Counseling our patients regarding cycle control

Highlights from a randomized clinical trial comparing a 21-day and a 24-day oral contraceptive regimen

Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville, Jacksonville, Florida

Clinical Assistant Professor, Department of Obstetrics and Gynecology, Washington University School of Medicine, Managing Partner, Women’s HealthPartners, Inc., St. Louis, Missouri

BACKGROUND

Unscheduled bleeding (ie, spotting/breakthrough bleeding) and early, late, or absent withdrawal bleeding are common reasons cited by women for discontinuing use of oral contraceptives (OCs).^3-5 A European survey of nearly 7000 current or past users of OCs found that women who experienced side effects such as unscheduled bleeding in the first 3 months of use were nearly twice as likely to discontinue use as those who reported no cycle control problems during this time.⁴

A recent Cochrane review of bleeding data from trials comparing OCs containing 20 mcg ethinyl estradiol (EE) and >20 mcg EE concluded that rates of early study discontinuation were higher among women taking OCs with 20 mcg EE than among those taking OCs with 30 to 35 mcg EE, reflecting a higher incidence of unscheduled bleeding with the 20 mcg EE formulations.³ These findings have prompted the development of novel regimens and/or OC formulations with a view toward improving bleeding patterns.

One approach employed with the goal of decreasing unscheduled bleeding is to use active hormonal treatment for 24 days rather than 21 days.⁶ In a comparative study of 21- and 24-day regimens of norethindrone acetate (NETA) 1 mg/EE 20 mcg, the pattern of unscheduled bleeding over 7 cycles of use appeared to be similar.⁶ However, in another comparative study, there was more unscheduled bleeding with the 21-day regimen of NETA 1 mg/EE 20 mcg than with a 21-day regimen of triphasic norgestimate (NGM)/EE 25 mcg.⁷

In a multicenter, noncomparative, 13-cycle trial of 24/4 day drospirenone (DRSP)/EE, a favorable bleeding profile was suggested by the finding that less than 1% of women discontinued the OC due to unscheduled bleeding.⁸ Two comparative trials assessing bleeding patterns of this 24-day OC regimen have been published.^9,10 One trial comparing the 24-day regimen of DRSP/EE and a 21-day regimen of desogestrel 150 mcg/EE 20 mcg found no significant difference in the number of bleeding/spotting episodes over 7 cycles of use.⁹ In the other trial comparing these 2 OC formulations, the number and duration of bleeding/spotting episodes was lower with the DRSP/EE 24/4-day regimen over 7 cycles of use. However, the incidence of unscheduled bleeding in the 2 groups was similar during cycles 2 to 6.¹⁰ A third trial comparing the 24/4-day regimen of DRSP/EE with an investigational OC formulation containing 2.5 mg nomegestrol acetate and 1.5 mg 17-beta estradiol (E2) was completed in July 2008, but the results have yet to be published.^11,12 This OC formulation is not currently approved for use in either the United States or abroad.

A “dynamic” 26/2-day dosing regimen was developed for another new OC formulation containing estradiol valerate (E2V) and the progestin dienogest (DNG) (TABLE 1). Although marketed in some European countries, this OC is not currently FDA-approved.

In a 7-cycle, randomized, multicenter, double-blind, double-dummy trial comparing E2V/DNG and a 21/7-day regimen of EE 20 mcg and levonorgestrel 100 mcg (EE/LNG), women randomized to the E2V/DNG OC formulation reported shorter and lighter bleeding than those who received EE/LNG, and fewer bleeding/spotting days for each 90-day reference period.¹³ Intracyclic bleeding with the 2 OC formulations was similar. However, absence of scheduled withdrawal bleeding occurred more often among users of E2V/DNG than users of EE/LNG.¹³

“Dynamic” 26/2-day dosing regimen of estradiol valerate and dienogest¹³

BLEEDING PATTERNS WITH A 21-DAY VS 24-DAY OC REGIMEN—RANDOMIZED CLINICAL TRIAL

All of the aforementioned studies used various definitions of bleeding. The US Food and Drug Administration’s (FDA) Reproductive Health Drugs Advisory Committee (RHDAC) has now endorsed the definitions of measuring bleeding published by Mishell and colleagues.^14-16 A recently published trial comparing bleeding patterns with a 21/7-day NGM/EE 25 mcg OC regimen and a 24/4-day DRSP/EE 20 mcg regimen incorporated these definitions, as well as the recommendation that an interactive voice-response system (IVRS) be used to collect bleeding data.¹⁶

Materials and Methods

This 3-cycle, randomized, open-label, active-controlled study was conducted at 20 centers in the United States. Inclusion and exclusion criteria are summarized in TABLE 2.²

Women in this study were randomized 1:1 to treatment with 21/7-day NGM/EE 25 mcg OC or 24/7-day DRSP/EE 20 mcg OC for three 28-day cycles, with randomization stratified by center and recent hormonal contraceptive exposure (ie, fresh starts vs switchers). Fresh starts were subjects who had not been on a hormonal contraceptive for 60 days or more, and switchers were those who had been on a hormonal contraceptive within the past 60 days.

Inclusion and exclusion criteria

Bleeding Definitions

Cycle control was evaluated using bleeding (blood loss) data recorded daily using an IVRS diary—one of the real-time methods recommended by Mishell and colleagues.^2,16 Bleeding was defined according to the RHDAC-endorsed criteria with one exception—an episode of bleeding/spotting was defined using the Belsey/WHO definition (TABLE 3).¹⁷

Terminology and definitions for bleeding variables^2,15,17

Study Endpoints

The primary efficacy endpoint was the participant’s total number of unscheduled bleeding days during cycles 1 to 3, as recorded daily using the IVRS diary. Secondary efficacy variables related to bleeding that were analyzed for each of cycles 1 to 3, and cumulatively, included: (1) incidence of unscheduled bleeding, (2) mean number of unscheduled bleeding episodes, (3) incidence of scheduled bleeding, and (4) mean number of scheduled bleeding days.

Consistent with the FDA-endorsed criteria, days 1 through 7 of cycle 1 were excluded from the analysis of bleeding. In addition, only participants who took study medication for at least 7 days and had bleeding data after day 7 were included in the analysis of cycle control. These measures eliminate biased results related to early dropouts.

Evaluation of Bleeding Patterns

The evaluation of bleeding patterns was based on the intent-to-treat population, defined as all randomized subjects who took the study drug and for whom there was post-baseline bleeding data after day 7.

RESULTS

A total of 334 women took study OCs (167 in each treatment group) and were included in the safety analysis. Demographic and baseline characteristics of the 2 treatment groups are shown in TABLE 4.² Age, racial distribution, and previous contraceptive status were comparable in the 2 groups; however, mean weight and body mass index were greater in the 24/4-day DRSP/EE group (TABLE 4).

Demographic and baseline characteristics

Bleeding Patterns

Efficacy data were evaluable for 165 of 167 participants in the 21/7-day NGM/EE group and all 167 participants in the 24/4-day DRSP/EE group.²

Unscheduled bleeding

The mean number of days of unscheduled bleeding in cycles 2 and 3 and cumulatively was significantly less in the 21/7 NGM/EE group as compared with the 24/4 DRSP/EE group (FIGURE 1).² Over the 3 cycles, participants using the 21/7-day NGM/EE OC experienced approximately 1.5 fewer days of unscheduled bleeding than users of the 24/4-day DRSP/EE OC.

Across all 3 cycles, 55 (33.3%) participants in the 21/7-day NGM/EE group and 29 (17.4%) participants in the 24/4-day DRSP/EE group did not experience any unscheduled bleeding episodes (FIGURE 2).² There were significantly fewer unscheduled bleeding episodes in the 21/7-day NGM/EE group than in the 24/4-day DRSP/EE group (mean 1.47 vs 2.01; P = 0.001).

A post hoc analysis controlling separately for weight and smoking found no difference from the primary endpoint finding.²

Absence of scheduled bleeding

The percentage of patients reporting the absence of scheduled bleeding was significantly lower in the 21/7-day NGM/EE group than in the 24/4-day DRSP/EE group in each cycle (P < 0.001 for each) (FIGURE 3).²

SAFETY AND TOLERABILITY

Safety was evaluated in all participants who took the study medication and provided post-baseline safety data after day 7 (N = 334; 167 in each study group). Treatment-emergent adverse events were reported by 34 of 167 participants in each group.

Serious adverse events reported (not considered related to study drug) were:
• Norgestimate/ethinyl estradiol: 2 subjects
  – Lumbar disc protrusion (1)
  – Uterine leiomyoma (fibroid) with ruptured ovarian cyst and pelvic hemorrhage (1)

Adverse events that led to discontinuation (possibly related to treatment):
• Norgestimate/ethinyl estradiol:
  – Nausea/vomiting
• Drospirenone/ethinyl estradiol:
  – Pulmonary embolism
  – Irritability
  – Mood swings

Other adverse events:
• Norgestimate/ethinyl estradiol:
  – Pregnancy

DISCUSSION

This study found that over the first 3 cycles of use, there was less unscheduled bleeding among users of the 21/7-day NGM/EE OC compared with users of the 24/4-day DRSP/EE OC. This high incidence of absence of scheduled bleeding among participants in the 24/4-day DRSP/EE group was not expected. The greater number of scheduled bleeding days in the 21/7-day NGM/EE group than in the 24/4-day DRSP/EE group was expected based on the longer hormone-free interval. However, among those trial participants who reported scheduled bleeding, the duration of scheduled bleeding was similar for the 2 OC formulations.

Women using a cyclical OC regimen expect to experience bleeding during the hormone-free interval, but do not expect to bleed while taking active hormones. Although many women can readily adjust to the experience of bleeding during the first few days of their next pill pack, this issue needs to be discussed when counseling women who are initiating therapy.

OC research and development continues to investigate novel dosing regimens that alter the length of the hormone-free period. Additionally, newer estrogen components are being evaluated as alternatives to EE. Consistent with past research, the goal for any novel OC formulation is that it will not only demonstrate contraceptive efficacy, but also improve on the safety and efficacy profiles of existing OCs. By meeting these goals, new OCs will afford clinicians the opportunity to offer, and women the option to select, OCs that meet their expectations and promote correct and consistent use.

CONCLUSIONS

In this 3-cycle study using FDA-recommended criteria to evaluate bleeding patterns, users of the 21/7-day NGM/EE OC experienced less unscheduled bleeding and more scheduled bleeding compared with users of the 24/4-day DRSP/EE OC. These findings can be a helpful guide for the clinician when counseling patients on what to expect when starting a 21-day or 24-day OC regimen.

INDICATION

ORTHO TRI-CYCLEN^® LO (norgestimate/ethinyl estradiol) is indicated for the prevention of pregnancy in women who elect to use oral contraception as their method of contraception.

IMPORTANT SAFETY INFORMATION

Serious as well as minor side effects have been reported with the use of oral contraceptives. Serious risks include blood clots, stroke and heart attacks. Cigarette smoking increases the risk of serious cardiovascular side effects, especially in women over 35. Women who use oral contraceptives are strongly advised not to smoke. The Pill does not protect against HIV or sexually transmitted diseases.

Please see full Prescribing Information, including Boxed WARNING in the back of the supplement.

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