Drospirenone was patented in 1976 and introduced for medical use in 2000.[15][16] It is available widely throughout the world.[10] The medication is sometimes referred to as a "fourth-generation" progestin.[17][18] It is available as ageneric medication.[19] In 2020, a formulation of drospirenone withethinylestradiol was the 145th most commonly prescribed medication in the United States, with more than 4million prescriptions.[20][21]
Birth control pills containingethinylestradiol and a progestin are associated with an increased risk ofvenous thromboembolism (VTE), includingdeep vein thrombosis (DVT) andpulmonary embolism (PE).[52] The incidence is about 4-fold higher on average than in women not taking a birth control pill.[52] Theabsolute 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.[53][54] The risk of VTE duringpregnancy is 5 to 20 in 10,000 women per year and during thepostpartum period is 40 to 65 per 10,000 women per year.[54] The higher risk of VTE with combined birth control pills is thought to be due to the ethinylestradiol component, as ethinylestradiol has estrogenic effects onliver synthesis ofcoagulation factors which result in aprocoagulatory state.[12] In contrast to ethinylestradiol-containing birth control pills, neitherprogestogen-only birth control nor the combination oftransdermalestradiol and an oral progestin inmenopausal hormone therapy is associated with an increased risk of VTE.[12][55]
Different progestins in ethinylestradiol-containing birth control pills have been associated with different risks of VTE.[12] Birth control pills containing progestins such asdesogestrel,gestodene, drospirenone, andcyproterone acetate have been found to have 2- to 3-fold the risk of VTE of birth control pills containinglevonorgestrel inretrospective cohort andnested case–controlobservational studies.[12][53] However, this area of research is controversial, andconfounding factors may have been present in these studies.[12][53][56] Other observational studies, specificallyprospective cohort andcase control studies, have found no differences in risk between different progestins, including between birth control pills containing drospirenone and birth control pills containing levonorgestrel.[12][53][56][57] These kinds of observational studies have certain advantages over the aforementioned types of studies, like better ability to control for confounding factors.[57]Systematic reviews andmeta-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.[58][59][53]
Androgenic progestins have been found to antagonize to some degree the effects of ethinylestradiol on coagulation.[60][61][62][63] As a result, more androgenic progestins, like levonorgestrel andnorethisterone, may oppose the procoagulatory effects of ethinylestradiol and result in a lower increase in risk of VTE.[12][64] 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 areantiandrogenic, like drospirenone and cyproterone acetate.[12][64]
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.[50]
Data on risk ofbreast cancer in women with newer progestins like drospirenone are lacking at present.[70] Progestogen-only birth control is not generally associated with a higher risk of breast cancer.[70] Conversely, combined birth control and menopausal hormone therapy with an estrogen and a progestogen are associated with higher risks of breast cancer.[71][70][72]
Drospirenone is anantagonist of the MR, thebiological target ofmineralocorticoids likealdosterone, and hence is an antimineralocorticoid.[73] 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][5][75][66] Drospirenone is about 5.5 to 11 times more potent as an antimineralocorticoid thanspironolactone in animals.[73][79][86] Accordingly, 3 to 4 mg drospirenone is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity.[87][4] It has been said that thepharmacological profile of drospirenone more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity.[73] 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.[88] Both drospirenone and progesterone are actually weakpartial agonists of the MR in the absence ofmineralocorticoids.[6][5][66]
Drospirenone is an antagonist of the AR, the biological target ofandrogens liketestosterone anddihydrotestosterone (DHT).[1][5] It has about 1 to 65% of the affinity of the syntheticanabolic steroidmetribolone for the AR.[1][5][6][66] The medication is more potent as an antiandrogen thanspironolactone, but is less potent thancyproterone acetate, with about 30% of its antiandrogenic activity in animals.[1][92][73][79] Progesterone displays antiandrogenic activity in some assays similarly to drospirenone,[5] although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.[93][1][6]
Drospirenone shows antiandrogenic effects on theserumlipid profile, including higherHDLcholesterol andtriglyceride levels and lowerLDL cholesterol levels, at a dose of 3 mg/day in women.[5] The medication does not inhibit the effects ofethinylestradiol onsex hormone-binding globulin (SHBG) and serum lipids, in contrast to androgenic progestins likelevonorgestrel but similarly to other antiandrogenic progestins like cyproterone acetate.[5][1][78] SHBG levels are significantly higher withethinylestradiol and cyproterone acetate than with ethinylestradiol and drospirenone, owing to the more potent antiandrogenic activity of cyproterone acetate relative to drospirenone.[94]Androgenic progestins like levonorgestrel have been found to inhibit theprocoagulatory effects of estrogens like ethinylestradiol on hepatic synthesis ofcoagulation factors, whereas this may occur less or not at all with weakly androgenic progestins likedesogestrel and antiandrogenic progestins like drospirenone.[12][64][60][61][62][63]
Theoralbioavailability of drospirenone is between 66 and 85%.[1][5][6]Peak levels occur 1 to 6 hours after an oral dose.[1][5][4][86] Levels are about 27 ng/mL after a single 4 mg dose.[4] There is 1.5- to 2-fold accumulation in drospirenone levels with continuous administration, withsteady-state levels of drospirenone achieved after 7 to 10 days of administration.[1][4][5] Peak levels of drospirenone at steady state with 4 mg/day drospirenone are about 41 ng/mL.[4] With the combination of 30 μg/dayethinylestradiol 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 attrough.[5][1] Thepharmacokinetics of oral drospirenone are linear with a single dose across a dose range of 1 to 10 mg.[4][5] Intake of drospirenone withfood does not influence theabsorption of drospirenone.[4]
Drospirenone isexcreted inurine andfeces, with slightly more excreted in feces than in urine.[4] Only trace amounts of unchanged drospirenone can be found in urine and feces.[4] At least 20 differentmetabolites can be identified in urine and feces.[5] Drospirenone and its metabolites are excreted in urine about 38% asglucuronideconjugates, 47% assulfate conjugates, and less than 10% in unconjugated form.[5] In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated.[5]
Theelimination half-life of drospirenone is between 25 and 33 hours.[4][5][1] The half-life of drospirenone is unchanged with repeated administration.[4] Elimination of drospirenone is virtually complete 10 days after the last dose.[5][4]
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 asyntheticsteroidal17α-spirolactone, or more simply a spirolactone.[10][96] It is ananalogue of other spirolactones likespironolactone,canrenone, andspirorenone.[10][96] Drospirenone differs structurally from spironolactone only in that the C7αacetylthiosubstitution of spironolactone has been removed and twomethylene groups have been substituted in at the C6β–7β and C15β–16β positions.[97]
Spirolactones like drospirenone and spironolactone arederivatives ofprogesterone, which likewise has progestogenic and antimineralocorticoid activity.[98][99][100] The loss of the C7α acetylthio group of spironolactone, a compound with negligible progestogenic activity,[101][102] appears to be involved in the restoration of progestogenic activity in drospirenone, asSC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity similarly to drospirenone.[103]
Drospirenone was patented in 1976 and introduced for medical use in 2000.[15][16]Schering AG ofGermany has been granted several patents on the production of drospirenone, including WIPO and US patents, granted in 1998 and 2000, respectively.[104][105] It was introduced for medical use in combination withethinylestradiol as acombined birth control pill in 2000.[15] Drospirenone is sometimes described as a "fourth-generation" progestin based on its time of introduction.[17][18] The medication was approved for use inmenopausal hormone therapy in combination withestradiol in 2005.[24] Drospirenone was introduced for use as aprogestogen-only birth control pill in 2019.[4] A combined birth control pill containingestetrol and drospirenone was approved in 2021.[106]
Drospirenone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name, whiledrospirénone is itsDCFTooltip Dénomination Commune Française.[10] Its name is a shortened form of the name1,2-dihydrospirorenone ordihydrospirenone.[10][96] Drospirenone is also known by its developmental code namesSH-470 andZK-30595 (alone),BAY 86-5300,BAY 98-7071, andSH-T-00186D (in combination withethinylestradiol),BAY 86-4891 (in combination withestradiol), andFSN-013 (in combination withestetrol).[10][96][107][108][109][110][106]
Drospirenone is marketed in combination with an estrogen under a variety of brand names throughout the world.[10] Among others, it is marketed in combination withethinylestradiol under the brand names Yasmin and Yaz, in combination with estetrol under the brand name Nextstellis, and in combination withestradiol under the brand name Angeliq.[10][106]
Many lawsuits have been filed againstBayer, the manufacturer of drospirenone, due to the higher risk ofvenous 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.[56]
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.[111] 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.[111]
As of 17 July 2015, there have been at least 4,000 lawsuits and claims still pending regarding VTE related to drospirenone.[112] This is in addition to around 10,000 claims that Bayer has already settled without admitting liability.[112] These claims of VTE have amounted to US$1.97 billion.[112] Bayer also reached a settlement forarterial thromboembolic events, includingstroke andheart attacks, for US$56.9 million.[112]
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