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.
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 and postmenopausal hormone replacement therapy pills.[1]

It is sold under the brand names Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, Daylette[2] and Angeliq, all of which are combination products of drospirenone with an estrogen such as ethinylestradiol or estradiol.

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.[3]

Adverse effects[edit]

Drospirenone is an aldosterone antagonist with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected.[4] 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.[4][5] 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,[4] and contraindicated in women with renal insufficiency, adrenal insufficiency, or liver disease according to FDA-approved labels.[6]

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.)[7]

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).[8]

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.[9]

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.[10]

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[edit]

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

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.[12]

See also[edit]

References[edit]

  1. ^ Buckingham, John, ed. (1994). "Spirorenone, INN S-01057". Dictionary of Natural Products, Volume 5, R–Z, R-00001 – Z-00072. London: Chapman & Hall. p. 5201. ISBN 0-412-46620-1. Retrieved May 28, 2012. 
  2. ^ http://www.doz.pl/leki/p8625-Daylette
  3. ^ Cerner Multum, Inc. (June 11, 2012). "drospirenone and ethinyl estradiol". Auckland, New Zealand: Drugs.com. Retrieved October 24, 2011. 
  4. ^ a b c Bayer (March 25, 2013). "Summary of Product Characteristics (SPC): Yasmin". London: electronic Medicines Compendium (eMC), Datapharm. Retrieved April 24, 2014. "4.3. Contraindications: • Severe renal insufficiency or acute renal failure. • Presence or history of severe hepatic disease as long as liver function values have not returned to normal." 
  5. ^ Nelson, Anita L.; Cwiak, Carrie (2011). "Combined oral contraceptives (COCs)". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. (eds.). Contraceptive Technology (20th revised ed.). New York: Ardent Media. pp. 249–341. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734.  pp. 287–288:

    Health issues incorrectly attributed to modern COC use
    9. Myth: Drospirenone-containing pills increase potassium levels in all women.
    Drospirenone has antimineralocorticoid activity, which introduces the potential for hyperkalemia in high-risk patients; the 3 mg of drospirenone in these formulations has the same impact on electrolytes as 25 mg of spironolactone. The EURAS multinational study noted no increase in arrhythmias in users of drospirenone-containing COCs compared with other COC formulations.216 Use of these pills in combination with chronic daily use of ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, and NSAIDs may increase serum potassium. Note that intermittent use of NSAIDs does not pose any problems. If a woman is using other potassium-sparing drugs, test her potassium about 14 days after starting her first pack; if that value is normal, no further testing is needed for potassium.

  6. ^ a b Bayer (April 10, 2012). "Yasmin full prescribing information". Silver Spring, Md.: Food and Drug Administration (FDA). Retrieved April 14, 2012. "4. Contraindications: • Renal impairment. • Adrenal insufficiency. • Liver disease." 
  7. ^ Lidegaard, Øjvind; Milsom, Ian; Skovlund, Charlotte Wessel; Skjeldestad, Finn Egil; Løkkegaard, Ellen (October 25, 2011). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9". BMJ 343: d6423. doi:10.1136/bmj.d6423. PMC 3202015. PMID 22027398. Retrieved November 26, 2011. 
  8. ^ Lidegaard, Øjvind; Milsom, Ian; Geirsson, Reynir Tomas; Skjeldestad, Finn Egil (July 2012). "Hormonal contraception and venous thromboembolism". Acta Obstetricia et Gynecologica Scandinavica 91 (7): 769–778. doi:10.1111/j.1600-0412.2012.01444.x. PMID 22568831. Retrieved October 22, 2012. 
  9. ^ Dunn, Nick (April 21, 2011). "The risk of deep venous thrombosis with oral contraceptives containing drospirenone. Data are inconclusive, but alternatives may be preferable unless specifically contraindicated. (editorial)". BMJ 342: d2519. doi:10.1136/bmj.d2519. PMID 21511807. Retrieved April 25, 2011. 
  10. ^ Genazzani, Andrea R.; Mannella, Paolo; Simoncini, Tommaso (February 2007). "Drospirenone and its antialdosterone properties". Climateric 10 (Supplement 1): 11–18. doi:10.1080/13697130601114891. PMID 17364593. Retrieved November 26, 2011. 
  11. ^ Johnson, Erica (January 20, 2011). "Video: Marketplace looks into alleged Yasmin risks". Marketplace (TV series). Vancouver, B.C.: CBC News. Retrieved October 13, 2011. 
  12. ^ Feeley, Jef; Kresge, Naomi (July 31, 2012). "Bayer's Yasmin lawsuit settlements rise to $402.6 million". Bloomberg News (New York). Retrieved November 11, 2012. 

Further reading[edit]

External links[edit]