Ethinylestradiol/Drospirenone

Ethinylestradiol 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. Receptor 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. Ethinylestradiol: 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. Oral 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. EE/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 (spotting, breakthrough bleeding or both) after the first cycle that is maintained for up to 26 cycles. Intermenstrual bleeding is greatest in the first cycle (25 to 66% of women), decreasing to 9 to 18% by cycle 2, 5 to 8% by cycle 13 and 6% in cycle 26. Spotting alone occurred in 20 to 44% of women in cycle 1, decreasing to 4 to 6% in cycle 13 and 5% in cycle 26. Approximately 50% of women receiving EE/DRSP reported no intermenstrual bleeding. The incidence of intermenstrual bleeding in women receiving EE/DRSP or EE/DSG appears to be similar. The percentages of women receiving EE/DSG who experienced breakthrough bleeding and/or spotting in cycles 1 and 2, 13 and 26 were similar to those in women receiving EE/DRSP. The majority of cycles in one study (91 %) in both treatment groups (8572 and 8351 cycles) were free of intermenstrual bleeding. Similar percentages of cycles in each treatment group were associated with spotting, breakthrough bleeding or both. Amenorrhea is uncommon, occurring in 3.2, 0.8 and 1.6% of cycles in women receiving EE/DRSP for 13 or 26 cycles and in 0.8% of cycles in those receiving EE/DSG in clinical trials. Other effects: EE/DRSP has a lesser effect on mean bodyweight gain compared with EE/DSG. However, similar numbers in both treatment groups maintained their bodyweight ±2kg in clinical trials (<26 cycles). Acne, seborrhea and hirsutism improved to a similar extent during treatment with EE/DRSP, EE/DSG or ethinyl-estradiol 35μg/cyproterone acetate 2mg over 9 to 13 cycles. Treatment with EE/DRSP significantly improves perceptions about negative affect, water retention and increased appetite during the menstrual cycle (p < 0.001). Oral EE/DRSP is indicated for use as a contraceptive in women of reproductive age. A treatment cycle consists of a once-daily tablet of ethinylestradiol 30μg/drospirenone 3mg for 21 consecutive days, followed in the US by an inert tablet for 7 days, and in the UK by 7 tablet-free days; for maximum contraceptive efficacy the interval between tablets should not exceed 24 hours. In the US, EE/DRSP is contraindicated in women with conditions that predispose to hyperkalemia, including renal or adrenal insufficiency or hepatic dysfunction. Drospirenone has potent antimineralocorticoid activity; according to the US and European manufacturer’s prescribing information, EE/DRSP has the potential to cause hyperkalemia when administered to women receiving daily, long-term treatment for chronic conditions or diseases with drugs that may increase serum potassium levels, including ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, potassium supplements and nonsteroidal anti-inflammatory drugs. Consequently, monitoring of serum potassium levels is required during the first treatment cycle. In Europe, CCs (including EE/DRSP) are contraindicated in patients with existing or previous serious liver disease, severe renal insufficiency or acute renal failure. CCs, including EE/DRSP, are contraindicated in the US in women over 35 years of age who smoke 15 or more cigarettes a day; furthermore, in the US and Europe, the manufacturer’s prescribing information strongly recommends that women who use this form of contraception should not smoke cigarettes. In addition, US and European prescribing information recommends that women with an increased risk of thrombophlebitis, thromboembolic disorders, cerebral vascular or coronary artery disease (including the presence or prior history of the condition or disorders increasing the risk) should not use CCs, nor should those with known or suspected estrogen-dependent neoplasia or pregnancy, undiagnosed abnormal genital bleeding, liver disease or liver tumors. Women with medical conditions associated with a lower increase in risk (including treated hyperlipidemia, diabetes mellitus and hypertension) who elect to take CCs require close monitoring.