-cycle contraception with Seasonale to conventional oral contraceptives.
- Review the bleeding profile on extended-cycle contraception with Seasonale with conventional oral contraceptives.
- Discuss the side effect profile of Seasonale.
1. Seasonale is composed of 84 continuous days of what monophasic combination?
A. Ethinyl estradiol (EE) 20 mcg/levonorgestrel 150 mcg
B. EE 20 mcg/levonorgestrel 200 mcg
C. EE 30 mcg/levonorgestrel 150 mcg
D. EE 30 mcg/levonorgestrel 200 mcg
2. Seasonale has been approved by the Food and Drug Administration as:
A. a contraceptive.
B. treatment for acne.
C. treatment for chronic pelvic pain.
D. All of the above
3. Which serious adverse event was noted in the Seasonale user group in the published clinical trial of Seasonale?
A. A case of endometrial cancer
B. A myocardial infarction
C. A pulmonary embolus
D. None of the above
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