Ethinylestradiol/Drospirenone
Tóm tắt
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.
Tài liệu tham khảo
Anon. Cardiovascular disease and steroid hormone contraception. Report of a WHO scientific Group. Geneva: World Health Organization Technical Report Series 1998; 877: 1-89
Abma J, Chandra A, Mosher W, et al. Fertility, family planning, and women’s health: new data from the 1995 National Survey of Family Growth. Vital Health Stat 1997; 23 (19): [online]. Available from URL: http://www.cdc.gov/nchs/ products/pubs/pubd/series/ser.htm UEL} [Accessed 2002 Feb 18]
Anon. Facts in Brief: contraceptive use [online]. Available from URL: http://www.guttmacher.org/pubs/fb_contr_use.pdf [Accessed 2002 Feb 18]
National Center for Health Statistics. Contraceptive use [online]. Available from URL: http://www.cdc.gov/nchs/fastats/usecontr.htm [Accessed 2002 Jan 31]
Llewellyn-Jones D. Fundamentals of obstetrics and gynaecology. Vol. 2. Gynaecology. 5th ed. London: Faber and Faber Ltd, 1990
Hatcher RA, Guillebaud J. The pill: combined oral contraceptives. In: Hatcher RA, Trussell J, Stewart F, et al., editors. Contraceptive technology. 17th ed. New York: Ardent Medicine, 1998: 405–66
Loose-Mitchell DS, Stancel GM. Estrogens and progestins. In: Hardman JG, Limbird LE, Goodman Gilman A, editors. The parmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001
Burkman RT, Shulman LP. Oral contraceptive practice guidelines. Contraception 1998 Sep; 58(3 Suppl.): 35S–43S
Borgelt-Hansen L. Oral contraceptives: an update on health benefits and risks. J Am Pharm Assoc 2001 Dec; 41(6): 875–86
Association of Reproductive Health Professionals. Clinical Proceedings®: understanding low-dose oral contraceptives [online]. Available from URL: http://www.arhp.org/clinical/CP_low_dose/index.html [Accessed 2002 Feb 21]
The European Society of Human Reproduction and Embryology (ESHRE) Capri Workshop Group. Ovarian and endometrial function during hormonal contraception. Hum Reprod 2001; 16(7): 1527–35
Bagshaw S. The combined oral contraceptive: risks and adverse effects in perspective. Drug Saf 1995 Feb; 12(2): 91–6
Fuchs N, Prinz H, Koch U. Attitudes to current oral contraceptive use and future developments: the women’s perspective. Eur J Contracept Reprod Health Care 1996; 1: 275–84
Mansour D. Yasmin — new oral contraceptive, a new progestogen: the reasons why. Eur J Contracept Reprod Health Care 2000 Dec; 5(Suppl. 3): 9–16
Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 2000 Jul; 62(1): 29–38
Foidart J-M. The contraceptive profile of a new oral contraceptive with antimineralocorticoid and antiandrogenic effects. Eur J Contracept Reprod Health Care 2000 Dec; 5Suppl. 3: 25–33
Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception 1994 Jan; 49: 1–32
Kuhl H. New gestagens — advantages and disadvantages [in German]. Ther Umsch 2001 Sep; 58(9): 527–33
Foidart J-M, 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 Jun; 5(2): 124–34
Oelkers WKH. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure. Steroids 1996 Apr; 61(4): 166–71
Oelkers W. Drospirenone — a new progestogen with antimineralocorticoid activity, resembling natural progesterone. Eur J Contracept Reprod Health Care 2000 Dec; 5Suppl. 3: 17–24
Oelkers W, BlUmel A, Schöneshöfer M, et al. Effects of ethinylestradiol on the renin-angiotensin-adosterone-system and on plasma transcortin in women and men. J Clin Endocrinol Metab 1976; 43(5): 1036–40
Crane MG, Harris JJ. Estrogens and hypertension: effect of discontinuing estrogens on blood pressure, exchangeable sodium, and the renin-aldosterone system. Am J Med Sci 1978 Jul; 276(1): 33–55
Skinner SL, Lumbers ER, Symonds EM. Alteration by oral contraceptives of normal menstrual changes in plasma renin activity, concentration and substrate. Clin Sci 1969; 36: 67–76
Oelkers W. Effects of oral contraceptives on the renin-aldosterone system: overview and report on a new natriuretic progestogen. Adv Contracept 1991; 7Suppl. 3: 195–206
Kuhl H. Comparative pharmacology of newer progestogens. Drugs 1996 Feb; 51(2): 188–215
Wambach G, Higgins JR, Kem DC, et al. Interaction of synthetic progestogens with renal mineralocorticoid receptors. Acta Endocrinol (Copenh) 1979; 92: 560–7
Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the reninaldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab 1995 Jun; 80(6): 1816–21
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 Oct; 73(4): 837–42
Laragh JH, Sealey JE, Ledingham JGG, et al. Oral contraceptives: renin, aldosterone and high blood pressure. JAMA 1967 Sep 18; 201(12): 98–102
Hollenberg_NK, Williams GH, Burger B, et al. Renal blood flow and its response to angiotensin II. An interaction between oral contraceptive agents, sodium intake, and the renin-angiotensin system in healthy young women. Circ Res 1976 Jan; 38(1): 35–40
McAreavey D, Cumming AMM, Boddy K, et al. The renin-angiotensin system and total body sodium and potassium in hypertensive women taking oestrogenprogestagen oral contraceptives. Clin Endocrinol (Oxf) 1983; 18: 111–8
Beckerhoff R, Luetscher JA, Beckerhoff I, et al. Effects of oral contraceptives on the renin-angiotensin system and on blood pressure of normal young women. Johns Hopkins Med J 1973 Feb; 132(2): 80–7
Anon. The WHO multicentre trial of the vasopressor effects of combined oral contraceptives. 1. Comparisons with IUD. Contraception 1989; 40: 129-45
Sundsfjord JA, Aakvaag A. Plasma angiotensin II and aldosterone excretion during the menstrual cycle. Acta Endocrinol (Copenh) 1970; 64: 452–8
Landau RL, Lugibihl K. Inhibition of the sodium-retaining influence of aldosterone by progesterone. J Clin Endocrinol Metab 1958 Nov; 18: 1237–45
Oparil S, Ehrlich EN, Lindheimer MD. Effect of progesterone on renal sodium handling in man: relation to aldosterone excretion and plasma renin activity. Clin Sci 1975; 49: 139–47
Wambach G, Higgins JR. Antimineralocorticoid action of progesterone. In: Agarval MK, editor. Antihormones. Amsterdam: Elsevier North-Holland Biomedical Press, 1979: 167–80
Oelkers W, Heimerhorst 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 Jun; 14(3): 204–13
Fuhrmann U, Krattenmacher R, Slater EP, et al. The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Contraception 1996 Oct; 54(4): 243–51
Losert W, Casals-Stenzel J, Buse M. Progestogens with antimineralocorticoid activity. Arzneimittel Forschung 1985; 35(2): 459–71
Nickisch K, Beier S, Bittier D, et al. Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones. J Med Chem 1991; 34(8): 2464–8
Freeman EW, Kroll R, Rapkin A, et al. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Women’s Health Gend Based Med 2001 Jul; 10(6): 561–9
Rosenbaum P, Schmidt W, Heimerhorst FM, et al. Inhibition of ovulation by a novel progestogen (drospirenone) alone or in combination with ethinylestradiol. Eur J Contracept Reprod Health Care 2000 Mar; 5(1): 16–24
Rauscher H. Die Bedeutung des Zevixfactors im Rahmen des Sterilitätsproblems. Wien Med Wochenschr 1966; 42/43: 903–9
Lüdicke F, Johannisson E, Heimerhorst FM, et al. Effect of a combined oral contraceptive containing 3 mg of drospirenone and 30 μg of ethinyl estradiol on the human endometrium. Fertil Steril 2001 Jul; 76(1): 102–7
Muhn P, Fuhrmann U, Fritzemeier KH, et al. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann N Y Acad Sci 1995 Jun 12; 761: 311–35
Blode H, Wuttke W, Loock W, et al. A 1-year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers. Eur J Contracept Reprod Health Care 2000 Dec; 5(4): 256–64
van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect of 2 combined oral contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea. Cutis 2002 Apr; 69Suppl. 4: 2–15
Food and Drug Administration. New Drug Application number 21-098: medical reviews part 3 [online]. Available from URL: http://www.fda.gov/cder/foi/ nda/2001/21-098_Yasmin_medr_P3.pdf [Accessed 2002 Sep 3]
Dibbelt L, Knuppen R, Jutting G, et al. Group comparison of serum ethinyl estradiol, SBHG and CBG levels in 83 women using two low-dose combination oral contraceptives for three months. Contraception 1991 Jan; 43(1): 1–21
Kuhnz W, Staks T, Jütting G. Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles. Contraception 1993 Dec; 48: 557–75
Berlex Laboratories. Yasmin® 28 tablets (drospirenone and ethinyl estradiol) [online]. Available from URL: http://www.yasmin-us.com/Yasmin_Physician_PI.html [Accessed 2002 Jan 23]
Food and Drug Administration. New Drug Application number 21-098: medical reviews part 2 [online]. Available from URL: http://www.fda.gov/cder/ foi/nda/2001/21-098_Yasmin_medr_P2.pdf [Accessed 2002 Sep 3]
Boschitsch E. Women’s well-being: the non-contraceptive benefits of Yasmin®. Gynaecology Forum 2002; 7(1): 23–6
Blode H, Foidart J-M, Heithecker R. Transfer of drospirenone to breast milk after a single oral administration of 3 mg drospirenone + 30 μg ethinylestradiol to healthy lactating women. Eur J Contracept Reprod Health Care 2001 Sep; 6(3): 167–71
Blode H. Pharmacokinetics of drospirenone. Gynaecol Forum 2002; 7(1): 18–22
Orme M, Back DJ, Ward S, et al. The pharmacokinetics of ethinylestradiol in the presence and absence of gestodene and desogestrel. Contraception 1991 Apr; 43(4): 305–16
Kuhnz W, Staks T, Jütting G. Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum. Contraception 1994 Dec; 50: 563–79
Nilsson S, Nygren K-G, Johansson EDB. Ethinyl estradiol in human milk and plasma after oral administration. Contraception 1978 Feb; 17(2): 131–9
Food and Drug Administration. New Drug Application number 21-098: clinical pharmacology and biopharmaceutics review(s) [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2001/21-098_Yasmin_biopharmr.pdf [Accessed 2002 Sep 3]
Bergink W, Assendorp R, Kloosterboer L, et al. Serum pharmacokinetics of orally administered desogestrel and binding of contraceptive progestogens to sex hormone-binding globulin. Am J Obstet Gynecol 1990 Dec; 163 (6 Pt 2): 2132–7
British National Formulary (BNF). BNF No. 43: ethinylestradiol [online]. Available from URL: http://bnf.vhn.net/bnf/documents/bnf.3418.html [Accessed 2002 Oct 1]
Jenapharm. Directions for use: petibelle® coated tablets [online]. Available from URL: httpV/www.jenapharm.de/fachkreise/uebersetzungen/englisch/pet_eng.pdf [Accessed 2002 Feb 8]
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 Mar; 5(1): 25–34
Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a lowdose combination oral contraceptive containing drospirenone, a new progestogen. Contraception 2000 Feb; 61(2): 105–11
Schering AG. Data on file. 2002 Nov 14
Tietze C, Lewit S. Statistical evaluation of contraceptive methods. Clin Obstet Gynaecol 1974 Mar; 17(1): 121–38
Trussell J, Hatcher RA, Cates Jr W, et al. A guide to interpreting contraceptive efficacy studies. Obstet Gynaecol 1990 Sep; 76 (3 Pt 2): 558–67
Speroff L, DeCherney A. Evaluation of a new generation of oral contraceptives. Obstet Gynaecol 1993 Jun; 81(6): 1034–47
Shelton JD, Taylor Jr RN. The Pearl Pregnancy Index reexamined: still useful for clinical trials of contraceptives. Am J Obstet Gynecol 1981 Mar; 139(5): 592–6
Rosenberg MJ, Long SC. Oral contraceptives and cycle control: a critical review of the literature. Adv Contracept 1992; 8Suppl. 1: 35–45
Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynaecol 1998; 179: 577–82
Oddens BJ. Women’s satisfaction with birth control: a population survey of physical and psychological effects of oral contraceptives, intrauterine devices, condoms, natural family planning, and sterilization among 1466 women. Contraception 1999; 59: 277–86
Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med 1995 May; 40(5): 355–60
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 Dec; 5(Suppl. 3): 34–40
Brown C, Ling F, Wan J. A new monophasic oral contraceptive containing drospirenone: effect on perimenstrual symptoms. J Reprod Med 2002 Jan; 47(1): 14–22
Endrikat J, Jaques M-A, Mayerhofer M, et al. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20μg ethinylestradiol/75μg gestodene and 20μg ethinylestradiol/150μg desogestrel, with respect to efficacy, cycle control and tolerance. Contraception 1995; 52: 229–35
Boerrigter PJ, Ellman H, Dolker M. International clinical experience with a new low-dose, monophasic oral contraceptive containing levonorgestrel 100μg and ethinyl estradiol 20μg. Clin Ther 1999; 21(1): 118–27
Archer DF, Maheux R, DelConte A, et al. Efficacy and safety of a low-dose monophasic combination oral contraceptive containing 100 μg levonorgestrel and 20 μg ethinyl estradiol (Alesse®). Am J Obstet Gynecol 1999 Nov; 181 (5 Pt 2): S39–44
Weisberg E. Prescribing oral contraceptives. Drugs 1995; 49(2): 224–31
MacGregor EA, de Lignières B. The place of combined oral contraceptives in contraception. Cephalalgia 2000; 20: 157–63
Lammers P, Blumenthal PD, Huggins GR. Developments in contraception: a comprehensive review of Desogen® (desogestrel and ethinyl estradiol). Contraception 1998; 57Suppl. 5: 1S–27S
Egarter C, Topcuoglu MA, Imhof M, et al. Low dose oral contraceptives and quality of life. Contraception 1999; 59: 287–91
Thorneycroft IH. Cycle control with oral contraceptives: areview of the literature. Am J Obstet Gynaecol 1999 Feb; 180 (2 Pt 2): S280–7
Darney PD. OC practice guidelines: minimizing side effects. Int J Fertil Womens Med 1997; 42Suppl. 1: 158–69
Hannaford PC, Webb AMC. Evidence-guided prescribing of combined oral contraceptives: consensus statement. Contraception 1996 Sep; 54: 125–9
Anon. IMAP statement on steroidal oral contraception. IPPF Med Bull 1998 Dec; 32 (6): 1-6
Düsterberg B, Ellman H, Müller U, et al. A three-year clinical investigation into efficacy, cycle control and tolerability of a new low-dose monophasic oral contraceptive containing gestodene. Gynaecol Endocrinol 1996; 10(1): 33–9
Endrikat J, Müller U, DUsterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20μg ethinyl estradiol/75μg gestodene and 30μg ethinylestradiol/75μg gestodene, with respect to efficacy, cycle control and tolerance. Contraception 1997; 55: 131–7
Chalmers TC, Smith Jr H, Blackburn B, et al. A method for assessing the quality of a randomized control trial. Control Clin Trials 1981; 2: 31–49
Rosenberg MJ, Waugh MS, Stevens CM. Smoking and cycle control among oral contraceptive users. Am J Obstet Gynecol 1996 Feb; 174(2): 628–32
The Writing Committee for the Second European Conference on Sex Steroids and Metabolism. Consensus development meeting 1995: combined oral contraceptives and cardiovascular disease. The consensus statement issued after the Second European Conference on sex steroids and metabolism, Amsterdam 1995. Gynaecol Endocrinol 1996; 10: 1-5
Lewis MA. The epidemiology of oral contraceptive use: a critical review of the studies on oral contraceptives and the health of young women. Am J Obstet Gynaecol 1998 Oct; 179(4): 1086–97
Farley TMM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks. Hum Reprod Update 1999; 5(6): 721–35
Spitzer WO. The aftermath of a pill scare: regression to reassurance. Hum Reprod Update 1999; 5(6): 736–45
Anon. Oral contraceptives and cardiovascular risk. Drug Ther Bull 2000 Jan; 38 (1): 1-5
Farmer RDT, Williams TJ, Simpson EL, et al. Effect of the 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: analysis of General Practice Research Database. BMJ 2000 Aug 19; 321: 477–9
Skegg DCG. Evaluating the safety of medicines, with particular refrence to contraception. Stat Med 2001; 20: 3357–69
Walker AM. Newer oral contraceptives and the risk of venous thromboembolism. Contraception 1998; 57: 169–81
Farmer RDT, Lawrenson RA, Todd J-C, et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000; 49: 580–90
Nightingale AL, Lawrenson RA, Simpson EL, et al. The effects of age, body mass index, smoking and general health in the risk of venous thromboembolismin in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000; 5: 265–74
Vandenbroucke JP, Rosing J, Bloemenkamp KWM, et al. Oral contraceptives and the risk of venous thrombosis. New Engl J Med 2001 May; 344(20): 1527–35
Odlind V, Milsom I, Persson I, et al. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet Gynecol Scand 2002; 81: 482–90
European Agency for the Evaluation of Medicinal Products. EMEA Committee for Proprietary Medicinal Products (CPMP) public assessment report: combined oral contraceptives and venous thromboembolism [online]. Available from URL: http://www.emea.eu.int/pdfs/human/regaffair/0220101en.pdf [Accessed 2002 Jul 27]
Smals AGH. Fluid retention with oral contraceptives [letter]. Gynecol Endocrinol 2000 Dec; 14(6): 477–8