Drospirenone

Source: Wikipedia, the free encyclopedia.

Drospirenone
Clinical data
PronunciationDroe-SPY-re-nown
Trade namesAlone: Slynd
With estradiol: Angeliq
With ethinylestradiol: Yasmin, Yasminelle, Yaz, others
With estetrol: Nextstellis
Other namesDihydrospirenone; Dihydrospirorenone; 1,2-Dihydrospirorenone; MSp; SH-470; ZK-30595; LF-111; 17β-Hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone
AHFS/Drugs.comProfessional Drug Facts
License data
Antimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability66–85%[1][4][5]
Protein binding95–97% (to albumin)[3][1][4]
MetabolismLiver (mostly CYP450-independent (reduction, sulfation, and cleavage of lactone ring), some CYP3A4 contribution)[4][6][7][8]
Metabolites• Drospirenone acid[3]
• 4,5-Dihydrodrospirenone 3-sulfate[3]
Elimination half-life25–33 hours[3][4][1]
ExcretionUrine, feces[3]
Identifiers
  • (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]phenantrene-17,2'(5'H)-furan]-3,5'(2H)-dione
JSmol)
  • 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=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 checkY
  • Key:METQSPRSQINEEU-HXCATZOESA-N checkY
  (verify)

Drospirenone is a

menopausal hormone therapy, among other uses.[1][9] It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others.[9][3] The medication is an analog of the drug spironolactone.[10] Drospirenone is taken by mouth.[1][3]

Common

bioidentical progesterone than other progestins.[12][13]

Drospirenone was patented in 1976 and introduced for medical use in 2000.[14][15] It is available widely throughout the world.[9] The medication is sometimes referred to as a "fourth-generation" progestin.[16][17] It is available as a generic medication.[18] In 2020, a formulation of drospirenone with ethinylestradiol was the 145th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[19][20]

Medical uses

Drospirenone (DRSP) is used by itself as a

hormone therapy for transgender women.[27][28]

Studies have found that EE/DRSP is superior to

body weight.[34]

Available forms

Drospirenone is available in the following formulations, brand names, and indications:[35][36]

Contraindications

hepatic impairment, undiagnosed abnormal uterine bleeding, and hyperkalemia (high potassium levels).[3][48][49] Renal impairment, hepatic impairment, and adrenal insufficiency are contraindicated because they increase exposure to drospirenone and/or increase the risk of hyperkalemia with drospirenone.[3]

Side effects

breast tenderness (1.2%), and irregular menstruation (1.2%).[3]

High potassium levels

Drospirenone is an

angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, antimineralocorticoids, or nonsteroidal anti-inflammatory drugs), a potassium level should be checked after two weeks of use to test for hyperkalemia.[48][50] Persistent hyperkalemia that required discontinuation occurred in 2 out of around 1,000 women (0.2%) with 4 mg/day drospirenone alone in clinical trials.[3]

Blood clots

Birth control pills containing

menopausal hormone therapy is associated with an increased risk of VTE.[11][54]

Different progestins in ethinylestradiol-containing birth control pills have been associated with different risks of VTE.

confounding factors may have been present in these studies.[11][52][55] Other observational studies, specifically prospective cohort and case control studies, have found no differences in risk between different progestins, including between birth control pills containing drospirenone and birth control pills containing levonorgestrel.[11][52][55][56] These kinds of observational studies have certain advantages over the aforementioned types of studies, like better ability to control for confounding factors.[56] Systematic reviews and meta-analyses of all of the data in the mid-to-late 2010s found that birth control pills containing cyproterone acetate, desogestrel, drospirenone, or gestodene overall were associated with a risk of VTE of about 1.3- to 2.0-fold compared to that of levonorgestrel-containing birth control pills.[57][58][52]

Androgenic progestins have been found to antagonize to some degree the effects of ethinylestradiol on coagulation.[59][60][61][62] As a result, more androgenic progestins, like levonorgestrel and norethisterone, may oppose the procoagulatory effects of ethinylestradiol and result in a lower increase in risk of VTE.[11][63] Conversely, this would be the case less or not at all with progestins that are less androgenic, like desogestrel and gestodene, as well as with progestins that are antiandrogenic, like drospirenone and cyproterone acetate.[11][63]

In the early 2010s, the FDA updated the label for birth control pills containing drospirenone and other progestins to include warnings for stopping use prior to and after surgery, and to warn that such birth control pills may have a higher risk of blood clots.[49]

Risk of venous thromboembolism (VTE) with hormone therapy and birth control (QResearch/CPRD)
Type Route Medications Odds ratio (95% CITooltip confidence interval)
Menopausal hormone therapy
 Oral Estradiol alone
    ≤1 mg/day
    >1 mg/day		 1.27 (1.16–1.39)*
1.22 (1.09–1.37)*
1.35 (1.18–1.55)*
Conjugated estrogens alone
    ≤0.625 mg/day
    >0.625 mg/day		 1.49 (1.39–1.60)*
1.40 (1.28–1.53)*
1.71 (1.51–1.93)*
Estradiol/medroxyprogesterone acetate 1.44 (1.09–1.89)*
Estradiol/dydrogesterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.18 (0.98–1.42)
1.12 (0.90–1.40)
1.34 (0.94–1.90)
Estradiol/norethisterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.68 (1.57–1.80)*
1.38 (1.23–1.56)*
1.84 (1.69–2.00)*
Estradiol/norgestrel or estradiol/drospirenone
 1.42 (1.00–2.03)
Conjugated estrogens/medroxyprogesterone acetate 2.10 (1.92–2.31)*
Conjugated estrogens/norgestrel
    ≤0.625 mg/day CEEs
    >0.625 mg/day CEEs		 1.73 (1.57–1.91)*
1.53 (1.36–1.72)*
2.38 (1.99–2.85)*
Tibolone alone 1.02 (0.90–1.15)
Raloxifene alone 1.49 (1.24–1.79)*
Transdermal
 Estradiol alone
   ≤50 μg/day
   >50 μg/day		 0.96 (0.88–1.04)
0.94 (0.85–1.03)
1.05 (0.88–1.24)
Estradiol/progestogen 0.88 (0.73–1.01)
Vaginal
 Estradiol alone 0.84 (0.73–0.97)
Conjugated estrogens alone 1.04 (0.76–1.43)
Combined birth control
 Oral Ethinylestradiol/norethisterone 2.56 (2.15–3.06)*
Ethinylestradiol/levonorgestrel 2.38 (2.18–2.59)*
Ethinylestradiol/norgestimate
 2.53 (2.17–2.96)*
Ethinylestradiol/desogestrel 4.28 (3.66–5.01)*
Ethinylestradiol/gestodene 3.64 (3.00–4.43)*
Ethinylestradiol/drospirenone 4.12 (3.43–4.96)*
Ethinylestradiol/cyproterone acetate 4.27 (3.57–5.11)*
Notes: (1)
Bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. Footnotes: * = Statistically significant
(p < 0.01). Sources: See template.

Breast cancer

Drospirenone has been found to stimulate the

breast density, an established risk factor for breast cancer, in postmenopausal women.[66][67][68]

Data on risk of breast cancer in women with newer progestins like drospirenone are lacking at present.[69] Progestogen-only birth control is not generally associated with a higher risk of breast cancer.[69] Conversely, combined birth control and menopausal hormone therapy with an estrogen and a progestogen are associated with higher risks of breast cancer.[70][69][71]

Overdose

These have been no reports of serious

symptoms.[3] Since drospirenone has antimineralocorticoid activity, levels of potassium and sodium should be measured and signs of metabolic acidosis should be monitored.[3]

Interactions

antimineralocorticoids, and nonsteroidal anti-inflammatory drugs to further increase potassium levels.[3] This may increase the risk of hyperkalemia (high potassium levels).[3]

Pharmacology

Pharmacodynamics

Drospirenone binds with high

antimineralocorticoid, and antiandrogen.[1][72][5][65] Drospirenone has no estrogenic activity and no appreciable glucocorticoid or antiglucocorticoid activity.[1][72][5][65]

Relative affinities (%) of drospirenone and related steroids
Progestogen PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid-binding globulin
Drospirenone 19–70 1–65 0–1 1–6 100–500 0 0
Progesterone 100 0–80 0–1 6–35 100–1000 0 0
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, and aldosterone for the MRTooltip mineralocorticoid receptor. Sources: [4][1][5][74][65]

Progestogenic activity

Drospirenone is an

endometrial transformation dose of drospirenone is about 50 mg per cycle, whereas its daily dose is 2 mg for partial transformation and 4 to 6 mg for full transformation.[1][79][78] The medication acts as a contraceptive by activating the PR, which suppresses the secretion of luteinizing hormone, inhibits ovulation, and alters the cervical membrane and endometrium.[80][3]

Due to its antigonadotropic effects, drospirenone inhibits the secretion of the

cynomolgus monkeys however, 4 mg/kg/day oral drospirenone strongly suppressed testosterone levels.[72]

Antimineralocorticoid activity

Drospirenone is an antagonist of the MR, the biological target of mineralocorticoids like aldosterone, and hence is an antimineralocorticoid.[72] It has about 100 to 500% of the affinity of aldosterone for the MR and about 50 to 230% of the affinity of progesterone for the MR.[1][4][74][65] Drospirenone is about 5.5 to 11 times more potent as an antimineralocorticoid than spironolactone in animals.[72][78][85] Accordingly, 3 to 4 mg drospirenone is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity.[86][3] It has been said that the pharmacological profile of drospirenone more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity.[72] Drospirenone is the only clinically used progestogen with prominent antimineralocorticoid activity besides progesterone.[1] For comparison to progesterone, a 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of spironolactone.[87] Both drospirenone and progesterone are actually weak partial agonists of the MR in the absence of mineralocorticoids.[5][4][65]

Due to its antimineralocorticoid activity, drospirenone increases

renin–angiotensin–aldosterone system.[4][1] As a result, they can produce undesirable side effects including increased sodium excretion, water retention, weight gain, and increased blood pressure.[4] Progesterone and drospirenone counteract these undesirable effects via their antimineralocorticoid activity.[4] Accumulating research indicates that antimineralocorticoids like drospirenone and spironolactone may also have positive effects on adipose tissue and metabolic health.[89][90]

Antiandrogenic activity

Drospirenone is an antagonist of the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT).[1][4] It has about 1 to 65% of the affinity of the synthetic anabolic steroid metribolone for the AR.[1][4][5][65] The medication is more potent as an antiandrogen than spironolactone, but is less potent than cyproterone acetate, with about 30% of its antiandrogenic activity in animals.[1][91][72][78] Progesterone displays antiandrogenic activity in some assays similarly to drospirenone,[4] although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.[92][1][5]

Drospirenone shows antiandrogenic effects on the

coagulation factors, whereas this may occur less or not at all with weakly androgenic progestins like desogestrel and antiandrogenic progestins like drospirenone.[11][63][59][60][61][62]

Other activity

Drospirenone stimulates the

progesterone receptor membrane component-1 (PGRMC1).[94] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[94] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[69]

Pharmacokinetics

Absorption

The

absorption of drospirenone.[3]

Distribution

The

plasma proteins in the circulation.[1]

Metabolism

The

oxidative metabolism by CYP3A4.[3][4][7][8]

Elimination

Drospirenone is

conjugates, 47% as sulfate conjugates, and less than 10% in unconjugated form.[4] In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated.[4]

The

elimination half-life of drospirenone is between 25 and 33 hours.[3][4][1] The half-life of drospirenone is unchanged with repeated administration.[3] Elimination of drospirenone is virtually complete 10 days after the last dose.[4][3]

Chemistry

See also: Spirolactone, List of progestogens § Spirolactone derivatives, and List of steroidal antiandrogens § Spirolactone derivatives
Chemical structures of spirolactones
The image above contains clickable links
Chemical structures of progesterone and spirolactones (steroid-17α-spirolactones).

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

acetyl thio substitution of spironolactone has been removed and two methylene groups have been substituted in at the C6β–7β and C15β–16β positions.[96]

Spirolactones like drospirenone and spironolactone are

derivatives of progesterone, which likewise has progestogenic and antimineralocorticoid activity.[97][98][99] The loss of the C7α acetylthio group of spironolactone, a compound with negligible progestogenic activity,[100][101] appears to be involved in the restoration of progestogenic activity in drospirenone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity similarly to drospirenone.[102]

History

Drospirenone was patented in 1976 and introduced for medical use in 2000.

progestogen-only birth control pill in 2019.[3] A combined birth control pill containing estetrol and drospirenone was approved in 2021.[105]

Society and culture

Generic names

Drospirenone is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while drospirénone is its DCFTooltip Dénomination Commune Française.[9] Its name is a shortened form of the name 1,2-dihydrospirorenone or dihydrospirenone.[9][95] Drospirenone is also known by its developmental code names SH-470 and ZK-30595 (alone), BAY 86-5300, BAY 98-7071, and SH-T-00186D (in combination with ethinylestradiol), BAY 86-4891 (in combination with estradiol), and FSN-013 (in combination with estetrol).[9][95][106][107][108][109][105]

Brand names

Drospirenone is marketed in combination with an estrogen under a variety of brand names throughout the world.[9] Among others, it is marketed in combination with ethinylestradiol under the brand names Yasmin and Yaz, in combination with estetrol under the brand name Nextstellis, and in combination with estradiol under the brand name Angeliq.[9][105]

Availability

See also: List of progestogens available in the United States

Drospirenone is marketed widely throughout the world.[9]

Generation

Drospirenone has been categorized as a "fourth-generation" progestin.[65]

Litigation

Many lawsuits have been filed against

venous thromboembolism (VTE) that has been observed with combined birth control pills containing drospirenone and certain other progestins relative to the risk with levonorgestrel-containing combined birth control pills.[55]

In July 2012, Bayer notified its stockholders that there were more than 12,000 such lawsuits against the company involving Yaz, Yasmin, and other birth control pills with drospirenone.[110] They also noted that the company by then had settled 1,977 cases for US$402.6 million, for an average of US$212,000 per case, while setting aside US$610.5 million to settle the others.[110]

As of 17 July 2015, there have been at least 4,000 lawsuits and claims still pending regarding VTE related to drospirenone.

heart attacks, for US$56.9 million.[111]

Research

See also:
Estetrol/drospirenone and Ethinylestradiol/drospirenone/prasterone

A combination of

testosterone deficiency caused by suppression of testosterone by ethinylestradiol and drospirenone.[112] As of August 2018, the formulation is in phase II/III clinical trials.[112]

Drospirenone has been suggested for potential use as a progestin in

male hormonal contraception.[82]

Drospirenone has been studied in forms for

parenteral administration.[113][114][115][116]

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Further reading