• DOI:10.2165/00024677-200302010-00005
• Corpus ID: 209144694

Ethinylestradiol/Drospirenone

@article{Keam2003EthinylestradiolDrospirenone,
  title={Ethinylestradiol/Drospirenone},
  author={Susan J. Keam and Antona J. Wagstaff},
  journal={Treatments in Endocrinology},
  year={2003},
  volume={2},
  pages={49-70}
}

• S. Keam, A. Wagstaff
• Published 2003
• Medicine, Biology
• Treatments in Endocrinology

SummaryAbstractEthinylestradiol 30μg/drospirenone 3mg (Yasmin®1, petibelle®) [EE/DRSP] is a combined contraceptive pill (CC) for the prevention of pregnancy in women of reproductive age. Drospirenone is a novel progestogen with antimineralocorticoid, progestogenic and antiandrogenic activity.The theoretical (0–0.07) and corrected (0.41–0.71) Pearl indices and pregnancy ratios (0.3–0.84) in young, healthy women aged 18–35 years (or 18–30 years if smokers) given 13–26 cycles of EE/DRSP in large multicenter trials indicate that this CC is highly effective in preventing pregnancy. EE/DRSP is equally as effective as ethinylestradiol 30μg/desogestrel 150μg (EE/DSG; corrected Pearl index 0.28–0.41) in preventing pregnancy.EE/DRSP is generally well tolerated. The frequency and type of adverse event reported in clinical trials are typical of those observed with other CCs, and comparable to those in women receiving EE/DSG.The incidence of intermenstrual bleeding (spotting, breakthrough bleeding or both) during treatment with EE/DRSP in young, healthy women decreased rapidly after the first cycle to 9 to 18% in the second cycle and 6% after 26 cycles, indicating good cycle control. The incidence of intermenstrual bleeding was similar in recipients of EE/DSG (9 and 14% in cycle 2 and 10% in cycle 26).Body weight was maintained ±2kg in most young women who received EE/DRSP for up to 26 cycles. Neither EE/DRSP nor EE/DSG showed clinically significant effects on blood pressure.EE/DRSP improved premenstrual and menstrual symptoms (negative affect, water retention, increased appetite) compared with baseline in a noncomparative trial. A similar improvement in skin condition (acne, seborrhea) was observed in women receiving EE/DRSP or ethinylestradiol 35μg/cyproterone acetate 2mg in a randomized, double-blind trial.
Conclusions: Data from several 1- to 2-year studies show that EE/DRSP is an effective oral contraceptive, with Pearl index values similar to those of established low-dose CCs. This combination is well tolerated, demonstrating good cycle control and a beneficial effect on skin condition and well-being (including some premenstrual and menstrual symptoms). EE/DRSP has demonstrated similar efficacy and tolerability to EE/DSG, but long-term clinical experience is required to establish the position of EE/DRSP among other available CCs and to clarify any potential tolerability advantages. Nevertheless, because the management of tolerability is complicated by the idiosyncratic nature of the response of women to CCs containing different progestogens, EE/DRSP appears to be a useful treatment option for women desiring oral contraception.Pharmacodynamic ProfileReceptor binding: The in vitro receptor binding affinity and pharmacologic profile of drospirenone are similar to those of progesterone; both have progestogenic, antiandrogenic and antimineralocorticoid activity.
Estrogenic activity: Estrogen acts synergistically with drospirenone in suppressing cyclic pituitary follicle stimulating hormone and luteinizing hormone (LH); in addition, estrogen maintains the endometrium and helps to prevent breakthrough bleeding. The ethinylestradiol-induced increases in levels of sex-hormone binding globulin (SHBG; 3- to 4-fold) and corticosteroid-binding globulin (CBG; 2- to 2.5-fold) were not affected when women were given 13 cycles of ethinylestradiol 30μg/drospirenone 3mg (Yasmin®, petibelle®1) [EE/DRSP]; in this study a treatment cycle consisted of a once-daily dose of the drug for 21 days followed by 7 drug-free days. Drospirenone had no effect on the estrogen-stimulated increase in plasma renin substrate levels over three cycles of ethinylestradiol 30μg/drospirenone 2 or 3mg.
Progestogenic activity: Drospirenone inhibits follicular stimulation and ovulation by suppressing LH. It also helps to prevent fertilization by slowing sperm transport through changes to the cervix and cervical mucus and affects implantation through atrophy of the endometrium during treatment. Drospirenone inhibits ovulation in a dose-dependent manner; results from a number of randomized studies in healthy, menstruating women indicate that the optimal oral dosage is 3mg. In these studies, treatment with EE/DRSP completely suppressed ovarian activity (follicular ripening or ovulation) in most women. Furthermore, none of the women receiving the 3mg dosage ovulated, unlike women receiving ethinylestradiol 30μg/drospirenone 2mg (three women receiving this dosage ovulated in a 3-cycle study). Ethinylestradiol/drospirenone inhibited cervical function and reduced spinnbarkeit and crystallization of cervical mucus irrespective of the dose of drospirenone; the effect on spinnbarkeit was partially reversed in a follow-up cycle. Long-term treatment (13 cycles) with EE/DRSP had a marked antiproliferative effect on the endometria of healthy, menstruating women.
Antimineralocorticoid activity: Like endogenous progesterone, drospirenone has an antimineralocorticoid effect on the renin-angiotensin-aldosterone system. In several small studies in healthy women, drospirenone treatment caused natriuresis when given as a single agent or in combination with ethinylestradiol. Unlike cyproterone acetate, desogestrel or levonorgestrel (which have no antimineralocorticoid activity), drospirenone affected the physiologic natriuresis observed in the normal menstrual cycle by significantly increasing urinary aldosterone and sodium excretion (p < 0.01 for both parameters), plasma renin activity (p < 0.05) and plasma aldosterone levels (p < 0.01) in the follicular phase.A small increase in serum potassium levels was noted when estradiol 1mg/drospirenone 3mg was coadministered with enalapril maleate in hypertensive women; however, this increase was not statistically or clinically significant, and clinical hyperkalemia was not observed.
Antiandrogenic activity: Drospirenone, cyproterone acetate and dienogest are the only progestogens demonstrating antiandrogenic activity at therapeutic dosages. Like ethinylestradiol 35μg/cyproterone acetate 2mg (a progestogen with antiandrogenic activity), EE/DRSP reduced ovarian androgen production and seborrhea in women with mild-to-moderate acne participating in a randomized, double-blind trial.Pharmacokinetic ProfileEthinylestradiol: Ethinylestradiol is absorbed within 2 hours of oral administration of EE/DRSP (absorption is slowed by food). Steady-state Cmax and AUC values are achieved during the second half of a treatment cycle. The absolute bioavailability is approximately 40%, and the apparent volume of distribution is 4 to 5 L/kg.Ethinylestradiol is rapidly metabolized, primarily by conjugation and aromatic hydroxylation via the hepatic cytochrome P450 (CYP) 3A4 isoenzyme, and is excreted in urine and feces.
Drospirenone: Drospirenone is absorbed within 2 hours of oral administration of EE/DRSP, and maximum serum concentrations (Cmax) and areas under curves of drug concentration versus time (AUC) increase in a dose-related fashion after single doses. The absolute bioavailability is 76%. Absorption is slowed by food. Steady-state Cmax values were achieved by day 7 to 10 of the first treatment cycle when young women weregiven EE/DRSP. Steady-state AUC values demonstrated a slight accumulation (12 vs 17%) during the first six treatment cycles. Serum drospirenone concentrations were increased in women with moderate renal impairment; EE/DRSP is contraindicated in women with renal insufficiency.Although drospirenone is extensively bound to serum albumin (95 to 97%), it does not bind to SHBG or CBG and the apparent volume of distribution is 4 L/kg.Prior to elimination (which is both fecal and renal), drospirenone is extensively metabolized in the liver; the two main metabolites found in the plasma (the acid form of drospirenone and 4,5-dihydrodrospirenone-3-sul-phate) are pharmacologically inactive. Although the CYP isoenzyme CYP2C19 is inhibited in vitro by drospirenone, the clearance of concomitant omeprazole was not affected. Elimination is moderately slow and biphasic; the terminal disposition half-life after single or multiple doses is approximately 30 hours.Clinical EfficacyOral EE/DRSP effectively prevented pregnancy, with theoretical Pearl indices of 0 to 0.07 (corrected Pearl indices were 0.41 to 0.71) and pregnancy rates of 0.3 to 0.7% in three large multicenter 13- or 26-cycle trials in 326 to 1657 women (3192 to 18 418 cycles). In two randomized, nonblind trials, the contraceptive efficacy of EE/DRSP was similar to that observed with ethinylestradiol 30μg/desogestrel 150μg (EE/DSG). Theoretical (0 to 0.28) and corrected (0.28 to 0.41) Pearl indices and pregnancy rates (0.2 to 0.7% of women) in women receiving EE/DSG (n = 412 and 445; 4685 to 9422 cycles) were similar to those of EE/DRSP recipients.TolerabilityEE/DRSP is generally well tolerated and the type and frequency of adverse event reported in clinical trials are typical of those reported with other combined contraceptive pills (CCs). The frequency of adverse events possibly, probably or definitely related to treatment with EE/DRSP (39 and 43%) was not significantly different to that with EE/DSG (32 and 42%). The most frequent adverse events reported in clinical trials (≤26 cycles) by women in both treatment groups were headache (6 to 14%) and breast pain (5 to 12%); other adverse events included nausea, abdominal pain, migraine, depression and acne (all <5%). No significant differences were observed between the two treatment groups. Approximately 10% of women in each treatment group withdrew prematurely from two randomized, comparative, nonblind 13- or 26-cycle studies because of adverse events.No clinically significant changes in hematology, urinalysis, chemistry profiles or systolic or diastolic blood pressure recordings were observed in clinical trials.
Cycle control: Cycle control in women receiving EE/DRSP appears to be good, with a low incidence of intermenstrual bleeding (spot