Drospirenone

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Drospirenone
Drospirenone.svg
Drospirenona3D.png
Systematic (IUPAC) name
(6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-
1,3',4',6,6a,7,8,9,10,11,12,13,14,15,15a,16-
hexadecahydro-10,13-dimethylspiro-
[17H-dicyclopropa-6,7:15,16]cyclopenta
[a]phenanthrene-17,2'(5H)-furan]-3,5'(2H)-dione)
Clinical data
Pregnancy cat. X (US)
Legal status ?
Routes Oral
Pharmacokinetic data
Bioavailability 76%
Protein binding 97%
Metabolism Hepatic, minor (CYP3A4-mediated)
Half-life 30 hours
Excretion Renal and fecal
Identifiers
CAS number 67392-87-4 YesY
ATC code G03AA12 G03FA17 (only combinations with estrogens)
PubChem CID 68873
DrugBank DB01395
ChemSpider 62105 YesY
UNII N295J34A25 YesY
KEGG D03917 YesY
ChEBI CHEBI:50838 YesY
ChEMBL CHEMBL1509 YesY
Chemical data
Formula C24H30O3 
Mol. mass 366.493 g/mol
 YesY (what is this?)  (verify)

Drospirenone (INN, USAN), also known as 1,2-dihydrospirorenone, is a synthetic hormone used in birth control pills.[1]

It is sold under the brand names Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, and Angeliq, all of which are combination products of drospirenone with an estrogen such as ethinylestradiol.

Medical uses[edit]

Drospirenone is an ingredient in some birth control pills and hormone replacement therapy. In combination with ethinyl estradiol 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.[2]

Adverse effects[edit]

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.)[3]

Drospirenone can increase potassium to dangerous levels (hyperkalemia).[medical citation needed] It could be dangerous or, in extreme cases, even fatal to certain women taking other drugs that also may increase potassium levels, such as ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.

Yasmin was the first oral contraceptive that used drospirenone, and Yaz, the best-selling oral contraceptive in the US, also contains drospirenone. The labels for all contraceptives containing drospirenone warn that the drugs should not be used by women with hepatic dysfunction, renal insufficiency, or adrenal insufficiency. Like all oral contraceptives, these birth control pills should also not be used by women who smoke or have a history of DVT, stroke, or other blood clots.

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. One study showed more than a 600 percent increased risk of these blood clots compared to non-users, compared to 360 percent higher for women taking birth control pills containing levonorgestrel, a different type of progesterone found in many generic birth control pills. (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.)[4]

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.[5]

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.[6]

Pharmacology[edit]

Pharmacodynamics[edit]

Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has potent antimineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and has also been shown to possess mild antiandrogen activity.

The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention.[7]

Pharmacokinetics[edit]

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[edit]

It is an analog to spironolactone, with a molecular weight of 366.5 and the molecular formula C24H30O3.

Formulations[edit]

The compound is part of certain newer oral contraceptive formulations:

  • Yasmin 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.
  • Yasminelle contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is used for contraception.
  • Yaz and Beyaz contain 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.
  • Ocella contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet and is taken daily.

It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the United States in 2007 as Angeliq.

Litigation and regulatory penalties[edit]

In 2008, a series of television commercials prompted the FDA to cite Bayer for overstating the approved uses of Yaz while failing to adequately warn viewers about the risks of the drug. Bayer was required to dispel the inaccurate information contained in those ads by creating new ads that clarified the drug's approved uses.[8]

In September 2009, the FDA cited Bayer for sending out potentially low-quality batches of drosperinone. Bayer justified the shipments by explaining that they monitor the "average" quality of all shipments, not the quality of each individual batch.

As of August 2012, Bayer has notified its stockholders that there are more than 12,000 lawsuits against the company involving Yaz, Yasmin, and other oral contraceptives with drospirenone, and the company thus far has 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.[9]

The allegations include (but are not limited to):

  • Glossing over risks associated with the products and overstating their approved uses in an effort to mislead users of Yaz and Yasmin into believing that the drugs were safe.[8][10]
  • Failure to properly research the medication.
  • Failure to use an intuitive, cutting edge, viral, disruptive technology.
  • Failing to recall the drug after post-marketing reports demonstrated that the risk of potentially life-threatening side effects of Yasmin and Yaz outweighed potential benefits that could be achieved via other available oral contraceptives.

In October 2011 the CBC TV program Marketplace ran a segment discussing issues involved with the usage of Yaz/Yasmin [11]

See also[edit]

References[edit]

  1. ^ Ch Tamm; D. C. Ayres; R. A. Raphael; M. Shamma (1994). Dictionary of Natural Products. CRC Press. p. 5201. ISBN 978-0-412-46620-5. Retrieved 28 May 2012. 
  2. ^ http://www.drugs.com/mtm/drospirenone-and-ethinyl-estradiol.html
  3. ^ Lidegaard et al. (2011). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses". BMJ 343: 1–15. doi:10.1136/bmj.d6423. 
  4. ^ Lidegaard, O.; Milsom, Geirsson, Skjeldestad (2012). "Hormonal Contraception and venous thromboembolism". Acta Obstetricia et Gynecologica Scandinavica 91: 796–788. doi:10.1111/j.1600-0412.2012.01444.x. 
  5. ^ Dunn, N (Apr 21, 2011). "The risk of deep venous thrombosis with oral contraceptives containing drospirenone.". BMJ (Clinical research ed.) 342: d2519. PMID 21511807. 
  6. ^ "Highlights of Prescribing Information for Yasmin". FDA. 
  7. ^ Genazzani, Mannella & Simoncini (2007). "Drospirenone and its antialdosterone properties". Climacteric 1: 11–18. 
  8. ^ a b http://www.courthousenews.com/2009/10/15/Yasmin_YAZ_Claims_Against_Bayer_Mount_Up.htm
  9. ^ "Bayer’s Yasmin Lawsuit Settlements Rise to $402.6 Million". Bloomberg. July 31, 2012. 
  10. ^ "Nurse Charges Dangerous Yaz Birth Control Drug "Altered My Life"". Reuters. October 21, 2009. 
  11. ^ "VIDEO: Marketplace looks into alleged Yasmin risks". CBC News. January 20, 2011. 

Further reading[edit]

External links[edit]