Prescription Yaz Drug InformationThis combination was 99% effective in preventing pregnancy in clinical trials. Ethinyl estradiol is one of two estrogens currently used in oral contraceptive pills. The other, mestranol, is converted to ethinyl estradiol before it is biologically active. The progestin drospirenone is an analog of spironolactone; drospirenone has antimineralocorticoid and antiandrogenic properties. The use of drospirenone as the progestin in this drug combination appears to improve many of the symptoms associated with mild premenstrual complaints, including negative mood, water retention, and increased appetite. The drug is currently being studied in females desiring contraception who experience mild premenstrual syndrome (PMS). Drospirenone may increase potassium levels in some patients; do not use this drug combination in those with kidney, liver, or adrenal disease. Patients taking drugs that could increase serum potassium should consult their health care professional before taking this oral contraceptive.
The FDA approved Yasmin® for routine contraception on May 14, 2001. In March 2006, the FDA approved for YAZ™, a low-estrogen formulation, for routine contraception. YAZ™ contains 3 mg of drospirenone, but only 20 mcg of ethinyl estradiol, compared to 30 mcg in Yasmin®; the dosage regimen of YAZ™ is unique in that it contains 24 days of active therapy, followed by 4 days of placebo, which may offer patients fewer hormone fluctuations than the traditional 21 days of active pills per 28 day cycle. YAZ™ received an approvable letter from the FDA for its use in premenstrual dysphoric disorder (PMDD) in December 2005; final approval for PMDD was granted by the FDA in October 2006. In January 2007, YAZ™ was approved for the treatment of acne in females 14 years of age and older who also desire an oral contraceptive for birth control. Mechanism of Action: The primary action of the contraceptive estrogen-progestin combination is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. Viscosity of the cervical mucus also increases with hormonal contraceptive use, preventing penetration of sperm; an alteration in endometrial tissue also occurs. When routine oral contraception is discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology. Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins.
Estrogens generally have a favorable effect on blood lipids, and lack of estrogen is recognized as a risk factor for myocardial infarction. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. As an analog of spironolactone, the drug exhibits both antimineralocorticoid and antiandrogenic activity. Thus this progestin inhibits testosterone production by the ovaries and adrenal glands, as well as some peripheral testosterone synthesis. Drospirenone's endocrine activity may improve luteal symptoms such as negative mood, water retention, and increased appetite. However, the antimineralocorticoid actions of 3 mg of drospirenone are comparable to 25 mg of spironolactone and may increase serum potassium levels in some patients. Progestins in general can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins, like drospirenone, have only slight effects on carbohydrate metabolism and are less likely to aggravate sebaceous glands and acne. Serious adverse events to OCs, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing OC formulations that take advantage of relative estrogen, progestin, and androgenic potencies. Pharmacokinetics: Following oral administration as single agents, roughly 76% of drospirenone is bioavailable and roughly 40% of ethinyl estradiol survives absorption and first pass through the liver. Food reduces the rate but not the extent of absorption. Both hormones are widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin (CBG). While drospirenone is 97% bound to other serum proteins, this progestin does not bind to SHBG or CBG. Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate. Ethinyl estradiol is primarily metabolized in the liver via CYP3A4 to 2-hydroxy-ethinylestradiol. Both ethinyl estradiol and its hydroxylated and methylated metabolites undergo glucuronide and sulfate conjugation. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract and then undergo entero-hepatic recycling. The progestin drospirenone is metabolized to two main metabolites, the acid form of drospirenone and the 4,5-dihydrodrospirenone-3-sulfate. The CYP450 microsomal enzymes (i.e., CYP3A4) minimally metabolize drospirenone. At least 20 non-active minor metabolites have been identified.
Excretion of both oral contraceptive steroids as inactive metabolites occurs via the urine and feces. The terminal elimination half-life is approximately 30 hours for drospirenone and 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormones that allow for once-daily administration.
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