Shortening the pill-free interval: New contraceptives take next step

Shorter interval may decrease incidence of hormone-withdrawal symptoms

Do you remember Enovid, the first oral contraceptive (OC)? Introduced in 1960 by GD Searle in Skokie, IL, the pill was formulated for 21 days of active hormones, followed by seven hormone-free days. During the pill-free interval, the superficial portion of the endometrium was sloughed, producing a withdrawal bleeding episode that simulated menstruation.1 Since that time, conventional pill packaging has contained three weeks of active pills followed by seven placebo pills to provide the same pattern of predictable, coordinated withdrawal bleeds.2

Get ready to see a change in pill formulations. The Food and Drug Administration (FDA) has just approved two oral contraceptives with a 24-day dosing regimen: Loestrin 24 Fe (Warner Chilcott, Rockaway, NJ), which uses 24 days of active hormonal therapy and four days of iron-containing placebo pills, and Yaz (Berlex, Montville, NJ), which uses 24 days of active hormones and four days of placebo pills. At press time, both pills were set for April 2006 product launches.

Both pills carry an indication for contraception. Berlex is continuing to work with the FDA for an additional indication for use in treatment of premenstrual dysphoric disorder (PMDD).

Loestrin 24 Fe consists of 24 pills containing 20 mcg of ethinyl estradiol and 1 mg of norethindrone acetate, with four pills of 75 mg ferrous fumarate. The Yaz formulation contains 24 pills of 20 mcg ethinyl estradiol and 3 mg of drospirenone, with four placebo pills.

Why shorten the interval?

When it comes to effectiveness, the Pill is a highly reliable method. It carries a first-year failure rate of 0.3% when it is used correctly and consistently. However, when it comes to typical use, the failure rate during the first year rises to 8%.3 Women may miss pills or fail to start a pill pack, thereby allowing follicles to develop. Unintended pregnancies also may occur when women discontinue their OC regimen without initiating another effective contraceptive method.

For women using low-dose OCs, the clearance of estrogen and progestin from circulation could lead to ovulation if a new cycle of OCs is not started, notes a recently published commentary.4 Reducing the number of hormone-free days should aid in decreasing the incidences of ovulation and pregnancy that occur in typical oral contraceptive use when women fail to begin their pill packs on time.

According to research, current low-dose pills provide a lesser degree of ovarian inhibition during a seven-day pill-free interval compared with higher-dose pills.1 Findings from three studies that examined the feasibility of shortening the pill-free interval show that women in the groups receiving regimens with such reduced intervals exhibited greater ovarian suppression than women who received the standard 21/7 regimen.5-7 In contrast, another study that looked at extending the hormone-free interval from seven to nine days with two low-dose formulations reported that some women had elevated circulating endogenous progesterone levels, providing evidence of luteal activity.8

Ease side effects

Side effects can lead women to discontinue Pill use. In a prospective study, 28% of 1,657 women initiating OC use had stopped taking the Pill by the end of six months. Almost half (46%) of the women who discontinued Pill use cited side effects as their primary reason. The most frequent side effects included bleeding irregularities (12%), nausea (7%), weight gain (5%), mood changes (5%), breast tenderness (4%), and headaches (4%).9

Shortening the duration of the hormone-free interval should aid in decreasing many of the adverse symptoms that women experience during the seven-day hormone-free interval.4

Symptoms worse in hormone-free interval

To look at this issue, scientists conducted a study to measure the timing, frequency, and severity of hormone-related symptoms in Pill users. To compare women’s experiences during active-pill and hormone-free intervals, investigators recruited women to use daily diaries to record pelvic pain, bleeding, headaches, analgesic use, nausea or vomiting, bloating or swelling, and breast tenderness during the two intervals. Scientists found that almost all the symptoms were significantly worse during the seven-day hormone-free interval than during the 21 days of hormone-containing pills.10

Some women are choosing to bypass the pill-free interval altogether with the use of the extended-regimen oral contraceptive Seasonale (Duramed Pharmaceuticals, Pomona, NY). The pill, which uses a 12-week regimen of 84 days of active pills, followed by seven hormone-free days, was approved for marketing in the United States in 2003. This extended regimen causes users to have only four withdrawal bleeding episodes per year.

Extended regimens mean fewer refills

Duramed’s parent company, Barr Pharmaceuticals, received an approval letter in 2005 for another extended-regimen contraceptive, Seasonique (levonorgestrel/ethinyl estradiol tablets 0.15 mg/0.03 mg and ethinyl estradiol tablets 0.01 mg.). The company is working with the FDA on product labeling and post-marketing commitments to gain final approval.

A big advantage of Seasonale and Seasonique is that there is no way a clinic or pharmacy can require a person to come back every month for refills, because pills are packaged 91 days at a time, says Robert Hatcher, MD, MPH, professor of gynecology and obstetrics at Emory University School of Medicine in Atlanta. This packaging means a maximum of only four visits a year instead of 13 visits, says Hatcher.

There is one pill with a shortened pill-free interval that will not be coming to American pharmacy shelves. Minesse (gestodene 60 mcg/ethinyl estradiol 15 mcg), a pill marketed overseas by American Home Products (AHP) Corp. in Madison, NJ, arrived in 2000 on pharmacy shelves in Austria, Belgium, Denmark, Finland, Greece, Ireland, Italy, Luxembourg, the Netherlands, Portugal, and Spain. Research indicates the OC, with its 24 days of active pills and four days of placebo, is safe and well tolerated, provides good cycle control, and improves premenstrual symptomatology.11 However, Wyeth-Ayerst Pharmaceuticals, AHP’s drug division, does not plan to seek FDA approval for the drug, says Natalie de Vane, company spokeswoman.

References

  1. Sulak PJ. Ovulation suppression of premenstrual symptoms using oral contraceptives. Am J Manag Care 2005; 11:S492-S497.
  2. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive Technology. 18th ed. New York: Ardent Media; 2004.
  3. Trussell J. Contraceptive failure in the United States. Contraception 2004; 70:89-96.
  4. 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.
  5. Sullivan H, Furniss H, Spona J, et al. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity. Fertil Steril1999; 72:115-120.
  6. Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 2000; 95:261-266.
  7. Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception 1996; 54:71-77.
  8. Creinin MD, Lippman JS, Eder SE, et al. The effect of extending the pill-free interval on follicular activity: Triphasic norgestimate/35 mcg ethinyl estradiol versus monophasic levonorgestrel/20 mcg ethinyl estradiol. Contraception 2002; 66:147-152.
  9. Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: A prospective evaluation of frequency and reasons. Am J Obstet Gynecol 1998; 179:577-582.
  10. Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 2000; 95:261-266.
  11. Barbosa IC, Filho CI, Faggion D Jr., et al. Prospective, open-label, noncomparative study to assess cycle control, safety and acceptability of a new oral contraceptive containing gestodene 60 mcg and ethinyl estradiol 15 mcg (Minesse). Contraception 2006; 73:30-33.