Wyeth-Ayerst introduces Alesse; OC expands range of low-dose pills

Cycle control, low side effects maintained with hormone combination

Clinicians now have a choice in 20 mcg oral contraceptives with the introduction of Alesse from Wyeth-Ayerst Laboratories in Philadelphia. The new monophasic pill is available in 21- and 28-day regimens. Recently cleared for release by the U.S. Food and Drug Administration (FDA), the pill offers a combination of 20 mcg of the estrogen ethinyl estradiol and 100 mcg of the progestin levonorgestrel. The only other 20 mcg pill, Loestrin 1/20, manufactured by Parke-Davis of Morris Plains, NJ, also relies on ethinyl estradiol for its estrogen but uses a 1 mg formulation of norethindrone acetate, another progestin.

The addition of a second low-dose pill can only mean good news for women’s health, says William Castelli, MD, medical director of the Framingham (MA) Cardiovascular Institute.

"We’re very happy to see this movement now toward the 20 mcg pill," says Castelli, who has researched estrogen’s effects on the cardiovascular system. "We think that would be a favored pill for most of the women today."

For women in their later contraceptive years, the availability of low-dose pills is highly desired, says Chris Knutson, MN, ARNP, chair of the Washington, DC-based National Association of Nurse Practitioners in Reproductive Health.

"The biggest interest is probably going to be for the older woman who still needs contraception but who is looking for relief from perimenopausal symptoms," says Knutson, co-coordinator of the Region X chlamydia project at The Center for Health Training in Seattle. "She’s still cycling, maybe not real regularly, but is certainly still fertile and needs reliable birth control and relief from those perimenopausal symptoms."

Alesse has been cleared by the FDA for use as an emergency contraceptive pill (ECP), says James Trussell, PhD, director of the Office of Population Research at Princeton (NJ) University and associate dean of the univer-sity’s Woodrow Wilson School of Public and International Affairs.

"Alesse is the seventh brand approved by the FDA for use as an ECP," says Trussell, who is active with the ECP movement. "The dose is five pills within 72 hours after unprotected sex followed by five pills 12 hours later. It is the only brand other than Ovral [also marketed by Wyeth-Ayerst] that provides the exact amounts of ethinyl estradiol and levonorgestrel studied in the clinical trials of the Yuzpe regimen. Five Alesse pills equal two Ovral pills."

Multicenter trial included 1,477 women

Alesse was evaluated in an open-label multicenter trial by the North American Levonorgestrel Study Group sponsored by Wyeth-Ayerst. Interim results from the ongoing clinical study were published in Contraception.1 David Archer, MD, professor of obstetrics and gynecology at The Jones Institute for Reproductive Medicine at The Eastern Virginia Medical School in Norfolk, served as lead investigator for the trial.

A total of 1,477 women were enrolled in the study, with almost 8,000 cycles recorded as of the data cutoff. Women ranged in age from 17 to 49, and most were white (87%) and nulliparous (47%). More than half the women were using another oral contraceptive in the cycle before beginning the new formulation.

A total of five pregnancies occurred during 7,720 efficacy cycles for a Pearl index of 0.84. (The Pearl index calculates the number of pregnancies per 100 woman-years of exposure.) Study participants failed to take at least one pill in 18.8% of the recorded cycles.

Headache most common side effect

Side effects such as spotting, nausea, breast tenderness, and weight gain are common problems associated with the dose of estrogen in OCs. In Alesse’s clinical trial, a breakdown of reported side effects shows 8% of the women with metro-rrhagia, 7% with nausea, and 4% with breast pain. Headache was the most common event, noted by 14% of the women; 7% reported dysmenorrhea. In total, 557 of the 1,477 women enrolled in the Alesse trial noted some form of side effect possibly related to the medication.

A total of 133 women discontinued the study due to side effects. Headache and metrorrhagia were the most common complaints, cited by 1% of the women who discontinued. Other reasons, which occurred in less than 1% of those who discontinued, included amenorrhea, depression, emotional lability, hypertension, acne, menorrhagia, nausea, hypercholesterolemia, weight gain, dysmenorrhea, and flatulence.

Cycle control, irregularities assessed

Breakthrough bleeding alone and spotting alone occurred during 4.3% and 12.1% of cycles respectively, the researchers found. A combination of both characteristics was noted in 11% of the cycles. Bleeding irregularities, such as met-rorrhagia and/or amenorrhea, were responsible for 29 discontinuations from the study for a 2% discontinuation rate. In comparative studies on bleeding irregularities and discontinuation in other oral contraceptives, bleeding irregularity was cited for discontinuation by 3.7% to 35.1% of women.2,3,4

The effectiveness of Alesse in the clinical trial was calculated using the Pearl index and life table methods. (A life table analysis calculates a failure rate for each month of use.)

Of the 7,870 cycles available for consideration in Alesse’s Pearl index, 7,720 were used for calculation. This was due to 141 women reporting a total of 150 cycles in which they had used a backup form of contraception (31 cycles), missed three or more consecutive active pills (136 cycles), or a combination of both (17 cycles).

"A total of five pregnancies occurred during treatment," the researchers state. "An additional five subjects became pregnant after stopping study medication or missing more than three consecutive days of active study medication. Based on 13 cycles per year, the Pearl index was 0.84."

In calculating the life table analysis, 94 cycles of the original 7,870 total were excluded due to the same type of violations reported in figuring the Pearl index: missing three or more consecutive active pills (50 cycles), use of a backup contraception method (46 cycles), or a combination of both (2 cycles).

The exclusion criteria used in the study may make it hard to compare Alesse’s effectiveness against other OCs, Trussell observes.

Trussell says he was surprised to discover that cycles in which women missed three or more pills were excluded from the efficacy analysis. He notes there were five pregnancies in the efficacy analysis and five excluded because "subjects became pregnant after stopping study medication or missing more than three consecutive days of active study medication."

"I have not seen any other published studies using this exclusion criterion, so it does not seem fair to compare their estimate to other estimates without such exclusions," he says. "The Pearl index as reported is 0.84; it seems likely that the index would exceed 1.0 if the three-missed-pill pregnancies were included, a threshold that in the past would have meant immediate rejection by the FDA."

Archer explains that once the study participants missed more than three pills, it was presumed that they were at increased risk for pregnancy. Since the trial was designed to detect method failure, these cycles were excluded.

Such questions as those raised by Trussell were not noted in the critique process that occurred prior to publication in the peer-reviewed journal, Archer notes. The FDA reviewed the same study results in clearing the OC for marketing, he adds.

More low-dose pills on the horizon?

With another 20 mcg pill added to the list, what’s on tap for future developments in low-dose OCs?

"I think what we are going to be seeing now, and for the next year or two, is a continued decline in the hormonal dose of the oral contraceptive," Archer says. "I wouldn’t be surprised to see some of the other pharmaceutical companies bringing their own [low-dose pill] on board. There’s a 20 mcg desogestrel available in Europe at the present time. I think what we’re going to see is a continued reduction in dose down at this level."

References

1. Archer DF, Maheux R, DelConte A, et al. A new low-dose monophasic combination oral contraceptive (Alesse) with levonorgestrel 100 µg and ethinyl estradiol 20 µg. Contraception 1997; 55:139-144.

2. Bounds W, Vessey M, Wiggins P. A randomized double-blind trial of two low-dose combined oral contraceptives. Br J Obst Gynaecol 1979; 86:325-329.

3. WHO Task Force on Oral Contraceptives. A randomized, double-blind study of six combined oral contraceptives. Contraception 1982; 25:231-241.

4. WHO Task Force on Oral Contraceptives. A randomized, double-blind study of two combined and two progestogen-only oral contraceptives. Contraception 1982; 25:243-252.