R. Heithecker

Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone.

Objective To assess the contraceptive reliability, cycle control and tolerability of a new monophasic oral contraceptive containing 30 g ethinylestradiol plus 3 mg drospirenone (Yasmin, Schering AG, Berlin, Germany), it was compared with an established oral contraceptive containing 30 g ethinylestradiol plus 150 g desogestrel (Marvelon, NV Organon, Oss, The Netherlands). Methods A randomized, open-label, 13–cycle study was performed at 80 European centers. Contraceptive reliability, cycle control, blood pressure, body weight, the incidence of adverse events and skin condition were assessed during 13 cycles of oral contraceptive use, and at follow-up. Subjects recorded body weight on three consecutive days pretreatment and weekly thereafter. Results Of 2069 women who started the study and received the trial preparations in a ratio of 4:1 (ethinylestradiol/drospirenone, n = 1657; ethinylestradiol/desogestrel, n = 412), 1615 completed the 13 cycles plus follow-up, providing data for over 23 000 evaluable cycles. Eleven pregnancies occurred during treatment, only one of which (in the ethinylestradiol/ drospirenone group) could not be ascribed to user failure or interaction with other factors. Both preparations provided effective contraception and cycle control. Pre-existing acne and seborrhea were improved and blood pressure was essentially unchanged. The two treatments differed in their effect on body weight, the difference being statistically significant. In the ethinylestradiol/drospirenone group, there was a distinct decrease over the whole treatment phase, while a subtle and less distinct decrease was documented in the ethinylestradiol/desogestrel group. Conclusions The combination of 30 g ethinylestradiol/3 mg drospirenone provides effective oral contraception, excellent cycle control, good tolerability and a level of weight loss that may have a significant beneficial effect on compliance in women with a tendency to weight gain due to water retention.

A comparative investigation of contraceptive reliability, cycle control and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel

OBJECTIVE To assess the contraceptive reliability, cycle control and tolerance of a new monophasic oral contraceptive (Yasmin) containing 30 microg ethinylestradiol and 3 mg drospirenone and compare it with a preparation containing an equal dose of ethinylestradiol combined with 150 microg desogestrel (Marvelon). METHODS A multicenter, open-label, randomized study was carried out in 26 European centers. Contraceptive efficacy, cycle control and tolerance (including body weight, blood pressure and heart rate) were assessed over 26 cycles, plus a 3-month follow-up period. RESULTS Of 900 women who were randomized, 887 started treatment and 627 completed the 26 cycles plus follow-up (310 in the ethinylestradiol/drospirenone group and 317 in the ethinylestradiol/desogestrel group). Both study preparations were found to be effective with regard to contraceptive reliability and cycle control was good. There were six pregnancies (three in each group), but none were considered to have been the result of method failures. The subjective and objective tolerances were good in both groups. A statistically significant difference was found in body weight changes between the two groups. While there was an increase in mean body weight in the ethinylestradiol/desogestrel group from cycle 5 onward, the mean body weight per cycle in the ethinylestradiol/drospirenone group was slightly below the baseline value throughout the study. The incidence ofpremenstrual symptoms was higher in the ethinylestradiol/drospirenone group than in the ethinylestradiol/desogestrel group during the 6 months prior to the study, but lower during treatment. The rates ofdysmenorrhea were identical under both treatments but the symptoms were more often mild and less often severe in the ethinylestradiol/drospirenone group. CONCLUSION The combination of 30 microg ethinylestradiol combined with 3 mg drospirenone provides effective oral contraception and good cycle control, and is well tolerated. Ethinylestradiol/drospirenone had a more favorable effect on body weight than ethinylestradiol/desogestrel, with the mean body weight remaining lower than baseline for the majority of the women.

Use of an oral contraceptive containing drospirenone in an extended regimen

As well as providing reliable contraception, modern low-dose oral contraceptives may offer some non-contraceptive advantages. Positive effects on problems such as edema with weight increase and breast tenderness, bloating, dysmenorrhea, and an improvement in skin and hair condition have been reported in several studies using an oral contraceptive containing drospirenone. If these disorders are cycle-dependent, use of the contraceptive in an extended regimen may be of additional benefit. The study reported in this paper followed 1433 women, 175 of whom took the drospirenone-containing pill continuously for between 42 and 126 days. Some symptoms of the premenstrual syndrome were influenced very satisfactorily by administration in an extended regimen.

A 1-year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers.

Drospirenone is a novel synthetic progestogen with a pharmacological profile similar to that of natural progesterone. It has been developed in combination with ethinylestradiol for use as an oral contraceptive (EE/DRSP, Yasmin®, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of drospirenone and ethinylestradiol have been assessed in healthy female volunteers over a 1-year period. During each of the 13 treatment cycles, volunteers received the combined active ingredients for 21 days, followed by a 7-day, tablet-free interval. The concentrations of the serum proteins, sex hormone binding globulin (SHBG) and corticoid binding globulin (CBG), were determined at intervals after the cessation of treatment (day 21) at the end of cycles 1, 6, 9 and 13. Drospirenone and ethinylestradiol were found to be absorbed rapidly and to reach a peak concentration in serum 1.5–2.0 h after dosing. Serum concentrations of drospirenone declined, with mean terminal half-lives of 30.8–32.5 h. Accumulation of both drospirenone and ethinylestradiol was observed within a treatment cycle, with a mean accumulation ratio of 3.0 for drospirenone and 2.1 for ethinylestradiol. In addition, serum drospirenone concentrations increased between treatment cycles 1 and 6, but remained steady thereafter, as reflected in the AUC values determined at the end of treatment cycles 1, 6, 9 and 13. Serum SHBG and CBG concentrations declined in a biphasic manner after cessation of treatment at the end of cycle 13, and physiological steady-state concentrations were reached within 4–6 weeks. In conclusion, drospirenone was absorbed at a similar rate as other synthetic progestogens contained in various oral contraceptives, as indicated by similar tmax values. The terminal half-life of drospirenone was intermediate between those of 19-nortestosterone derivatives like desogestrel, levonorgestrel or gestodene and C21-progestogens like cyproterone acetate. Both active ingredients of the new contraceptive EE/DRSP showed accumulation within a treatment cycle, which is also the case with other synthetic progestogen/ethinylestradiol combinations. Similar to other oral contraceptives, a reversible induction of serum SHBG and CBG concentrations was observed under EE/DRSP treatment.

Effect of an oral contraceptive containing drospirenone on the renin-angiotensin-aldosterone system in healthy female volunteers.

Drospirenone is a new synthetic progestogen with both progestational, antimineralocorticoid and antiandrogenic properties. In combination with ethinylestradiol, it is being developed as an oral contraceptive which will contain 30 μg ethinylestradiol and 3 mg drospirenone (Yasmin®, Schering AG, Germany). The effects of drospirenone alone, and in combination with ethinylestradiol, upon the renin–angiotensin–aldosterone system (RAAS) have been evaluated in healthy female volunteers. RAAS activity was assessed by measurement of plasma renin substrate (PRS) concentration (otherwise known as angiotensinogen), plasma renin activity (PRA), and plasma aldosterone (P-Aldo) concentration. An antimineralocorticoid effect was observed when volunteers received drospirenone alone at doses in the range 0.5–3.0 mg/day for one cycle. The effect was dose-dependent for P-Aldo but was not dose-dependent for PRA. When ethinylestradiol (30 μg) was combined with either 2 mg or 3 mg drospirenone and given to volunteers for three cycles, an increase in PRS was observed with both preparations, which was indicative of estrogenic stimulation, and increases in PRA and P-Aldo were shown which were indicative of an antimineralocorticoid effect of drospirenone. Increases in PRA and P-Aldo were significantly higher with the preparation containing 3 mg drospirenone in cycle 1 but not in cycle 3. The effect of the preparation containing 30 μg ethinylestradiol/3 mg drospirenone upon RAS activity was also compared with that of a commercially available preparation also containing 30 μg ethinylestradiol but combined with 150 μg desogestrel (Marvelon®). Over a period of 13 cycles, increases in PRS were seen with both treatments, the effect being slightly more pronounced with 30 μg ethinylestradiol/150 μg desogestrel. A markedly greater increase in PRA was seen following treatment with 30 μg ethinylestradiol/3 mg drospirenone, and, in cycle 3, this difference was statistically significant. In contrast, P-Aldo was increased markedly with 30 μg ethinylestradiol/3 mg drospirenone in all measured cycles, whereas, in the 30 μg ethinylestradiol/150 μg desogestrel group, changes were minimal. The increases in PRA and P-Aldo are interpreted as endogenous counter-regulation against the antimineralocorticoid activity of drospirenone. PRS increases under all combinations are an expression of estrogenic stimulation. Measurement of body weight and blood pressure in the studies with combined ethinyl-estradiol and drospirenone revealed that drospirenone was associated with either stable body weight or with a slight loss in body weight, while blood pressure remained largely unchanged. Overall, the results indicate that 30 μg ethinylestradiol/3 mg drospirenone has a distinct antimineralocorticoid effect.

Inhibition of ovulation by a novel progestogen (drospirenone) alone or in combination with ethinylestradiol

Objective To investigate ovulation inhibition with drospirenone, a novel progestogen that has a profile similar to natural progesterone, when given alone or in combination with ethinylestradiol. Method Hormonal parameters (LH, FSH, 17ß-estradiol and progesterone) and peripheral parameters (cervical score, spinnbarkeit and crystallization), as well as follicle size assessed by ultrasonography, were measured in two groups of healthy women. Forty-eight women aged 19–35 years were randomly assigned to receive 0.5 mg, 1.0 mg, 2.0 mg or 3.0 mg of drospirenone over a single treatment cycle, and 52 women aged 20–35 years were randomized to receive either 2 mg drospirenone/30 μg ethinylestradiol or 3 mg drospirenone/30 μg ethinylestradiol over three treatment cycles. Baseline measurements were taken during a control pretreatment cycle. Results Adequate ovarian suppression with drospirenone alone was evident at dose levels of 2 and 3 mg, and at 3 mg all subjects had anovulatory cycles. Although both combined preparations (2 mg and 3 mg drospirenone/30 μg ethinylestradiol) inhibited the hypothalamic–pituitary–ovarian axis, follicular maturation leading to escape ovulation was observed in three subjects in the 2 mg drospirenone/30 μg ethinylestradiol group. Only one of these ovulations was considered to be definitely the result of treatment failure. All cycles in the 3 mg drospirenone/30 μg ethinylestradiol group were anovulatory. No statistically significant difference was found between treatment groups. Conclusion The combination of 3 mg drospirenone/30 μg ethinylestradiol (Yasmin ®, Schering AG) reliably inhibits ovulation, with a low frequency of follicular maturation, and provides a reasonable safety margin.

Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives

The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (alpha = 0.05, beta = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample 24 h, after drug intake on 1 day between the 10th and the 21st day of the cycle. The concentrations of sex-hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and cortisol were measured in a 0- to 4-hour serum pool by radioimmunoassay. Ethinyl estradiol (EE2) levels were analyzed in single and pooled samples using anti-EE2-6 beta-carboxymethyloxime-bovine serum albumin antiserum. The area under the curves (AUC) up to 4 and 24 h and Cmax and tmax were evaluated. Statistical analysis (analysis of covariance) did not reveal a dependence of values on duration of treatment or day of cycle. Both treatments resulted in almost identical values for all parameters evaluated. The mean levels of SHBG, CBG and cortisol were in the range of 186-226 nmol/l, 89-93 mg/l and 280-281 micrograms/l, respectively. Mean maximum EE2 levels of 106-129 pg/ml were found 1.6-1.8 h after pill intake and AUC0-4 h accounted for 329-374 pg.h.ml-1. The recently reported differences in serum EE2 and CBG levels between two groups of 11 women each treated with desogestrel- and gestodene-containing pills, respectively, could not be confirmed.

Protein binding of active ingredients and comparison of serum ethinyl estradiol sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels in women using a combination of gestodene/ ethinyl estradiol (Femovan) or a combination of desogestrel/ ethinyl estradiol (Marvelon) and single-dose ethinyl estradiol bioequivalence from both oral contraceptives

Results from two clinical pharmacokinetic studies are given. The first study was an observational study in oral contraceptive users who took either a combination of gestodene and ethinyl estradiol (pill A, Femovan) or desogestrel and ethinyl estradiol (pill B, Marvelon). A total of 69 women (39 receiving pill A and 30 receiving pill B) were evaluated to determine serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels. Samples were obtained on 1 day during the tenth to twenty-first days of pill intake. All women received the respective oral contraceptive for at least 3 months. The test power was such that an 80% difference of 1 standard deviation of each target variable would have been detected (alpha = 0.05; beta = 0.1). No statistically significant differences were found in sex hormone-binding globulin, corticosteroid-binding globulin, or cortisol serum levels between both groups. Time and height of maximum ethinyl estradiol levels were identical as was the area under the curves. Ex vivo protein-binding analysis of the progestins revealed a free portion of 0.6% for gestodene and 2.5% for 3-ketodesogestrel as the active metabolite of desogestrel. Sex hormone-binding globulin-bound portions were much higher for gestodene (75.3% +/- 9.1%) than for 3-ketodesogestrel (31.6% +/- 12%). The remaining fractions were bound to albumin. In a second study, ethinyl estradiol-bioequivalence from pills A and B was investigated in 18 women in a controlled, single-dose, randomized, crossover design. The area under the ethinyl estradiol serum levels were identical up to 4 hours after pill intake between both treatments. According to the relatively low variation in data in this group of women, a 10% difference in ethinyl estradiol-availability could have been detected. Both studies indicate that the pharmacokinetics of ethinyl estradiol were independent of the concomitantly administered progestin, that is, desogestel and gestodene.

Transfer of drospirenone to breast milk after a single oral administration of 3 mg drospirenone + 30 μg ethinylestradiol to healthy lactating women

Drospirenone (DRSP) is a synthetic progestogen which has been developed in combination with ethinylestradiol (EE) for use as an oral contraceptive (Yasmin, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of DRSP were evaluated in serum and breast milk from lactating women who received a single oral dose of 3 mg DRSP + 30 microg EE, to determine the fraction of the dose of DRSP which transfers to breast milk. Nine healthy, lactating women were included into the present study and pharmacokinetic data were obtained from six participants. The maximum DRSP concentrations (data given as mean +/- standard deviation) were reached on average 2.5+/-1.2 and 2.8+/-1.3 h in serum and breast milk, respectively after oral administration of 3 mg DRSP + 30 microg EE, and amounted on average to 30.8+/-14.4 and 13.5+/-11.7 ng DRSP/ml in serum and breast milk. The mean breast milk versus serum concentration ratios of DRSP increased from 0.16 to 0.57 within 2 h after dosing and decreased to 0.16 after 24 h. The average ratio of AUC0-48 h, values in breast milk versus serum was 0.23+/-0.09. The mean DRSP concentration in breast milk over the 24-h period after dosing was 3.7+/-1.9 ng/ml. The amount of DRSP measured to be transferred into breast milk in the six women participating in the present study was, on average, 635 ng (range 256.2-1357.9 ng) within 24 h, corresponding to about 0.02% of the maternal dose. Based on the average concentration of the drug in breast milk over 24 h and assuming a daily ingestion of approximately 800 ml breast milk, the daily dose that reaches an infant via breast milk is estimated to be approximately 3 microg DRSP. The subjective and objective tolerances of 3 mg DRSP + 30 microg EE were good, with no adverse events reported.