Oral contraceptive with unique progestin receives FDA approval
Drospirenone, ethinyl estradiol combined in new monophasic, Yasmin
Add another oral contraceptive (OC) to the list of choices for American women: Yasmin, a monophasic birth control pill from Berlex Laboratories of Montville, NJ.
Developed by Berlex Laboratories’ parent company, Schering AG of Berlin, the OC is the first to use the progestin drospirenone. The pills will be packaged with 21 active tablets, each containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, and seven inert tablets.
Yasmin was approved by the Food and Drug Administration on May 11. At press time, the new OC was scheduled for market delivery by mid-June, according to Julie Mandell, Berlex Laboratories spokeswoman. According to Berlex Laboratories, more than 500,000 European women now are using the OC. Yasmin already is available in the Netherlands, Germany, and other European countries.
"The second- and third-generation progestins we have seen in recent years are derivatives of norgestrel or norethindrone acetate," observes Susan Wysocki, RNC, NP, president and CEO of the Washington, DC-based National Association of Nurse Practitioners in Women’s Health. "Drospirenone is in its own class," she adds.
While initial research suggests Yasmin may provide relief from common physical and emotional symptoms associated with the menstrual cycle, such as negative moods, water retention, and increased appetite, these effects must be confirmed in placebo-controlled comparative studies.1 The drug currently is labeled for no other indication other than contraception; however, the company is studying Yasmin for other potential benefits beyond birth control, confirms Mandell.
Look at new progestin
Drospirenone is derived from 17alpha-spirolactone. To understand its unique characteristics, review the following explanation of progesterone’s impact in the menstrual cycle:
In the second half of a normal menstrual cycle, progesterone levels rise. Progesterone binds to its specific receptor, but also to the mineralocorticoid receptor, acting as a mineralocorticoid antagonist.
Natriuresis (loss of sodium in the urine) is slightly enhanced in the luteal phase and, as a reflection of the negative sodium balance, plasma renin and aldosterone rise by 20%-50%. This rise prevents further sodium loss.
Synthetic progestins, whether they are derivatives of 17alpha-hydroxyprogesterone or 19-nortestosterone, lack the antimineralocorticoid effect of natural progesterone. Ethinyl estradiol, as the estrogenic component of combined OCs, is a sodium-retaining drug. This effect mainly is due to a significant increase of the hepatic synthesis of renin substrate (angiotensinogen). Even with low-dose OCs, systolic and diastolic blood pressure might be slightly raised in susceptible individuals.2
However, the relationship between drospi-renone’s progestogenic and its antimineralocorticoid potency almost is identical to that of natural progesterone.2
In two European studies, Yasmin had a more favorable effect on body weight than a comparable OC, with mean body weight remaining lower in the Yasmin group.3 In one study, there was a distinct weight decrease in Yasmin users over the entire treatment phase, with a less distinct decrease in the comparative group.4 In the other study, the mean body weight per cycle in the Yasmin group was slightly below the baseline value throughout the study, with an increase in the comparison group from cycle five onward.5
Impact on weight gain?
Yasmin represents an interesting addition to existing OC options because of the suggestion that antimineralocorticoid activity may improve symptoms associated with the late portions of the cycle (or in this case, OC use), remarks Michael Rosenberg, MD, MPH, clinical professor of obstetrics and gynecology at the school of medicine and adjunct professor of epidemiology at the school of public health, both at the University of North Carolina at Chapel Hill, and president of Health Decisions, a Chapel Hill private research firm specializing in reproductive health.
For most women, there is a cyclic gain of about one pound during the first half of each OC cycle and the loss of the same amount over the latter half, which probably reflects fluid retention.6 However, the bloating that is commonly experienced toward the end of each cycle is probably related to estrogen as well as progestin, along with timing, says Rosenberg.
Look at efficacy rates
A randomized, open-label, 13-cycle study was conducted at 80 European centers, assessing contraceptive reliability, cycle control, blood pressure, body weight, adverse events and skin condition during 13 cycles of OC use and at follow-up.4 Two pills were used in the trial: Yasmin and Marvelon (NV Organon, Oss, The Netherlands), a 30 mcg ethinyl estradiol/0.15 desogestrel pill marketed by Organon US as Desogen.
The 2,069 women who started the study were assigned to two groups; 1,657 women received Yasmin, and 412 received Marvelon. A total of 1,615 women completed the 13 cycles plus follow-up, providing data for over 23,000 evaluable cycles.
Eleven pregnancies occurred during treatment, with only one (which occurred in the Yasmin group) unable to be ascribed to user failure or interaction with other factors.
26-cycle study completed
A separate multicenter, open-label, randomized study was carried out in 26 European centers, using Yasmin and Marvelon.5 Contraceptive efficacy, cycle control, and tolerance (including body weight, blood pressure, and heart rate) were assessed over 26 cycles, plus a three-month follow-up period.
Of the 900 women who were randomized, 887 started treatment and 627 completed the 26 cycles plus follow-up (310 in the Yasmin group and 317 in the Marvelon group). Both OCs were found to be effective with regard to contraceptive reliability, and cycle control was good. Researchers reported six pregnancies (three in each group), but none were considered to have been the result of method failures.
An American open-label, multicenter investigation of the drug was conducted to evaluate the efficacy, safety, and cycle control of Yasmin.7 In this study, 326 women were evaluated, and 220 (67%) completed all 13 treatment cycles. One subject became pregnant during the study. The yearlong study used the Pearl index (the number of unintended pregnancies divided by the number of woman-years of exposure to risk of pregnancy) to measure contraceptive efficacy. The uncorrected Pearl index was 0.406 based on one pregnancy in 3,201 cycles of 326 women; the corrected Pearl index was 0.407 based on 3,192 cycles. The pregnancy ratio, based on 220 women completing 13 cycles without the use of alternative contraception, was 0.455.
In all, 20 women discontinued participation in the study because of adverse events. The most frequently reported events leading to discontinuation included emotional lability, nausea, dysmenorrhea, intermenstrual bleeding, and depression. Only one woman discontinued due to weight gain.
Review candidacy for OC
Yasmin’s antimineralocorticoid activity influences the regulation of water and electrolyte balance in the body, which may increase potassium levels in some patients. Therefore, it is recommended on the package insert that women with kidney, liver, or adrenal disease should not take Yasmin, because this antimineralocorticoid activity could cause serious heart and health problems. (Other conditions that preclude use are listed in the box on p. 75, upper right.)
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If women are currently on daily, long-term treatment for a chronic condition with any of the medications listed in the box (p. 75, bottom right), discuss with them whether Yasmin is the right OC for them. If they do choose the OC, the package insert states that they should have their potassium level checked during the first month of OC use.
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Women and health care providers will welcome the addition of a new contraceptive product that has great efficacy and might address some of the troublesome symptoms of PMS, predicts Linda Dominguez, RNC, NP, assistant medical director of the Albuquerque-based Planned Parenthood of New Mexico. However, a careful history of other medication use that impact potassium levels will be critical, given that the population providers serve is aging and might be taking drugs for associated health problems, she observes.
Many clinicians might be reluctant to pre- scribe Yasmin for two reasons, observes Andrew Kaunitz, MD, professor and assistant chair in the obstetrics and gynecology department at the University of Florida Health Science Center/Jack-sonville. First, in contrast with other OCs formulated with widely used and studied progestins, experience to date is limited with drospirenone. Second, the list of concomitant medications that should be checked prior to prescribing complicates what is, for existing OCs, a relatively simple prescribing process, he notes.
References
1. Brown C, Ling F, Wan J. Effect of a new monophasic oral contraceptive on perimenstrual symptoms. Obstet Gynecol 2001; 97:9S1.
2. Oelkers W. Drospirenone — a new progestogen with antimineralocorticoid activity resembling natural progesterone. Eur J Contracept Reprod Health Care 2000; 5 Suppl 3:17-24.
3. Foidart JM. The contraceptive profile of a new oral contraceptive with antimineralocorticoid and antiandrogenic effects. Eur J Contracept Reprod Health Care 2000; 5(suppl 3):25-33.
4. Huber J, Foidart JM, Wuttke W, et al. Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone. Eur J Contracept Reprod Health Care 2000; 5:25-34.
5. Foidart JM, Wuttke W, Bouw GM, et al. A comparative investigation of contraceptive reliability, cycle control, and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel. Eur J Contracept Reprod Health Care 2000; 5:124-134.
6. Rosenberg M. Weight change with oral contraceptive use and during the menstrual cycle. Results of daily measurements. Contraception 1998; 58:345-349.
7. Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen. Contraception 2000; 61:105-111.
For more information on Yasmin, contact:
• Susan Wysocki, RNC, NP, National Association of Nurse Practitioners in Women’s Health, 503 Capitol Court N.E., Suite 300, Washington, DC 20002. E-mail: [email protected].
• Michael Rosenberg, MD, MPH, Health Decisions, 1512 E. Franklin St., Suite 200, Chapel Hill, NC 27514.
• Linda Dominguez, RNC, NP, Planned Parenthood of New Mexico, 719 San Mateo N.E., Albuquerque, NM 87108. Telephone: (505) 265-5976.
• For more information on Yasmin, providers should call Berlex Laboratories’ toll-free product information line, (888) BERLEX4 [(888) 237-5394]. Consumers who would like to learn more about Yasmin should visit its web site, www.yasmin. com, or call the toll-free number (866) YASMIN1 [(866) 927-6461] to receive a complimentary, informational product brochure by mail.
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