Drospirenone, sold under the brand names Yasmin and Angeliq among others, is a progestin medication which is used in birth control pills and in menopausal hormone therapy. The medication is available only in combination with an estrogen. It is taken by mouth.
Drospirenone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has additional antimineralocorticoid and antiandrogenic activity and no other important hormonal activity.
Drospirenone was introduced for medical use in 2000. It is available widely throughout the world. The medication is sometimes referred to as a "fourth-generation" progestin. It is available as a generic medication.
Video Drospirenone
Medical uses
Drospirenone is an ingredient in some birth control pills and is used in menopausal hormone therapy. In combination with ethinylestradiol it is used as contraception, and for women who want contraception it is also approved by the U.S. Food and Drug Administration (FDA) to treat moderate acne and premenstrual dysphoric disorder. Although FDA approved, this does come with a higher risk of venous thrombosis than with other contraceptives containing other progestins, and therefore all individuals would have to be individually assessed for appropriateness. Studies have found that the Yaz formulation was superior to placebo in reducing premenstrual emotional and physical symptoms while also improving quality of life.
Angeliq, a drospirenone and estradiol combination, has also been approved by the Food and Drug Administration (FDA) for treatment of moderate to severe vasomotor symptoms and/or vaginal atrophy associated with menopause.
The FDA has several approved indications for drospirenone. It is approved as a first-line therapy for menopause symptoms such as the relief of hot flashes. Additionally, it has been shown to reduce the occurrence of bone fractures in postmenopausal women.
Available forms
Drospirenone is sold as a combined birth control pill under the brand names Yasmin (US, EU, Latin America), Jasmine (France), Yarina (Russia) in a dosage containing drospirenone 3 mg/ethinylestradiol 30 µg. In the United States, Bayer Schering released a pill based on Yasmin with the B vitamin folate (B9), which is marketed under the names Safyral and Beyaz. Worldwide it is also sold under the brand names Yaz and Yasminelle in a lower dosage containing drospirenone 3 mg/ethinylestradiol 20 µg. The drug is also available in combination with estradiol for use in menopausal hormone therapy. Drospirenone is not available on its own (i.e., as a standalone medication).
Maps Drospirenone
Side effects
Drospirenone is an aldosterone antagonist with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected. In women with mild or moderate renal insufficiency, or in combination with chronic daily use of other potassium-sparing medications (ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, or NSAIDs), a potassium level should be checked after two weeks of use to test for hyperkalemia. In addition to contraindications common to all combined estrogen-progestin medications, drospirenone-containing medications are contraindicated in women with severe renal insufficiency according to European Medicines Agency (EMA)-approved labels, and contraindicated in women with renal insufficiency, adrenal insufficiency, or liver disease according to FDA-approved labels.
Women who take contraceptive pills containing drospirenone have a six- to sevenfold risk of developing thromboembolism (dangerous blood clots) compared to women who do not take any contraceptive pill, and have twice the risk (some epidemiological studies suggest thrice, according to the FDA) compared to women who take a contraceptive pill containing levonorgestrel, though the actual risk is small, in the neighborhood of 9 to 27 out of 10,000 women on an oral contraceptive for a year (up to 9 for levonorgestrel vs up to 27 for drospirenone, or about 0.09% vs 0.3% per year.)
While all oral contraceptives can increase the risk for venous thrombembolic events, including fatal blood clots, several studies have reported a greater risk for women taking contraceptives containing drospirenone. (Before becoming alarmed at the huge "relative" differences in risk, one must remember that the "actual" risks involved are quite small -- in the neighborhood of 1 in 10,000 to 27 in 10,000 in a year).
When the U.S. Food and Drug Administration (FDA) became concerned about the risks of drospirenone, they funded studies based on the medical records of more than 800,000 women taking oral contraceptives. They found that the risk of VTE, which includes dangerous and potentially fatal blood clots, was 93% higher for women who had been taking oral contraceptives made with drospirenone for only 3 months or less and 290% higher for women taking drospirenone oral contraceptives for 7-12 months, compared to women taking other types of oral contraceptives. To determine the exact risk for women of different ages and different circumstances, further study is warranted.
The FDA recently updated the label for contraceptives containing drospirenone to include warnings for stopping use prior to and after surgery, and to warn that contraceptives with drospirenone may have a higher risk of dangerous blood clots.
Pharmacology
Pharmacodynamics
Drospirenone binds strongly to the progesterone receptor (PR) and mineralocorticoid receptor (MR), with lower affinity, to the androgen receptor (AR), and very low affinity for the glucocorticoid receptor (GR). It is an agonist of the PR and an antagonist of the MR and AR, and hence, a progestogen, antimineralocorticoid, and antiandrogen. Drospirenone is said to be devoid of any estrogenic or glucocorticoid or antiglucocorticoid activity. It has potent antigonadotropic effects at sufficient dosages as a result of PR activation. It has been regarded that drospirenone has a pharmacological profile that is very closely related to that of natural progesterone, due to the combination of both progestogenic and antimineralocorticoid actions.
Drospirenone is 8 to 10 times more potent as an antimineralocorticoid relative to spironolactone (3 mg drospirenone is equivalent to about 20-25 mg spironolactone in this regard). It is more potent as an antiandrogen relative to spironolactone also but is less potent relative to cyproterone acetate, having about one-third the potency of this drug. Progestogenic, antimineralocorticoid, and mild antiandrogenic effects have been observed in humans during treatment with drospirenone at a dosage range of 0.5 to 4 mg per day orally.
The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention.
Mechanism of action
Drospirenone works by binding to PR. This creates an activated complex that binds to specific DNA sites, which suppresses the activity of luteinizing hormone, inhibits ovulation, and alters the cervical membrane and endometrium.
Pharmacokinetics
Drospirenone is taken orally with about 76% bioavailability. It is bound not by sex hormone-binding globulin or corticosteroid binding globulin, but by other serum proteins. Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days.
Chemistry
Drospirenone, also known as 1,2-dihydrospirorenone or as 17?-hydroxy-6?,7?:15?,16?-dimethylene-3-oxo-17?-pregn-4-ene-21-carboxylic acid, ?-lactone, is a synthetic steroidal 17?-spirolactone, or more simply a spirolactone. It is an analogue of other spirolactones like spironolactone and canrenone. Drospirenone differs structurally from spironolactone only in that the C7? acetylthio substitution of spironolactone has been removed and two methylene groups have been substituted in at the 6?,7? and 15?,16? positions. The loss of the C7? acetylthio group of spironolactone, a compound with negligible progestogenic activity, appears to be involved in the restoration of progestogenic activity in drospirenone, as SC-5233, the analogue of spironolactone without a C7? substitution, has potent progestogenic activity similarly to drospirenone. Drospirenone has a molecular weight of 366.493 g/mol and a molecular formula of C24H30O3.
History
Drospirenone was introduced for medical use in 2000. It is sometimes described as a "fourth-generation" progestin based on its time of introduction.
Society and culture
Generic names
Drospirenone is the generic name of the drug and its INN, USAN, BAN, and JAN, while drospirénone is its DCF.
Formulations
The compound is part of certain newer oral contraceptive formulations:
- Yasmin/Jamine/Yarina contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive.
- Safyral contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive as well as to provide a daily dose of folate supplementation, which is recommended for women in their reproductive years. Folate lowers the risk of having rare neural tube birth defects in a pregnancy occurring during Safyral use or shortly after stopping.
- Yaz/Gianvi/Vestura contains 3 mg drospirenone and 20mcg ethinylestradiol per tablet. It is indicated for prevention of pregnancy as well as treatment of premenstrual dysphoric disorder for women who choose to use an oral contraceptive for contraception. There has also been evidence for this formulation to treat moderate acne for women 14 years of age or older who choose to use an oral contraceptive for birth control.
- A complete list of FDA approved oral contraceptives containing drospirenone as of October 2012: Beyaz (Drospirenone 3 mg, ethinyl estradiol 0.02 mg and levomefolate calcium 0.451 mg), Drospirenone and ethinyl estradiol (Drospirenone 3 mg and ethinyl estradiol 0.03 mg), Gianvi (Drospirenone 3 mg and ethinyl estradiol 0.02 mg), Loryna (Drospirenone 3 mg and ethinyl estradiol 0.02 mg), Ocella (Drospirenone 3 mg and ethinyl estradiol 0.03 mg), Safyral (Drospirenone 3 mg, ethinyl estradiol 0.03 mg, and levomefolate calcium 0.451 mg), Syeda (Drospirenone 3 mg and ethinyl estradiol 0.03 mg), Yasmin (Drospirenone 3 mg and ethinyl estradiol 0.03 mg), Zarah (Drospirenone 3 mg and ethinyl estradiol 0.03 mg), Yaz (Drospirenone 3 mg and ethinyl estradiol 0.02 mg)
Litigation
In July 2012, Bayer notified its stockholders that there were more than 12,000 lawsuits against the company involving Yaz, Yasmin, and other oral contraceptives with drospirenone, and that the company by then settled 1,977 cases for $402.6 million, for an average of $212,000 per case, while setting aside $610.5 million to settle the others.
As of July 17, 2015, there have been at least 4,000 lawsuits and claims still pending regarding venous thromboembolic events. This doesn't include the roughly 10,000 claims that Bayer has already settled without admitting liability. These claims of venous thromboembolic events have amounted to 1.97 billion dollars. Bayer also reached a settlement for arterial thromboembolic events, including stroke and heart attacks, for 56.9 million dollars.
References
Further reading
- Krattenmacher, Rolf (July 2000). "Drospirenone: pharmacology and pharmacokinetics of a unique progestogen". Contraception. 62 (1): 29-38. doi:10.1016/S0010-7824(00)00133-5. PMID 11024226.
External links
- Yasmin product information
- Yaz product information
- Angeliq product information
Source of the article : Wikipedia
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