24+4 drsp final

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  • Drospirenone is structurally different from all currently available progestins in that it is a spironolactone analogue
    3 mg of drospirenone is approximately equivalent to 25 mg of spironolactone
    Drospirenone exhibits antiandrogenic activity
    Antimineralocorticoid effects of drospirenone have been demonstrated in rats and humans
    Background Information
    The pharmacologic profile of drospirenone is more closely related to that of natural progesterone than any other synthetic progestin in use today. Pharmacologic activities of drospirenone include potent progestogenic, antimineralocorticoid, and antiandrogenic activities.
    The equivalence of 3 mg of drospirenone to 25 mg of spironolactone is based on dose-response curves with respect to urinary sodium and potassium excretion rates observed in animals and humans. As a consequence of the antimeneralocorticoid activity of these compounds, the urinary sodium/potassium ratio increases with increasing treatmnt doses. The results showed that the antimeneralocorticoid potency of drospirenone is approximately 8 times that of spironolactone. Thus, with respect to the antimineralocorticoid activity, 3 mg of drospirenone is equivalent to 25 mg of spironolactone.
    Progestogenic activities of drospirenone have been demonstrated in a variety of animal models. The compound efficiently promotes the maintenance of pregnancy in rats, inhibits ovulation in rats, and stimulates endometrial transformation in rabbits. The progestogenic potency of drospirenone is in the same range as that of norethisterone acetate and cyproterone acetate.
    The antimineralocorticoid effects of drospirenone have been demonstrated in rats and humans. The compound has a long-lasting natriuretic activity in rats at a daily dose of 10 mg administered subcutaneously for 3 weeks.
    Drospirenone exhibits antiandrogenic activity in castrated, testosterone-substituted male rats as shown by dose-dependent inhibition of accessory sex organ growth (ie, prostate and seminal vesicles). This antiandrogenic activity is intrinsic to the molecular structure of drospirenone in that the agent is antagonistic at the androgen receptor.
  • Search strategy yielded 69 English-language reports of randomized controlled trials with at least three treatment cycles that compared a combination OC containing ≤20 µg EE to at least one combination OC containing a higher estrogen dose. Five articles were secondary reports & 46 were excluded; 18 primary articles were eligible for this review, as summarized here.
  • Key Points:
    Follicular development can be estimated by a combination of the diameter of follicle-like structures on ultrasound, and by estrogen and progesterone levels.
    Endogenous estrogen levels can serve as one surrogate marker for follicular development. As a follicle develops, it secretes increasing amounts of estradiol.
    This graph from an article by Spona, et al, shows that, by shortening the pill-free interval by 2 days (i.e., 21 vs. 23 days of active treatment), ovarian activity (follicular development), reflected by surrogates of follicles >13 mm and estradiol levels >0.1 nmol/L, is suppressed.
    Thus, the shorter pill-free interval can result in decreased follicular development.
    The study used pills composed of 20 µg of ethinyl estradiol plus 75 µg of gestodene for 21 or 23 days. The lower follicular development in the 1st cycle for both regimens is a manifestation of the study design. That is, for Cycle 1, the patients had a Day 1 start equivalent to no pill-free interval.
    Reference:
    Spona J, Elstein M, Feichtinger W, Sullivan H, Ludicke F, Muller U, Düsterberg B. Shorter Pill-free Interval in Combined Oral Contraceptives Decreases Follicular Development. Contraception. 1996;54:71-77.
  • Drospirenone is a spironolactone analogue and shows antimineralocorticoid, antiandrogenic and progestogenic properties, and thus demonstrates a ‘physiological profile’ similar to progesterone. The antimineralocorticoid and antiandrogenic effects are observed at dose levels which are applicable for fertility control. No other agonistic activities, in particular, no estrogenic, no androgenic, and no glucocorticoid effects were observed for DRSP in clinical studies.
    In the 24-day regimen of YAZ®, 3 additional active tablets in combination with the shortening of the active tablet-free interval to 4 days and the 30h half-life of drsp, are expected to show therapeutic benefits in androgen-related diseases and in symptoms associated with hormone withdrawal.
    Blode H, Wuttke W, Loock W, Roll G, Heithecker R. A 1-year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers. Eur J Contracept Reprod Health Care 2000; 5(4) 256–64.
  • Cycle control is one of the most important factors influencing compliance with a contraceptive method.
    Bachmann G, Sulak PJ, Sampson-Landers C, Benda N, Marr J. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone. Contraception 2004; 70(3): 191–8.
    Data on file, Bayer Schering Pharma AG (protocol number 303740).
  • Cycle control with 3mg DRSP/EE 20ug 24/4 ® (n=229) was compared with the OC desogestrel 150 µg/ EE 20 µg (Mercilon® n=220) in an open-label, randomized study over 7 cycles.
    Overall, withdrawal bleeding intensity tended to be lighter in the 3mg DRSP/EE 20ug 24/4 ® group than in the Mercilon® group.
    Anttila L, Kunz M, Marr J. Bleeding pattern with drospirenone 3 mg+ethinyl estradiol 20 mcg 24/4 combined oral contraceptive compared with desogestrel 150 mcg+ethinyl estradiol 20 mcg 21/7 combined oral contraceptive. Contraception 2009; 80(5): 445–451.
  • 3mg DRSP/EE 20ug 24/4 provides cycle control comparable to that of 3mg DRSP/EE 20ug 21/7 , based on findings in two separate studies.
    Reference
    Data on file, Bayer HealthCare Pharmaceuticals Inc.
  • White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:S34–7
  • White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:S34–7
  • Bachmann et al conducted the efficacy and safety study of the oral contraceptive containing drospirenone 3 mg plus ethinyl estradiol 20 mcg, administered for 24 days in a 28-day cycle.1
    1027 women completed 11,140 treatment cycles
    12 pregnancies occurred, for a Pearl Index of 1.41 per 100 women-years of use.
    86% of the women in the study stated that they were satisfied or very satisfied with the treatment medication, and 70% would continue using the study medication.2
    7 women (0.7%) discontinued the study because of irregular bleeding over the 13 cycles of the study.2
    Reference
    3mg DRSP/EE 20ug 24/4 ® (drospirenone/ethinyl estradiol) prescribing information. Berlex, Montville, NJ, 2006.
    Bachmann G, Sulak PJ, Sampson-Landers C, et al. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone. Contraception 2004; 70: 191–198.
  • 24+4 drsp final

    1. 1. 24+4 with DRSP Putting An Innovative Contraceptive Option Into Practice
    2. 2. Contraception An International Perspective • Steady increase in contraceptive use in both developed and developing countries • Contraceptive needs remain largely unmet • Number of unplanned pregnancies continues to increase Sitruk-Ware R. Population Council New York. Contraception 2006; 73:215-222
    3. 3. Contraception An International Perspective • Actual use of contraception differs from region to region • By 2025, an estimate of 2,600 million new couples will require contraception • Unintended pregnancy remains a worldwide scourge with a profound adverse impact on maternal morbidity and mortality as well as society at large Sitruk-Ware R. Population Council New York. Contraception 2006; 73:215-222
    4. 4. Areas in OCP development • Tolerability • Acceptability • Efficacy • Reduction in estrogen dosage • Introduction of new progestins with more acceptable clinical profiles • Hormone ‘phasing’ and changing pill usage from the conventional 21/7 regimen
    5. 5. Summary of the unique pharmacology of drospirenone • Spironolactone analogue • 3 mg ≈ 25 mg spironolactone • Pharmacologic profile similar to that of natural progesterone • Combines progestogenic, anti mineralocorticoid, and anti androgenic activities • May prevent estrogen-related bloating and weight gain secondary to water retention • No androgenic activity Krattenmacher R. Contraception. 2000;62:29-38.
    6. 6. Cochrane Database of Systematic Reviews According to this review, use of 20 mcg estrogen combination OCs in 21/7 regimens is associated with higher incidence of bleeding pattern disruptions and early/premature discontinuation when compared to combination pills with 21/7 regimens with higher estrogen levels Gallo M 2006
    7. 7. Breakthrough Approach 24/4 Day Regimen
    8. 8. Potential Benefits for Shortening Pill Free Interval • Better Ovarian Suppression • Lower gonadotropin levels (FSH, LH) • Lower production of estradiol and inhibin B • Better Cycle Control • Less endometrial stimulation by endogenous estrogen • No increase in unscheduled bleeding/spotting at lower estrogen levels • More forgiving of forgetfulness • Higher continuation rates Wills SA et al. Contraception 2000; 74: 100-6.
    9. 9. Hormonal Fluctuations during HFI Menstrual Cycle 0 7 14 21 24 Menses Menses Progesterone 28 0 Menses Estrogen 7 14 Day 21 24 28 0 7 14 21 24 28 0 7 14 21 24 28 Hormone 7 14 Day 21 24 28 7 Placebo Menses Estrogen Menses Menses Conventional Regimen Contraceptive (21+7) 14 21 24 28 14 21 24 28 Extended Regimen Contraceptives / Shortened HFI (24+4) Estrogen Progesterone 0 7 14 21 24 28 7 14 Day 21 24 28 7 Shorter Hormone Free Interval (24+4 Regimen) leads to more stable Hormonal levels and lesser fluctuations than conventional (21+7) Klipping C et al. Contraception 2008;78:16–25
    10. 10. Shorter Pill-free Interval Can Decrease Follicular Development (23 vs. 21 Day) Residual Ovarian Activity (%) Percentage of Women with Follicular Growth using 23-day or 21-day Regimens 50 40 21-day regimen 30 23-day regimen 20 10 0 1st Cycle Spona J, et al. Contraception. 1996;54:71-77. 2nd Cycle 3rd Cycle
    11. 11. DRSP 3mg/EE 20ug 24/4 Dosing with Drospirenone Delivers 28 Day Presence™ e th to e in on s rm al nd o r v te y h nte Ex d a e i 4 fre Drospirenone level 3 extra days of Drospirenone 28-day presence™ Cycle 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Cycle 2 Days 24+4 with drsp regimen provides 3 extra days of anti-mineralocorticoid and antiandrogenic activity per 28-day cycle relative to conventional 21+7 day OCs Blode H, et al. Eur J Contracept Reprod Health Care 2000;5:256–64
    12. 12. Indications of 24+4 drsp • Pregnancy Prevention • Treatment of moderate acne vulgarus in women seeking oral contraception • Treatment of physical and emotional symptoms of premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive as their method of contraception
    13. 13. Contraceptive Profile 3mg/EE 20ug 24/4 • 3mg/EE 20ug 24/4 is highly effective for the prevention of pregnancy.1,2 • The Pearl Index: • 0.8 for typical use • 0.41 for perfect use 1 Bachmann G, et al. Contraception 2004;70(3):1918 2 ACOG 2008
    14. 14. Bleeding Profile • In a pivotal efficacy study, there was a trend towards shorter scheduled withdrawal bleeding episodes over time1 • The intensity of withdrawal bleeding was ‘spotting’ to ‘normal’ in ≥88% of women2 • The majority of women (>80% during cycles 2–13) experienced no intra cyclic bleeding (unexpected bleeds during treatment)1 Data on file, Bayer Schering Pharma AG (protocol number 303740); Bachmann G, et al. Contraception. 2004;70:191–8 1 2
    15. 15. Bleeding Profile 21+7 with desogestrel 24+4 with drsp® Proportion of women with scheduled bleeding (%) 100 80 60 40 20 0 1 2 3 4 5 6 1 2 3 4 5 6 Cycles Bleeding (spotting/light) Bleeding (normal) Bleeding (heavy) Bleeding Profile and Cycle Control of 24+4 with drospirenone comparable to 21+7 with desogestrel Anttila L, et al. Contraception 2009;80:445–451
    16. 16. 3mg DRSP/EE 20ug 24/4 Provides Bleeding Patterns Similar to 3mg DRSP/EE 30ug 21/7® Results from Two Separate Studies with Similar Design and Methodology Comparable Incidence rates of intermenstrual bleeding Incidence Rate (%) 30 20 mcg EE / 3 mg drsp with 24/4 dosing regimen 25 30 mcg EE / 3 mg drsp with 21/7 dosing regimen 20 15 10 5 1 2 3 4 5 6 7 Month 0 Data on file, Bayer HealthCare Pharmaceuticals Inc. 8 9 10 11 12
    17. 17. Androgenic disorders: Acne • Acne is a distressing condition that affects approximately 80% of adolescent girls, 8% of women aged 25–34 years, and 3% of women aged 35–44 years1 • Over-production of androgen or hypersensitivity of the sebaceous glands to ‘normal’ androgen levels can lead to increased sebum production and acne White GM. J Am Acad Dermatol. 1998;39:S34–7 1
    18. 18. Androgenic disorders: Acne • The anti-androgenic effects of 24+4 with drsp® are based on the dual action of EE on sex-hormone binding globulin & the direct anti-androgenic effects of drospirenone • An effective alternative for women with moderate acne, also desiring concomitant Contraception White GM. J Am Acad Dermatol. 1998;39:S34–7 1
    19. 19. Effective reduction of all types of acne lesion with 3 mg DRSP and 20 mcg EE Study 1 Study 2 Change in mean number of acne lesions from baseline 0 Papules Pustules Open Comedones Closed Comedones Papules Pustules Open Comedones Closed Comedones -2 -4 -6 p=0.0119 -8 -10 p=0.0269 p=0.0693 p=0.0002 p=0.0269 p=0.0002 p=0.0016 -12 3mg DRSP/EE 20ug 24/4 Koltun et al. 2008; Lucky et al. 2006, Maloney et al. 2007 p=0.0076 Placebo
    20. 20. Androgenic disorders Acne & Hirsutism • A study by Batukan et al. demonstrated the efficacy of EE + Drospirenone in improving Hirsutism in patients • The study was open, controlled and prospective in nature • n=50, 1 year duration Fertility and Sterility Vol. 85, No. 2, February 2006
    21. 21. Androgenic disorders Acne & Hirsutism • The study demonstrated statistically significant improvement in the Ferriman–Gallwey score • Reduction of 67% in the score at six months and 78% at 12 months compared to baseline was observed
    22. 22. Androgenic disorders Acne & Hirsutism Significant: • Reduction in Free Testosterone and Androstenedione levels • Increase in SHBG levels, at 6 & 12 months Fertility and Sterility Vol. 85, No. 2, February 2006
    23. 23. PMDD Rx with 3mg DRSP/EE 20ug 24/4 Parallel and Crossover Studies DRSP Sum – Score: Items 1-21, by Treatment Sequence ITT 90 Group 1 (3mg DRSP/EE 20ug 24/4 – Placebo) 75 3mg DRSP/EE 20ug 24/4 Placebo 80 Group 2 (Placebo- 3mg DRSP/EE 20ug 24/4 70 65 70 60 50 * 40 DRSP Sum Score DRSP Sum Score DRSP Sum – Score: Items 1-21, by Treatment Sequence ITT 60 55 50 45 *** 40 35 30 Run-in cycle1 30 Treatment cycle2 cycle1 Baseline cycle2 cycle3 * p = 0.0001 End of Treatment Period 1 End of Washout Phase End of Treatment Period 2
    24. 24. Parallel randomized controlled trial: Changes in Physical, Mood, and Behavioral Symptoms Daily Record of Severity of Problems scale (DRSP) 0 -5 Change from baseline -10 * † * * * * -15 † -20 -25 1 2 3 Physical *p <0.01 vs. placebo †p <0.001 vs. placebo Yonkers KA et al. Obstet Gynecol 2005;106(3). Cycles 1 2 Mood * 3 3mg DRSP/EE 20ug 24/4 * Placebo 1 2 3 Behavioral
    25. 25. 3mg DRSP/EE 20ug 24/4 Satisfaction • 86% were satisfied/very satisfied with drsp/EE - 24/41 • 0.7% discontinued trial because of bleeding (over a period of 1 year)1 1. Bachmann G et al. Contraception 2004; 70: 191–198.
    26. 26. Return to Fertility Cronin et al. Obstetrics and Gynecology 2009; Vol 144 (3): 616-22.
    27. 27. Summarizing benefits of 24+4 with DRSP Provides: •Effective Contraception •Effective in management of moderate acne in users desiring contraception •Effective in relieving physical and emotional symptoms in users suffering with PMDD
    28. 28. Summarizing benefits of 24+4 with DRSP Additional Benefits: •No/minimal pill related weight gain •Improves hyper androgenic disorders like acne and hirsutism in patients with PCOS •Regularization of menstrual cycles •Favorable glycemic and lipid profile

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