Drospirenone

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Drospirenone
Drospirenone.svg
Drospirenone molecule ball.png
Clinical data
PronunciationDroe-SPY-re-nown
Trade names Alone: 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.com Professional Drug Facts
License data
Routes of
administration
By mouth [1]
Drug class Progestogen; Progestin; Antimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 66–85% [1] [4] [5]
Protein binding 95–97% (to albumin) [3] [1] [4]
Metabolism Liver (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-life 25–33 hours [3] [4] [1]
Excretion Urine, 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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.060.599 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H30O3
Molar mass 366.501 g·mol−1
3D model (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 Yes check.svgY
  • Key:METQSPRSQINEEU-HXCATZOESA-N Yes check.svgY
   (verify)

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in 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]

Contents

Common side effects include acne, headache, breast tenderness, weight increase, and menstrual changes. [3] Rare side effects may include high potassium levels and blood clots (when taken as a combined oestrogen-progestogen pill), among others. [3] [11] Drospirenone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [1] It has additional antimineralocorticoid and antiandrogenic activity and no other important hormonal activity. [1] Because of its antimineralocorticoid activity and lack of undesirable off-target activity, drospirenone is said to more closely resemble 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 progestogen-only birth control pill, in combination with the estrogens ethinylestradiol (EE) or estetrol (E4), with or without supplemental folic acid (vitamin B9), as a combined birth control pill, and in combination with the estrogen estradiol (E2) for use in menopausal hormone therapy. [3] A birth control pill with low-dose ethinylestradiol is also indicated for the treatment of moderate acne, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea (painful menstruation). [21] [22] For use in menopausal hormone therapy, E2/DRSP is specifically approved to treat moderate to severe vasomotor symptoms (hot flashes), vaginal atrophy, and postmenopausal osteoporosis. [23] [24] [25] The drospirenone component in this formulation is included specifically to prevent estrogen-induced endometrial hyperplasia. [26] Drospirenone has also been used in combination with an estrogen as a component of hormone therapy for transgender women. [27] [28]

Studies have found that EE/DRSP is superior to placebo in reducing premenstrual emotional and physical symptoms while also improving quality of life. [29] [30] E2/DRSP has been found to increase bone mineral density and to reduce the occurrence of bone fractures in postmenopausal women. [31] [26] [32] [33] In addition, E2/DRSP has a favorable influence on cholesterol and triglyceride levels and decreases blood pressure in women with high blood pressure. [32] [33] Due to its antimineralocorticoid activity, drospirenone opposes estrogen-induced salt and water retention and maintains or slightly reduces body weight. [34]

Available forms

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

Contraindications

Contraindications of drospirenone include renal impairment or chronic kidney disease, adrenal insufficiency, presence or history of cervical cancer or other progestogen-sensitive cancers, benign or malignant liver tumors or 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

Adverse effects of drospirenone alone occurring in more than 1% of women may include unscheduled menstrual bleeding (breakthrough or intracyclic) (40.3–64.4%), acne (3.8%), metrorrhagia (2.8%), headache (2.7%), breast pain (2.2%), weight gain (1.9%), dysmenorrhea (1.9%), nausea (1.8%), vaginal hemorrhage (1.7%), decreased libido (1.3%), breast tenderness (1.2%), and irregular menstruation (1.2%). [3]

High potassium levels

Drospirenone is an antimineralocorticoid with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected. [48] In women with mild or moderate chronic kidney disease, or in combination with chronic daily use of other potassium-sparing medications (ACE inhibitors, 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 ethinylestradiol and a progestin are associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). [51] The incidence is about 4-fold higher on average than in women not taking a birth control pill. [51] The absolute risk of VTE with ethinylestradiol-containing birth control pills is small, in the area of 3 to 10 out of 10,000 women per year, relative to 1 to 5 out of 10,000 women per year not taking a birth control pill. [52] [53] The risk of VTE during pregnancy is 5 to 20 in 10,000 women per year and during the postpartum period is 40 to 65 per 10,000 women per year. [53] The higher risk of VTE with combined birth control pills is thought to be due to the ethinylestradiol component, as ethinylestradiol has estrogenic effects on liver synthesis of coagulation factors which result in a procoagulatory state. [11] In contrast to ethinylestradiol-containing birth control pills, neither progestogen-only birth control nor the combination of transdermal estradiol and an oral progestin in 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. [11] Birth control pills containing progestins such as desogestrel, gestodene, drospirenone, and cyproterone acetate have been found to have 2- to 3-fold the risk of VTE of birth control pills containing levonorgestrel in retrospective cohort and nested case–control observational studies. [11] [52] However, this area of research is controversial, and 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)
TypeRouteMedications Odds ratio (95% CI Tooltip 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 alone1.02 (0.90–1.15)
Raloxifene alone1.49 (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 alone0.84 (0.73–0.97)
Conjugated estrogens alone1.04 (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) Nested case–control studies (2015, 2019) based on data from the QResearch and Clinical Practice Research Datalink (CPRD) databases. (2) 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 proliferation and migration of breast cancer cells in preclinical research, similarly to certain other progestins. [64] [65] However, some evidence suggests that drospirenone may do this more weakly than certain other progestins, like medroxyprogesterone acetate. [64] [65] The combination of estradiol and drospirenone has been found to increase 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 adverse effects with overdose of drospirenone. [3] Symptoms that may occur in the event of an overdose may include nausea, vomiting, and vaginal bleeding. [3] There is no antidote for overdose of drospirenone and treatment of overdose should be based on 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

Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may influence the levels and efficacy of drospirenone. [3] Treatment for 10 days with 200 mg twice daily ketoconazole, a strong CYP3A4 inhibitor among other actions, has been found to result in a moderate 2.0- to 2.7-fold increase in exposure to drospirenone. [3] Drospirenone does not appear to influence the metabolism of omeprazole (metabolized via CYP2C19), simvastatin (metabolized via CYP3A4), or midazolam (metabolized via CYP3A4), and likely does not influence the metabolism of other medications that are metabolized via these pathways. [3] Drospirenone may interact with potassium-sparing medications such as ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, potassium supplements, heparin, 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 affinity to the progesterone receptor (PR) and mineralocorticoid receptor (MR), with lower affinity to the androgen receptor (AR), and with very low affinity to the glucocorticoid receptor (GR). [1] [72] [73] [5] It is an agonist of the PR and an antagonist of the MR and AR, and hence is a progestogen, 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 PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid-binding globulin
Drospirenone19–701–650–11–6100–50000
Progesterone 1000–800–16–35100–100000
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, and aldosterone for the MR Tooltip mineralocorticoid receptor. Sources: [4] [1] [5] [74] [65]

Progestogenic activity

Drospirenone is an agonist of the PR, the biological target of progestogens like progesterone. [1] [72] It has about 35% of the affinity of promegestone for the PR and about 19 to 70% of the affinity of progesterone for the PR. [1] [4] [65] Drospirenone has antigonadotropic and functional antiestrogenic effects as a result of PR activation. [1] [72] The ovulation-inhibiting dosage of drospirenone is 2 to 3 mg/day. [75] [76] [1] [77] Inhibition of ovulation occurred in about 90% of women at a dose of 0.5 to 2 mg/day and in 100% of women at a dose of 3 mg/day. [78] The total 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 gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses gonadal sex hormone production, including of estradiol, progesterone, and testosterone. [1] [81] [4] Drospirenone alone at 4 mg/day has been found to suppress estradiol levels in premenopausal women to about 40 to 80 pg/mL depending on the time of the cycle. [81] No studies of the antigonadotropic effects of drospirenone or its influence on hormone levels appear to have been conducted in men. [82] [83] [84] In male 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 natriuresis, decreases water retention and blood pressure, and produces compensatory increases in plasma renin activity as well as circulating levels and urinary excretion of aldosterone. [4] [88] [1] This has been shown to occur at doses of 2 to 4 mg/day. [4] Similar effects occur during the luteal phase of the menstrual cycle due to increased progesterone levels and the resulting antagonism of the MR. [4] Estrogens, particularly ethinylestradiol, activate liver production of angiotensinogen and increase levels of angiotensinogen and angiotensin II, thereby activating the 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 serum lipid profile, including higher HDL cholesterol and triglyceride levels and lower LDL cholesterol levels, at a dose of 3 mg/day in women. [4] The medication does not inhibit the effects of ethinylestradiol on sex hormone-binding globulin (SHBG) and serum lipids, in contrast to androgenic progestins like levonorgestrel but similarly to other antiandrogenic progestins like cyproterone acetate. [4] [1] [77] SHBG levels are significantly higher with ethinylestradiol and cyproterone acetate than with ethinylestradiol and drospirenone, owing to the more potent antiandrogenic activity of cyproterone acetate relative to drospirenone. [93] Androgenic progestins like levonorgestrel have been found to inhibit the procoagulatory effects of estrogens like ethinylestradiol on hepatic synthesis of 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 proliferation of MCF-7 breast cancer cells in vitro , an action that is independent of the classical PRs and is instead mediated via 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 oral bioavailability of drospirenone is between 66 and 85%. [1] [4] [5] Peak levels occur 1 to 6 hours after an oral dose. [1] [4] [3] [85] Levels are about 27 ng/mL after a single 4 mg dose. [3] There is 1.5- to 2-fold accumulation in drospirenone levels with continuous administration, with steady-state levels of drospirenone achieved after 7 to 10 days of administration. [1] [3] [4] Peak levels of drospirenone at steady state with 4 mg/day drospirenone are about 41 ng/mL. [3] With the combination of 30 μg/day ethinylestradiol and 3 mg/day drospirenone, peak levels of drospirenone after a single dose are 35 ng/mL, and levels at steady state are 60 to 87 ng/mL at peak and 20 to 25 ng/mL at trough. [4] [1] The pharmacokinetics of oral drospirenone are linear with a single dose across a dose range of 1 to 10 mg. [3] [4] Intake of drospirenone with food does not influence the absorption of drospirenone. [3]

Distribution

The distribution half-life of drospirenone is about 1.6 to 2 hours. [4] [1] The apparent volume of distribution of drospirenone is approximately 4 L/kg. [3] The plasma protein binding of drospirenone is 95 to 97%. [3] [1] It is bound to albumin and 3 to 5% circulates freely or unbound. [3] [1] Drospirenone has no affinity for sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), and hence is not bound by these plasma proteins in the circulation. [1]

Metabolism

The metabolism of drospirenone is extensive. [4] It is metabolized into the acid form of drospirenone by opening of its lactone ring. [1] [3] The medication is also metabolized by reduction of its double bond between the C4 and C5 positions and subsequent sulfation. [1] [3] The two major metabolites of drospirenone are drospirenone acid and 4,5-dihydrodrospirenone 3-sulfate, and are both formed independently of the cytochrome P450 system. [3] [4] Neither of these metabolites are known to be pharmacologically active. [3] Drospirenone also undergoes oxidative metabolism by CYP3A4. [3] [4] [7] [8]

Elimination

Drospirenone is excreted in urine and feces, with slightly more excreted in feces than in urine. [3] Only trace amounts of unchanged drospirenone can be found in urine and feces. [3] At least 20 different metabolites can be identified in urine and feces. [4] Drospirenone and its metabolites are excreted in urine about 38% as glucuronide 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

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. [9] [95] It is an analogue of other spirolactones like spironolactone, canrenone, and spirorenone. [9] [95] Drospirenone differs structurally from spironolactone only in that the C7α 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. [14] [15] Schering AG of Germany has been granted several patents on the production of drospirenone, including WIPO and US patents, granted in 1998 and 2000, respectively. [103] [104] It was introduced for medical use in combination with ethinylestradiol as a combined birth control pill in 2000. [14] Drospirenone is sometimes described as a "fourth-generation" progestin based on its time of introduction. [16] [17] The medication was approved for use in menopausal hormone therapy in combination with estradiol in 2005. [23] Drospirenone was introduced for use as a 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 generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name, while drospirénone is its DCF Tooltip 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

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 Bayer, the manufacturer of drospirenone, due to the higher risk of 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. [111] This is in addition to around 10,000 claims that Bayer has already settled without admitting liability. [111] These claims of VTE have amounted to US$1.97 billion. [111] Bayer also reached a settlement for arterial thromboembolic events, including stroke and heart attacks, for US$56.9 million. [111]

Research

A combination of ethinylestradiol, drospirenone, and prasterone is under development by Pantarhei Bioscience as a combined birth control pill for prevention of pregnancy in women. [112] It includes prasterone (dehydroepiandrosterone; DHEA), an oral androgen prohormone, to replace testosterone and avoid 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]

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Levonorgestrel</span> Hormonal medication used for birth control

Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57–93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norelgestromin</span> Pharmaceutical drug

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel is a progestin which is used in birth control pills sold under the brand name Ovral in combination with the estrogen ethinylestradiol and Opill by itself. It is also used in menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Ethisterone</span> Chemical compound

Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

<span class="mw-page-title-main">Chlormadinone acetate</span> Chemical compound

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Drospirenone/ethinylestradiol/levomefolic acid</span> Pharmaceutical combination

Drospirenone/ethinylestradiol/levomefolic acid (EE/DRSP/LMF), sold under the brand name Beyaz among others, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestogen, antimineralocorticoid, and antiandrogen, and levomefolic acid (LMF), a form of vitamin B9, which is used as a birth control pill to prevent pregnancy in women. The formulation contains folate as the calcium salt of levomefolic acid to lower the risk of complications such as fetal neural tube defects should the medication fail as a form of birth control. EE/DRSP/LMF was approved for use by the US Food and Drug Administration (FDA) in September 2010.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

Combined birth control pills that contain natural estradiol or an estradiol ester include:

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.

<span class="mw-page-title-main">Estetrol (medication)</span> Estrogen medication

Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.

Ethinylestradiol/drospirenone/prasterone (EE/DRSP/DHEA), known under developmental code names like Androgen Restored Contraceptive (ARC), Female Balance Pill, Pill-Plus, and Triple Oral Contraceptive, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestin, antimineralocorticoid, and antiandrogen, and prasterone, an androgen prohormone and neurosteroid, which is under development for use as a birth control pill to prevent pregnancy in women. Clinical studies of this formulation have been conducted and published. Estrogens and progestogens suppress testosterone levels in women, and the addition of 50 mg prasterone, an oral prohormone of testosterone, has been found to restore total testosterone levels to normal levels. However, free testosterone levels, although higher with the addition of prasterone, remain significantly lower than usual despite prasterone inclusion.

<span class="mw-page-title-main">Ethinylestradiol/drospirenone</span> Combination drug

Ethinylestradiol/drospirenone (EE/DRSP), sold under the brand name Yasmin among others, is a combination of ethinylestradiol (EE), an estrogen, and drospirenone (DRSP), a progestin, antimineralocorticoid, and antiandrogen, which is used as a birth control pill to prevent pregnancy in women. It is also indicated for the treatment of moderate acne, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea (painful menstruation) in women. The medication is taken by mouth and contains 30 μg EE and 3 mg DRSP per tablet (brand names Yasmin, others) or 20 μg EE and 3 mg DRSP per tablet (brand names Yaz, Yasminelle, Nikki, others). A formulation with levomefolic acid (vitamin B9) has also been marketed (brand names Beyaz, Safyral, others), with similar indications. EE/DRSP is marketed widely throughout the world.

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