Open main menu

Wikipedia β

Drospirenone is a progestin used in birth control pills and in menopausal hormone therapy for the treatment of menopausal symptoms.[4] In addition to its progestogenic activity, it also has antiandrogenic and antimineralocorticoid activity.

Drospirenone
Drospirenone.svg
Drospirenona3D.png
Clinical data
Trade names Numerous
Synonyms Dihydrospirenone; 1,2-Dihydrospirorenone; BRN-4765500; CCRIS-6523; MSp; SH-470; ZK-30595; 17β-Hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration
By mouth
Drug class Progestogen; Antimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 76%[1]
Protein binding 95–97% (albumin)[1]
(Not to SHBG or CBG)[1]
Metabolism Hepatic (mostly CYP450-independent (reduction/sulfation and cleavage of lactone); minor CYP3A4 contribution (<10%))[1][2][3]
Biological half-life 25–33 hours[1]
Excretion Renal and fecal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.060.599
Chemical and physical data
Formula C24H30O3
Molar mass 366.493 g/mol
3D model (JSmol)
  (verify)

It is sold as a combined birth control pill under the brand names Yasmin (US, EU, Latin America), Jasmine (France), Yarina (Russia) [5] 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.

Contents

Medical usesEdit

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.[6] 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.[7]

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.[8]

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. [9] Additionally, it has been shown to reduce the occurrence of bone fractures in postmenopausal women. [10]

Side effectsEdit

Drospirenone is an aldosterone antagonist with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected.[11] 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.[11][12] 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,[11] and contraindicated in women with renal insufficiency, adrenal insufficiency, or liver disease according to FDA-approved labels.[13]

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.)[14]

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).[15]

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.[16]

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.[13]

PharmacologyEdit

PharmacodynamicsEdit

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).[17][18] It is an agonist of the PR and an antagonist of the MR and AR, and hence, a progestogen, antimineralocorticoid, and antiandrogen.[17] Drospirenone is said to be devoid of any estrogenic or glucocorticoid or antiglucocorticoid activity.[17] It has potent antigonadotropic effects at sufficient dosages as a result of PR activation.[17] 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.[17]

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[19]).[17][20] 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.[17][20] 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.[20]

The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention.[21]

Mechanism of actionEdit

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.[22]

PharmacokineticsEdit

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.

ChemistryEdit

Drospirenone, also known as 1,2-dihydrospirorenone or as 17β-hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone, is a synthetic steroidal 17α-spirolactone, or more simply a spirolactone. It is an analogue of other spirolactones like spironolactone and canrenone. The compound has a molecular weight of 366.493 g/mol and a molecular formula of C24H30O3.[23]

Society and cultureEdit

Generic namesEdit

Drospirenone is the generic name of the drug and its INN, USAN, BAN, and JAN, while drospirénone is its DCF.[24]

FormulationsEdit

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.[25]
  • 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.[26]
  • 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)[27]

LitigationEdit

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.[28]

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. [29]

See alsoEdit

ReferencesEdit

  1. ^ a b c d e Krattenmacher, Rolf (2000). "Drospirenone: pharmacology and pharmacokinetics of a unique progestogen". Contraception. 62 (1): 29–38. doi:10.1016/S0010-7824(00)00133-5. ISSN 0010-7824. PMID 11024226. 
  2. ^ Bachmann, Gloria (2009). "Drospirenone/ethinyl estradiol 3 mg/20 µg (24/4 day regimen): hormonal contraceptive choices – use of a fourth-generation progestin". Patient Preference and Adherence: 259. doi:10.2147/PPA.S3901. ISSN 1177-889X. 
  3. ^ Wiesinger, Herbert; Berse, Matthias; Klein, Stefan; Gschwend, Simone; Höchel, Joachim; Zollmann, Frank S.; Schütt, Barbara (2015). "Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol". British Journal of Clinical Pharmacology. 80 (6): 1399–1410. doi:10.1111/bcp.12745. ISSN 0306-5251. 
  4. ^ 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. 
  5. ^ http://www.doz.pl/leki/p8625-Daylette
  6. ^ Cerner Multum, Inc. (June 11, 2012). "drospirenone and ethinyl estradiol". Auckland, New Zealand: Drugs.com. Retrieved October 24, 2011. 
  7. ^ Lanza di Scalea, Teresa (June 2017). "Premenstrual Dysphoric Disorder". Psychiatric Clinics of North America. 40 (2): 201-206. doi:10.1016/j.psc.2017.01.002. PMID 28477648. 
  8. ^ "ANGELIQ Tablets" (PDF). Food and Drug Administration. 
  9. ^ Maclennan, A. H.; Broadbent, J. L.; Lester, S.; Moore, V. (18 October 2004). "Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes". The Cochrane Database of Systematic Reviews (4): CD002978. doi:10.1002/14651858.CD002978.pub2. ISSN 1469-493X. 
  10. ^ Torgerson, D. J.; Bell-Syer, S. E. (13 June 2001). "Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials". JAMA. 285 (22): 2891–2897. ISSN 0098-7484. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ a b Bayer (April 10, 2012). "Yasmin full prescribing information" (PDF). Silver Spring, Md.: Food and Drug Administration (FDA). Retrieved April 14, 2012. 4. Contraindications: • Renal impairment. • Adrenal insufficiency. • Liver disease. 
  14. ^ 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" (PDF). BMJ. 343: d6423. doi:10.1136/bmj.d6423. PMC 3202015 . PMID 22027398. Retrieved November 26, 2011. 
  15. ^ Lidegaard, Øjvind; Milsom, Ian; Geirsson, Reynir Tomas; Skjeldestad, Finn Egil (July 2012). "Hormonal contraception and venous thromboembolism" (PDF). Acta Obstetricia et Gynecologica Scandinavica. 91 (7): 769–778. doi:10.1111/j.1600-0412.2012.01444.x. PMID 22568831. Retrieved October 22, 2012. 
  16. ^ 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)" (PDF). BMJ. 342: d2519. doi:10.1136/bmj.d2519. PMID 21511807. Retrieved April 25, 2011. [permanent dead link]
  17. ^ a b c d e f g Muhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R, Schillinger E (1995). "Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity". Ann. N. Y. Acad. Sci. 761: 311–35. doi:10.1111/j.1749-6632.1995.tb31386.x. PMID 7625729. 
  18. ^ Fuhrmann, Ulrike; Krattenmacher, Rolf; Slater, Emily P.; Fritzemeier, Karl-Heinrich (1996). "The novel progestin drospirenone and its natural counterpart progesterone: Biochemical profile and antiandrogenic potential". Contraception. 54 (4): 243–251. doi:10.1016/S0010-7824(96)00195-3. ISSN 0010-7824. 
  19. ^ Hermann P.G. Schneider; Frederick Naftolin (22 September 2004). Climacteric Medicine - Where Do We Go?: Proceedings of the 4th Workshop of the International Menopause Society. CRC Press. pp. 133–. ISBN 978-0-203-02496-6. 
  20. ^ a b c Elger W, Beier S, Pollow K, Garfield R, Shi SQ, Hillisch A (2003). "Conception and pharmacodynamic profile of drospirenone". Steroids. 68 (10-13): 891–905. doi:10.1016/j.steroids.2003.08.008. PMID 14667981. 
  21. ^ 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. 
  22. ^ "Drospirenone". pubchem.ncbi.nlm.nih.gov. 
  23. ^ "Drospirenone". pubchem.ncbi.nlm.nih.gov. 
  24. ^ https://www.drugs.com/international/drospirenone.html
  25. ^ "Yasmin/Safyral". Retrieved February 9, 2015. 
  26. ^ "Yaz" (PDF). Retrieved October 31, 2017. 
  27. ^ Research, Center for Drug Evaluation and. "Drug Safety and Availability - FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone". www.fda.gov. Retrieved 2017-11-07. 
  28. ^ 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. 
  29. ^ "Interim Report Second Quarter 2015". 

Further readingEdit

External linksEdit