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.
Common include acne, headache, breast tenderness, weight gain, and menstrual changes.
Drospirenone was patented in 1976 and introduced for medical use in 2000.[ Generic Yasmin Availability via at Drugs.com] In 2020, a formulation of drospirenone with ethinylestradiol was the 145th most commonly prescribed medication in the United States, with more than 4million prescriptions.
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 B
9), as a combined birth control pill, and in combination with the estrogen estradiol (E2) for use in menopausal hormone therapy.
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).
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.
The drospirenone component in this formulation is included specifically to prevent estrogen-induced endometrial hyperplasia.
Drospirenone has also been used in combination with an estrogen as a component of hormone therapy for transgender women.
Studies have found that EE/DRSP is superior to placebo in reducing premenstrual emotional and physical symptoms while also improving quality of life.
Available forms
Drospirenone is available in the following formulations, brand names, and indications:
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Drospirenone 4 mg ( Slynd) – progestogen-only birth control pill
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Drospirenone 3 mg and estetrol 14.2 mg ( Nextstellis (US)) – combined birth control pill
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Ethinylestradiol 30 μg and drospirenone 3 mg ( Ocella, Syeda, Yasmin, Zarah, Zumandimine) – combined birth control pill
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Ethinylestradiol 20 μg and drospirenone 3 mg ( Gianvi, Jasmiel, Loryna, Lo-Zumandimine, Nikki, Vestura, Yaz) – combined birth control pill, acne, PMS, PMDD, dysmenorrhea
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Ethinylestradiol 30 μg, drospirenone 3 mg, and levomefolate calcium 0.451 mg ( Beyaz, Tydemy) – combined birth control pill with vitamin B9 supplementation, acne, PMS
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Estetrol 15 mg and drospirenone 3 mg ( Nextstellis (CA)) – combined birth control pill
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Estradiol 0.5 or 1 mg and drospirenone 0.25 or 0.5 mg ( Angeliq) – menopausal hormone therapy (menopausal syndrome, postmenopausal osteoporosis)
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).
Renal impairment, hepatic impairment, and adrenal insufficiency are contraindicated because they increase exposure to drospirenone and/or increase the risk of hyperkalemia with drospirenone.
Side 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%).
High potassium levels
Drospirenone is an antimineralocorticoid with
potassium-sparing properties, though in most cases no increase of potassium levels is to be expected.
In women with mild or moderate chronic kidney disease, or in combination with chronic daily use of other potassium-sparing medications (
, 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.
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.
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).
The incidence is about 4-fold higher on average than in women not taking a birth control pill.
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.
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.
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
procoagulation state.
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.
Different progestins in ethinylestradiol-containing birth control pills have been associated with different risks of VTE.
progestins have been found to antagonize to some degree the effects of ethinylestradiol on coagulation.
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.
Breast cancer
Drospirenone has been found to stimulate the proliferation and
cell migration of
breast cancer cells in preclinical research, similarly to certain other progestins.
However, some evidence suggests that drospirenone may do this more weakly than certain other progestins, like medroxyprogesterone acetate.
The combination of estradiol and drospirenone has been found to increase
breast density, an established risk factor for breast cancer, in postmenopausal women.
Data on risk of breast cancer in women with newer progestins like drospirenone are lacking at present.
Overdose
These have been no reports of serious
with
overdose of drospirenone.
Symptoms that may occur in the event of an overdose may include
nausea,
vomiting, and
vaginal bleeding.
There is no
antidote for overdose of drospirenone and treatment of overdose should be based on
.
Since drospirenone has antimineralocorticoid activity, levels of
potassium and
sodium should be measured and signs of metabolic acidosis should be monitored.
Interactions
Enzyme inhibitor and
enzyme inducer of the cytochrome P450
enzyme CYP3A4 may influence the levels and efficacy of drospirenone.
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.
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.
Drospirenone may interact with
potassium-sparing medications such as
, angiotensin II receptor antagonists, potassium-sparing diuretics, potassium supplements,
heparin, antimineralocorticoids, and nonsteroidal anti-inflammatory drugs to further increase potassium levels.
This may increase the risk of
hyperkalemia (high potassium levels).
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).
It is an
agonist of the PR and an antagonist of the MR and AR, and hence is a progestogen, antimineralocorticoid, and
antiandrogen.
Drospirenone has no estrogenic activity and no appreciable
glucocorticoid or antiglucocorticoid activity.
| Relative affinities (%) of drospirenone and related steroids |
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| 0 |
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Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the , metribolone for the , estradiol for the , dexamethasone for the , and aldosterone for the . Sources: |
Progestogenic activity
Drospirenone is an
agonist of the PR, the biological target of progestogens like progesterone.
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.
Drospirenone has
antigonadotropic and functional
effects as a result of PR activation.
The
ovulation-inhibiting dosage of drospirenone is 2 to 3 mg/day.
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.
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.
The medication acts as a contraceptive by activating the PR, which suppresses the
secretion of luteinizing hormone, inhibits ovulation, and alters the
cervix and
endometrium.
Due to its antigonadotropic effects, drospirenone inhibits the secretion of the , luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses sex hormone biosynthesis, including of estradiol, progesterone, and testosterone.
Antimineralocorticoid activity
Drospirenone is an antagonist of the MR, the biological target of mineralocorticoids like
aldosterone, and hence is an antimineralocorticoid.
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.
Drospirenone is about 5.5 to 11 times more potent as an antimineralocorticoid than
spironolactone in animals.
Accordingly, 3 to 4 mg drospirenone is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity.
It has been said that the
pharmacology profile of drospirenone more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity.
Drospirenone is the only clinically used progestogen with prominent antimineralocorticoid activity besides progesterone.
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.
Both drospirenone and progesterone are actually weak
of the MR in the absence of mineralocorticoids.
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 urine excretion of aldosterone.
Antiandrogenic activity
Drospirenone is an antagonist of the AR, the biological target of
like
testosterone and dihydrotestosterone (DHT).
It has about 1 to 65% of the affinity of the synthetic
anabolic steroid metribolone for the AR.
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.
Progesterone displays antiandrogenic activity in some assays similarly to drospirenone,
although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.
Drospirenone shows antiandrogenic effects on the serum lipids lipid profile, including higher HDL cholesterol and triglyceride levels and lower LDL cholesterol levels, at a dose of 3 mg/day in women.
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).
Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.
It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in
clinical trial.
Pharmacokinetics
Absorption
The oral
bioavailability of drospirenone is between 66 and 85%.
Peak levels occur 1 to 6 hours after an oral dose.
Levels are about 27 ng/mL after a single 4 mg dose.
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.
Peak levels of drospirenone at steady state with 4 mg/day drospirenone are about 41 ng/mL.
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.
The
pharmacokinetics of oral drospirenone are linear with a single dose across a dose range of 1 to 10 mg.
Intake of drospirenone with
food does not influence the absorption of drospirenone.
Distribution
The distribution half-life of drospirenone is about 1.6 to 2 hours.
The apparent volume of distribution of drospirenone is approximately 4 L/kg.
The plasma protein binding of drospirenone is 95 to 97%.
It is bound to albumin and 3 to 5% circulates freely or unbound.
Drospirenone has no affinity for sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), and hence is not bound by these
in the circulation.
Metabolism
The
metabolism of drospirenone is extensive.
It is
metabolism into the
acid form of drospirenone by opening of its
lactone ring.
The medication is also metabolized by
redox of its
double bond between the C4 and C5 positions and subsequent
sulfation.
The two major
of drospirenone are drospirenone acid and 4,5-dihydrodrospirenone 3-sulfate, and are both formed independently of the cytochrome P450 system.
Neither of these metabolites are known to be pharmacologically active.
Drospirenone also undergoes
oxidation metabolism by CYP3A4.
Elimination
Drospirenone is
excretion in
urine and
feces, with slightly more excreted in feces than in urine.
Only trace amounts of unchanged drospirenone can be found in urine and feces.
At least 20 different
can be identified in urine and feces.
Drospirenone and its metabolites are excreted in urine about 38% as
glucuronide conjugates, 47% as
sulfate conjugates, and less than 10% in unconjugated form.
In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated.
The elimination half-life of drospirenone is between 25 and 33 hours.
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
17α-spirolactone, or more simply a spirolactone.
It is an analogue of other spirolactones like
spironolactone,
canrenone, and
spirorenone.
Drospirenone differs structurally from spironolactone only in that the C7α
acetyl thio- substituent of spironolactone has been removed and two
methylene bridge have been substituted in at the C6β–7β and C15β–16β positions.
Spirolactones like drospirenone and spironolactone are derivatives of progesterone, which likewise has progestogenic and antimineralocorticoid activity.
History
Drospirenone was patented in 1976 and introduced for medical use in 2000.
[ 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.][ ][ ] It was introduced for medical use in combination with ethinylestradiol as a combined birth control pill in 2000.
Society and culture
Generic names
Drospirenone is the generic term of the drug and its , , , and , while drospirénone is its .[drospirenone at Drugs.com: ] Its name is a shortened form of the name 1,2-dihydrospirorenone or dihydrospirenone.
Brand names
Drospirenone is marketed in combination with an estrogen under a variety of brand names throughout the world.
Availability
Drospirenone is marketed widely throughout the world.
Generation
Drospirenone has been categorized as a "fourth-generation" progestin.
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.
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.
As of 17 July 2015, there have been at least 4,000 lawsuits and claims still pending regarding VTE related to drospirenone.
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.
Drospirenone has been suggested for potential use as a progestin in male hormonal contraception.
Drospirenone has been studied in forms for parenteral administration.
Further reading
