drospirenone

ドロスピレノン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/02/16 05:48:55」(JST)

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Drospirenone

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 Y
ATC code	G03AA12 G03FA17 (only combinations with estrogens)
PubChem	CID 68873
DrugBank	DB01395
ChemSpider	62105 Y
UNII	N295J34A25 Y
KEGG	D03917 Y
ChEBI	CHEBI:50838 Y
ChEMBL	CHEMBL1509 Y
Chemical data
Formula	C24H30O3
Mol. mass	366.493 g/mol
SMILES O=C7O[C@@]6([C@@]3([C@H]([C@@H]2[C@@H]4[C@H](/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)C4)[C@@H]5C[C@@H]56)C)CC7
InChI InChI=1S/C24H30O3/c1-22-6-3-12(25)9-17(22)13-10-14(13)20-16(22)4-7-23(2)21(20)15-11-18(15)24(23)8-5-19(26)27-24/h9,13-16,18,20-21H,3-8,10-11H2,1-2H3/t13-,14+,15-,16+,18+,20-,21+,22-,23+,24+/m1/s1 Y Key:METQSPRSQINEEU-HXCATZOESA-N Y
Y (what is this?)  (verify)

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

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

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.

Adverse effects

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 compared to women who take a contraceptive pill containing levonorgestrel.

Drospirenone can increase potassium to dangerous levels (hyperkalemia). It is likely to be especially dangerous or fatal for patients 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.

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 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.

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

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

Formulations

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

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.

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.

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.
• Failure to properly research the medication.
• 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

See also

• Progestin
• Combined oral contraceptive pill
• Oral contraceptive formulations
• Hormone replacement therapy
• Spironolactone

References

Further reading

• Krattenmacher R (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

UpToDate Contents

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• 1. エストロゲン・プロゲスチン避妊剤の使用に関する概要 overview of the use of estrogen progestin contraceptives
• 2. エストロゲン・プロゲスチン避妊剤と関連したリスクおよび副作用 risks and side effects associated with estrogen progestin contraceptives
• 3. 尋常性ざ瘡を有する女性のホルモン療法 hormonal therapy for women with acne vulgaris
• 4. ホルモン避妊法の併用を考慮した女性のカウンセリング counseling women considering combined hormonal contraception
• 5. 月経前症候群および月経前不快気分障害の治療 treatment of premenstrual syndrome and premenstrual dysphoric disorder

English Journal

• Activity of binary mixtures of drospirenone with progesterone and 17α-ethinylestradiol in vitro and in vivo.

• Rossier NM1, Chew G2, Zhang K2, Riva F3, Fent K4.
• Aquatic toxicology (Amsterdam, Netherlands).Aquat Toxicol.2016 May;174:109-22. doi: 10.1016/j.aquatox.2016.02.005. Epub 2016 Feb 22.
• Despite potential exposure of aquatic organisms to mixtures of steroid hormones, very little is known on their joint activity in fish. Drospirenone (DRS) is a new synthetic progestin used in contraceptive pills in combination with 17α-ethinylestradiol (EE2). Here we systematically analyzed effects
• PMID 26930480

• Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives.

• Dinger J1, Möhner S2, Heinemann K2.
• Contraception.Contraception.2016 May;93(5):378-85. doi: 10.1016/j.contraception.2016.01.012. Epub 2016 Jan 26.
• OBJECTIVES: The "Long-term Active Surveillance Study for Oral Contraceptives" investigated the risks of long-term use of a 21-day regimen of drospirenone and ethinylestradiol (DRSP) compared to established oral contraceptives (OCs) in a routine clinical setting.STUDY DESIGN: Prospective, controlled,
• PMID 26825258

• Trends in direct-to-consumer advertising of prescription contraceptives.

• Wu MH1, Bartz D2, Avorn J3, Seeger JD4.
• Contraception.Contraception.2016 May;93(5):398-405. doi: 10.1016/j.contraception.2016.01.010. Epub 2016 Jan 22.
• OBJECTIVE: Despite much speculation about the role of direct-to-consumer advertising (DTCA) in increasing demand for prescription contraceptives in the United States, there is little published research on this topic. We sought to quantify the prevalence and magnitude of DTCA for prescription contrac
• PMID 26808088

Japanese Journal

• ISP-32-5 Anti-inflammatory effects of drospirenone on endometriosis(Group 32 Endometriosis/Endometrium,International Session Poster)

• 日本産科婦人科學會雜誌 68(2), 571, 2016-02-01
• NAID 110010034823

• ドロスピレノン含有LEP投与中にVTEを発症し,血栓治療のためTLHを施行した一例

• 新潟産科婦人科学会会誌 110(2), 51-54, 2015
• NAID 40020760347

• 症例報告 ドロスピレノン・エチニルエストラジオール内服中に生じた無症候肺血栓塞栓症の1例

• 東京産科婦人科学会会誌 63(4), 719-723, 2014-10
• NAID 40020303776

Related Links

• Drospirenone: pharmacology and pharmacokinetics of a ...

1. Contraception. 2000 Jul;62(1):29-38. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Krattenmacher R(1). Author information: (1)Berlex Laboratories, 300 Fairfield Road, 07470 ...

• Drospirenone/estradiol: Indications, Side Effects, Warnings ...

Drospirenone/estradiol should not be used to prevent heart disease, heart attacks, strokes, or dementia. Estrogens may increase the risk of heart disease (including heart attacks), stroke, serious blood clots (eg, in the lungs or legs ...

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