CTU Technology Reports-Evaluation of a new oral contraceptive progestogen, drospirenone with ethinyl estradiol (Yasmin)
Author: David F. Archer, MD, Professor, Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA.
Peer Reviewer: Steven J. Sondheimer, MD, Professor of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia.
The Food and Drug Administration in May 2001 approved Yasmin from Montville, NJ-based Berlex Laboratories as an oral contraceptive. Yasmin is composed of ethinyl estradiol 30 mcg and drospirenone 3 mg (EE/DRSP 3 mg). Drospironone is a new progestin derived from 17 alpha spironolactone and is an analogue of spironolactone.1 This progestational compound is reported to have biologic effects similar to progesterone, including less water retention, no evidence of premenstrual weight gain, and a favorable effect on premenstrual and menstrual symptoms.2 The cost of Yasmin is $84.57 for one package of three cycles. This article reviews the available literature on drospironone.
Oral estrogens and progestogens that are effective contraceptives have been available since 1960. Over the last 30 years, there has been a decline in the dose of the steroids used in oral contraceptives. Other changes are the introduction of a new synthetic progestin, levonorgestrol, in the late ’60s and further modifications of the levonorgestrol molecule to produce desogestrol, gestodene, and norgestimate in the ’80s. These latter events were changes in the progestogen molecule. All of the current oral contraceptive progestogens continued to be derived from norethindrone, the parent 19 nor-testosterone compound.
Drospirenone is different. It was synthesized from 17 alpha spironolactone and is biologically similar to progesterone.3 Drospirenone has antimineralocorticoid activity, with clinical findings indicating effects on electrolytes and the renin-angiotensin system similar to progesterone.3-5 Because of this, drospirenone is a uniquely new progestin now available for use in the United States.
Anti-Ovulatory Effects
The progestogen in oral contraceptives should have evidence of anti-ovulatory activity. The effect of drospirenone on ovulation inhibition was assessed in women by using ultrasound and hormonal parameters such as 17 Beta estradiol, the occurrence of the luteinizing hormone (LH) surge, and increases of plasma progesterone greater than 5 nanomoles per liter. These studies were performed using drospirenone either alone or in combination with 30 mcg of ethinyl estradiol.1
Drospirenone alone over several dose strengths was found to have evidence of anti-ovulatory activity. Drospirenone 3.0 mg alone had a 100% suppression of ovulation in 11 women. The other doses of drospirenone, 2, 1, and 0.5 mg, had one ovulation in each of the three groups (n = 12 for each group).1 Overall, the ovulatory rate was approximately 10% for these three lower doses of drospirenone. Evidence of no follicular activity (development of a follicle > 10 mm) also was dose-proportional beginning at 0.5 mg of drospirenone with 36% of the women who had evidence of inhibition of follicular activity and rising to 91% in the 3 mg drospirenone group.1
The oral combination of drospirenone 2 mg and 3 mg with 30 mcg of EE was investigated in the same study. The incidence of ovulation was zero in the EE 30 mcg/drospirenone 3 mg (EE/DRSP) group.1 One ovulation occurred out of 20 women in the 2 mg drospirenone/30 mcg EE group.1 Three women in three separate cycles had evidence of ovulation while using the EE/DRSP 2 mg.1 The incidence of complete inhibition of ovulation was 82.6% in the DRSP 2 mg group compared to 89.9% in the DRSP 3 mg group.1
This clinical trial had other evidence for inhibition of fertility with DRSP, with a marked decrease in cervical mucus score during active treatment compared to control values.1
During treatment with both DRSP 2 and 3 mg, there was evidence of decreased E2 serum levels, associated with low (anovulatory) levels of progesterone. The authors concluded it would be better to use the DRSP 3 mg with EE in contrast to the DRSP 2 mg dose with EE because of the complete suppression of ovulation with the higher DRSP dose.1 The progestin alone at the higher dose was found not to have evidence of ovulation, based on progesterone levels, and follicular development.
Breakthrough bleeding and cycle control appeared to be very acceptable in this limited trial, with only 20 women in each study arm contributing 72 and 74 cycles of treatment with DRSP 2 mg and 3 mg, respectively. The EE 30/DRSP 3 mg group had an incidence of no breakthrough bleeding of 61.5% in the first cycle and 91.7% and 87.5% in the second and third cycles, respectively.1
Clinical Contraceptive Efficacy
Three randomized, multicenter clinical trials were carried out to evaluate the contraceptive efficacy of the EE 30/DRSP 3 mg combination. One was a multicenter trial carried out in the United States in which the Pearl Index was found to be 0.4.2 There was one pregnancy in 3,201 evaluable cycles of 326 subjects. The Pearl Index in a second multicenter comparative trial carried out in Europe was 0.71 for the EE 30 mcg/DRSP 3 mg combination, after excluding the nonmethod failures.6 In this latter trial, 11 pregnancies occurred in the EE/DRSP group; only one of them was considered to be a method failure.6 The other nine pregnancies were due to other confounding cofactors such as missed tablets, diarrhea, and other activities not further described by the authors. These findings are comparable to what has been reported from other clinical trials of new low-dose oral contraceptive formulations.7-10 The third trial found comparable pregnancy rates between DRSP and a marketed oral contraceptive containing EE and desogestrol.11
Breakthrough Uterine Bleeding or Cycle Control
One of the principal concerns of the consumer is that of good cycle control. This means that the occurrence of intermenstrual bleeding or spotting, usually characterized as breakthrough bleeding (BTB), should be as low as possible. The need for this reduction in BTB is two-fold: 1) the concern that BTB raises in the patient as to problems with the oral contraceptive itself; and 2) the continuation of the BTB becoming more than a simple nuisance and resulting in the consumer stopping the oral contraceptive.12 BTB rates range from 15%-40%, depending on the product and the clinical trial.8,12 BTB has been identified as one of the principal causes of discontinuation of oral contraceptives and occurs in roughly 10%-12% of women who were using oral contraceptives.2,6-8
There are three clinical trials that address the BTB incidence with EE /DRSP 3.1,2,6 The total percentage of subjects experiencing BTB is more than 50% in the first cycle. This incidence rapidly declines to less than 20% in subsequent cycles. 1,2 In a comparative trial, the percentage of women in the first cycle having intermenstrual bleeding was more than 60% in the EE/DRSP group, but this incidence was similar compared to women using desogestrol 150 mcg and ethinyl estradiol 30 mcg.6 There was a rapid reduction in BTB with or without spotting to less than 10% in the subsequent cycle, and this low level of intermenstrual bleeding/spotting was maintained throughout the following 12 cycles.6 The most important finding was that BTB was less than 1% of the participants per cycle after the first cycle, while spotting alone occurred between 3.8 and 7% in the EE/ DRSP group, with comparable findings in the EE/DSG group.6
There is a similar lower incidence of BTB: 2% of all subjects during at least one cycle, but in only 1% of subjects for all cycles.2 These data are similar to those reported in other clinical trials of low-dose oral contraceptives.7-10
Blood Pressure and Weight Gain
Drospirenone is unique in that it is a derived from 17 alpha spironolactone. Early reports indicated that this progestational agent had a unique profile on body weight and blood pressure because of its antimineralocorticoid effect.3, 4
Clinical data indicated that there was no change in mean systolic and diastolic blood pressure in the published clinical trials.1,2,6 A reduction in body weight occurred during the course of a clinical trial of EE/DRSP 3 mg compared to 150 mcg of levonorgestrol and 30 mcg EE over a six-month period.4 In this group of women (n = 20), body weight changes declined in the DRSP-treated individuals by approximately 1 kg (2.2 pounds), while it rose in the levonorgestrol group by approximately 0.5 kg (1.1 pound).4 Mean systolic and diastolic blood pressures were reduced in the DRSP group by approximately 2-3 mm of mercury, and it was increased by 1.1 mm of mercury in the EE/levonorgestrol group. The changes in the systolic blood pressure and diastolic blood pressure were significant only in the groups using 15 mcg EE plus 3 mg of DRSP, whereas changes in diastolic blood pressure statistically different from the levonorgestrol group occurred in the 3 mg DRSP and 30 mcg EE group. Of interest is that there was no correlation between body weight and blood pressure in these individuals.4
The hypothesis to explain the lack of change in blood pressure and body weight is that DRSP has antimineralocorticoid activity similar to that identified with progesterone.3-5, 13-15 The basis for this is that drospirenone was found to be devoid of glucocorticoid activity in rodents.5, 16 This statement is based on the fact that there were no changes in the adrenal gland weights in rodents. This finding was confirmed by measuring thymus weight in adrenalectomized juvenile rats. Thymus weight is thought to be a sensitive assay of antiglucocorticoid activity. Use of DRSP was not associated with any significant change in thymus weights.16
Supporting the antimineralocorticoid activity of DRSP was the finding that there was a greater change in the sodium+/potassium+ excretion rate with DRSP compared to spironolactone.4,17,18 With time, counter regulation sets in, and these electrolyte changes do not persist with the parent compound spironolactone.16 Counter regulation is a rapid regression of the antimineralocorticoid effect during use of spironolactone due to compensatory changes in serum aldosterone. DRSP does not result in a sustained change in the sodium+/potassium+ excretion ratio without any of the compensatory changes in the animal model.16
The utilization of EE/DRSP 3 mg found increased plasma renin substrate activity and found plasma aldosterone levels, higher than in the pretreatment cycle, which were consistent and unchanged - similar to that reported from clinical trials.4 Explanation of the biochemical events in this particular trial suggest that blood pressure fell instead of rising in the presence of an increase in renin, which reflects a mild sodium depletion. Generally, a mild sodium depletion blunts the vascular effect of angiotensin II. Therefore, this rise in plasma renin activity and aldosterone found with DRSP seem to be a compensatory mechanism, not a hypertensinogenic mechanism.4,17,18
The other clinical trials also support a negative effect on weight gain. There was no weight gain or a decrease in weight gain in both of the clinical trials.2,6 This lack of a change in weight reflects the more progesterone-like effects of DRSP in terms of reducing the water retention that often is found with use of EE with 19 nor-testosterone compounds.
Antiandrogenic Properties
Many gynecologists have used spironolactone as a treatment for hirsutism in women. Drospirenone, being derived from spironolactone, has been found to have antiandrogenic activity. Drospirenone did not stimulate prostate and seminal vesicle growth in rats.16 There is evidence in the cynomologous monkey that oral DRSP had an increased antigonadotropic activity associated with a reduction in serum LH and testosterone levels.16 n humans, the antiandrogenic biochemical changes are not as clearly documented. Granted, the clinical end point of androgenicity is difficult to ascertain in women, but there was a very low incidence of adverse events reported for acne (1.1%) in the multicenter comparative clinical trial.6,11,19 There was a decline in the incidence and severity of acne from 21.5% to 7.8% in one of the comparative contraceptive trials, but this was not a primary end point of the study.6 This change in acne should be contrasted to a comparable change found with a reduction from 20.1% to 8.2% in the EE 30 mcg desogestrol 150 mcg group.6 These data, along with other published information, indicate that oral contraceptives have an anti-acne activity.20-22
Other reported adverse events and safety data indicate an incidence of headache, breast discomfort, depression, migraine, and nausea comparable to those found in other oral contraceptive clinical trials.2, 11
Premenstrual Symptoms
Because drospirenone is similar to progesterone in terms of its antimineralocorticoid activity, it has been hypothesized that there would be less premenstrual symptomotology in the group of women treated with the EE/DRSP 3 mg. This is based on the finding that water retention is a common premenstrual symptom and that other synthetic progestational agents appear to enhance edema and premenstrual symptomotology.2,11 The incidence of premenstrual symptoms was higher at baseline in the DRSP/EE group and fell significantly during treatment. It should be pointed out that there was no significant difference between these changes in premenstrual symptoms between DRSP/EE and desogestrol/EE in terms of occurrence of premenstrual symptoms: 18% vs. 20% during treatment, respectively.11 The effect of EE/DRSP 3 mg on specific quality of life scores also was evaluated in two recent trials and found to be very effective for relieving premenstrual and menstrual symptoms.11,19
Contraindications for Yasmin
It is recommended on the package insert that women with kidney, liver, or adrenal disease should not take Yasmin because the antimineralocorticoid activity could cause serious heart and health problems. If women are currently on daily, long-term treatment for a chronic condition with any of the following medications, discuss with them whether Yasmin is the right OC for them:
• nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil) and naprosyn (Aleve), when taken long-term and daily for treatment of arthritis or other problems;
• potassium-sparing diuretics such as spironolactone;
• potassium supplementation;
• ACE (angiotensin converting enzyme) inhibitors;
• angiotensin-II receptor antagonists;
• heparin.23
If patients choose Yasmin, the package insert states that they should have their potassium levels checked during the first month of OC use.
Summary
There is definite evidence that the new progestin DRSP has in vitro antimineralocorticoid activity. In vivo data strongly support a compensatory change in plasma renin and angiotensin II, which is reflected in a significant alteration in terms of sodium and potassium excretion similar to that found with progesterone. As part of this activity, there appears to be less premenstrual and menstrual changes with the EE/DRSP 3 mg than other oral contraceptive formulations.
The EE/DRSP 3 mg oral contraceptive has been shown to be efficacious in terms of inhibition of ovulation using ultrasound and hormonal parameters as well as having a low Pearl Index in Phase III multicenter trials.
The slight but significant improvement in blood pressure and weight may be a benefit for those individuals in the United States who are experiencing blood pressure increases or weight gain with commonly utilized current oral contraceptives. This statement remains to be confirmed in actual clinical practice.
With the introduction of DRSP as a progestational agent, we now are seeing a new class of progestational compounds being used in oral contraceptives. The effectiveness of these compounds for premenstrual symptoms, weight gain, and blood pressure on a larger scale in the general population remains to be determined.
References
1. Rosenbaum P, Schmidt W, Helmerhorst FM, et al. Inhibition of ovulation by a novel progestogen (drospirenone) alone or in combination with ethinylestradiol. Eur J Contracept Reprod Health Care 2000; 5:16-24.
2. 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.
3. Oelkers W, Berger V, Bolik A, et al. Dihydrospirorenone, a new progestogen with antimineralocorticoid activity: Effects on ovulation, electrolyte excretion, and the renin-aldosterone system in normal women. J Clin Endocrinol Metab 1991; 73:837-842.
4. Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab 1995; 80:1,816-1,821.
5. Muhn P, Fuhrmann U, Fritzemeier KH, et al. Drospirenone: A novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann N Y Acad Sci 1995; 761:311-335.
6. 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.
7. Archer DF, Maheux R, DelConte A, et al. Efficacy and safety of a low-dose monophasic combination oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol (Alesse). North American Levonorgestrel Study Group (NALSG). Am J Obstet Gynecol 1999; 181(5 Pt 2):39-44.
8. Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: A randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception 1999; 60:321-329.
9. An open-label, multicenter, noncomparative safety and efficacy study of Mircette, a low-dose estrogen-progestin oral contraceptive. The Mircette Study Group. Am J Obstet Gynecol 1998; 179:S2-S8.
10. Endrikat J, Dusterberg B, Ruebig A, et al. Comparison of efficacy, cycle control, and tolerability of two low-dose oral contraceptives in a multicenter clinical study. Contraception 1999; 60:269-274.
11. 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.
12. 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.
13. Krattenmacher R. Drospirenone: Pharmacology and pharmacokinetics of a unique progestogen. Contraception 2000; 62:29-38.
14. Losert W, Casals-Stenzel J, Buse M. Progestogens with antimineralocorticoid activity. Arzneimittelforschung 1985; 35:459-471.
15. Oelkers W. Drospirenone - a new progestogen with antimineralocorticoid activity, resembling natural progesterone. Eur J Contracept Reprod Health Care 2000; 5 (Suppl 3):17-24.
16. Muhn P, Krattenmacher R, Beier S, et al. Drospirenone: A novel progestogen with antimineralocorticoid and antiandrogenic activity. Pharmacological characterization in animal models. Contraception 1995; 51:99-110.
17. Oelkers WK. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure. Steroids 1996; 61:166-171.
18. Oelkers W, Helmerhorst FM, Wuttke W, et al. Effect of an oral contraceptive containing drospirenone on the renin-angiotensin-aldosterone system in healthy female volunteers. Gynecol Endocrinol 2000; 14:204-213.
19. Boschitsch E, Skarabis H, Wuttke W, et al. The acceptability of a novel oral contraceptive containing drospirenone and its effect on well-being. Eur J Contracept Reprod Health Care 2000; 5 (Suppl 3):34-40.
20. Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol 1997; 37(5 Pt 1):746-754.
21. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: A randomized, placebo-controlled trial. Obstet Gynecol 1997; 89:615-622.
22. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, et al. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception 1999; 60:255-262.
23. Yasmin Prescribing Information, Berlex Laboratories, Montville, NJ.
CME Objective/Question
To earn CME credit for this issue of Contraceptive Technology Reports, please refer to the enclosed Scantron form for directions on taking the test and submitting your answer.
• After reading Contraceptive Technology Reports, the participant will be able to identify the impact of drosperinone.
1. Drosperinone, a new progestogen used in oral contraception, has been found to:
A. have no effect on weight gain in women in clinical trials.
B. increase sodium and potassium excretion in animal models.
C. have a low rate of breakthrough bleeding.
D. both A and C
E. all of the above
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