• DOI:10.2165/00003495-200767120-00007
• Corpus ID: 46976925

Drospirenone/Ethinylestradiol 3mg/20µg (24/4 Day Regimen)

@article{Fenton2012DrospirenoneEthinylestradiol3,
  title={Drospirenone/Ethinylestradiol 3mg/20µg (24/4 Day Regimen)},
  author={Caroline Fenton and Keri David. Wellington and Marit D. Moen and Dean M. Robinson},
  journal={Drugs},
  year={2012},
  volume={67},
  pages={1749-1765}
}

• C. Fenton, K. Wellington, +1 author D. M. Robinson
• Published 2012
• Medicine
• Drugs

SummaryAbstractDrospirenone 3mg with ethinylestradiol 20µg (Yaz®) is a low-dose combined oral contraceptive (COC) administered in a regimen of 24 days of active tablets followed by a short hormone-free interval (4 days; 24/4 regimen). Drospirenone, unlike other synthetic progestogens used in COCs, is a 17α-spirolactone derivative and a 17α-spironolactone analogue with antimineralocorticoid and antiandrogenic properties. Drospirenone/ethinylestradiol 3mg/20µg (24/4) is approved in the US for the prevention of pregnancy in women, for the treatment of the symptoms of premenstrual dysphoric disorder (PMDD) and for the treatment of moderate acne vulgaris in women who wish to use an oral contraceptive for contraception.Drospirenone/ethinylestradiol 3mg/20µg (24/4) provided 99% contraceptive protection over 1 year of treatment in two large studies. The same treatment regimen over three treatment cycles also significantly improved the emotional and physical symptoms associated with PMDD, and improved moderate acne vulgaris over six treatment cycles in double-blind trials. It was generally well tolerated, with adverse events generally typical of those experienced with other COCs and which were most likely to occur in the first few cycles. Clinical trials indicate that drospirenone/ethinylestradiol 3mg/20µg (24/4) is a good long-term contraceptive option, and additionally offers relief of symptoms that characterise PMDD and has a favourable effect on moderate acne vulgaris.Pharmacological PropertiesThe pharmacological properties of ethinylestradiol are well established. Drospirenone is a 17α-spirolactone derivative and an analogue of 17α-spironolactone that resembles endogenous progesterone and has antimineralocorticoid and antian-drogenic properties. Drospirenone/ethinylestradiol 3mg/20µg administered as a 24/4 (Yaz®) or 21/7 regimen for two treatment cycles suppressed ovarian activity during daily recommended use; however, stronger suppression of ovarian activity was observed with the 24/4 regimen during intentional dosing errors (three active tablets replaced with placebo at the start of a third treatment cycle).Like natural progesterone, drospirenone induces mild natriuresis, which counteracts estrogen-stimulated fluid retention and weight gain. The effects of drospirenone/ethinylestradiol 3mg/20µg on metabolic parameters, including lipoproteins, were generally neutral or favourable, although, as with other COCs, the serum glucose response to an oral glucose tolerance test in healthy women volunteers increased from baseline. As drospirenone is a spironolactone analogue with antimineralocorticoid activity, it has the potential to induce hyperkalaemia in high-risk patients (those with conditions that predispose them to hyperkalaemia [i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency] or those receiving other medications that may increase serum potassium).Both drospirenone and ethinylestradiol are rapidly absorbed, with maximum serum concentration reached after 1.5 hours. Both are ≥97% plasma bound, with volumes of distribution of ≈4–5 L/kg. Steady-state levels of drospirenone are reached on day 8, and of ethinylestradiol in the second half of the cycle. Metabolism of both components, including first pass metabolism of ethinylestradiol, is extensive. The elimination half-life of drospirenone is ≈30 hours andthat of ethinylestradiol is ≈24 hours. Drospirenone exposure is slightly increased in women with renal impairment and markedly increased in those with hepatic dysfunction, with drospirenone/ethinylestradiol 3mg/20µg (24/4) contraindicated in both of these groups.Therapeutic EfficacyIn two 1-year (13 contraceptive treatment cycles), noncomparative, international and EU trials enrolling 1027 and 1101 healthy women aged 17–36 years, oral drospirenone/ethinylestradiol 3mg/20µg (24/4) provided 99% contraceptive protection. The uncorrected Pearl index (PI) in the international trial was 1.29 and the PI adjusted for noncompliance was 0.72; in the EU trial, the uncorrected PI was 0.49. The cumulative pregnancy rates were 1.26% and 0.5% in the international and EU trials. Subjective satisfaction ratings (overall satisfaction, emotional and physical well-being, and interest in continuing medication if available) assessed in the international trial were positive in 73–88% of women.The drospirenone/ethinylestradiol 3mg/20µg (24/4) regimen was shown to improve the emotional and physical symptoms associated with PMDD over three treatment cycles in two double-blind, parallel-group (n = 449) or crossover (n = 64) studies. In both trials, the improvement in overall luteal phase Daily Record of Severity of Problems (DRSP) scores (primary outcome) versus baseline was significantly greater in drospirenone/ethinylestradiol 3mg/20µg (24/4) than placebo recipients, while in the parallel-group trial, scores for physical, behavioural and mood subscales were also significantly improved. In both trials, the improvement from baseline in all individual DRSP items, including premenstrual depression, were significantly greater in drospirenone/ethinylestradiol 3mg/20µg (24/4) than in placebo recipients.In the treatment of moderate acne vulgaris, drospirenone/ethinylestradiol 3mg/20µg (24/4) was generally well tolerated and was more effective than placebo in reducing the number of acne lesions and increasing the proportion of patients with ‘clear’ or ‘almost clear’ ratings on an Investigator Static Global Assessment scale in two large (n = 431 and 458) randomised, double-blind, placebo-controlled multicentre trials over six treatment cycles.TolerabilityOnce-daily drospirenone/ethinylestradiol 3mg/20µg in a 24/4 day regimen was generally well tolerated. Irregular bleeding (actively solicited), headache, nausea and breast pain were the most common adverse events; all tended to decrease over time in the 1-year, international trial. There were no clinically significant changes in potassium levels or other laboratory investigations and no abnormalities in adequate-sample endometrial biopsies after 13 cycles.Adverse events were generally similar in the double-blind, 3-month studies in PMDD, although irregular bleeding (spontaneously reported) was more common in the parallel-group trial. The proportion of drospirenone/ethinylestradiol 3mg/20µg (24/4) recipients who discontinued treatment for this reason was <4% in the parallel-group PMDD study and <1% in the international contraceptive trial. Other common adverse events were headache, nausea and breast pain in 13–20% of patients.