Comprehensive Monograph: Drospirenone (DB01395)

I. Executive Summary

Drospirenone is a fourth-generation synthetic progestin distinguished by a unique pharmacological profile that closely mimics endogenous progesterone. Structurally derived from the aldosterone antagonist spironolactone, drospirenone exhibits potent progestogenic, antimineralocorticoid, and antiandrogenic activities, setting it apart from earlier classes of progestins. This multi-receptor engagement forms the basis of its primary therapeutic applications. In combination with an estrogen, it is a widely prescribed oral contraceptive and is also indicated for the treatment of premenstrual dysphoric disorder (PMDD) and moderate acne vulgaris. As a progestin-only formulation, it offers an effective estrogen-free contraceptive option. The deliberate chemical design of drospirenone to possess antimineralocorticoid and antiandrogenic properties provides distinct clinical advantages, such as mitigating estrogen-induced fluid retention and addressing hyperandrogenic symptoms. However, this unique profile is intrinsically linked to its principal safety concerns. The drug has been the subject of extensive regulatory review regarding a contested but potentially elevated risk of venous thromboembolism (VTE) compared to older contraceptives. Furthermore, its antimineralocorticoid action creates a clear and predictable risk of hyperkalemia, particularly in susceptible populations or when co-administered with other potassium-sparing agents. Consequently, the clinical use of drospirenone necessitates a thorough, individualized assessment of benefits versus risks, demanding a sophisticated understanding of its pharmacology, contraindications, and potential for drug interactions.

II. Drug Identification and Developmental History

2.1 Nomenclature and Chemical Profile

Drospirenone is a small molecule synthetic steroid, classified as a progestin.[1] Its definitive chemical and regulatory identifiers are crucial for accurate scientific communication and database referencing. The primary generic name is Drospirenone, with the corresponding DrugBank Accession Number DB01395.[1] Its Chemical Abstracts Service (CAS) Registry Number is 67392-87-4.[2] The molecular formula of drospirenone is

C24​H30​O3​, with a molecular weight of approximately 366.50 g/mol.[3]

The systematic International Union of Pure and Applied Chemistry (IUPAC) name is (1R,2R,4R,10R,11S,14S,15S,16S,18S,19S)-10,14-dimethylspiro[hexacyclo[9.8.0.0$^{2,4}.0^{5,10}.0^{14,19}.0^{16,18}$]nonadec-5-ene-15,5'-oxolane]-2',7-dione.[2] Further chemical structure identifiers include the InChIKey (METQSPRSQINEEU-HXCATZOESA-N) and the canonical SMILES string (C[C@]12CCC(=O)C=C1[C@@H]3C[C@@H]3[C@@H]4[C@@H]2CC[C@]5([C@H]4[C@@H]6C[C@@H]6[C@@]57CCC(=O)O7)C).[2] Drospirenone is also known by alternate names such as Dihydrospirorenone, 1,2-dihydro Spirorenone, and ZK 30595.[3] A consolidated list of these identifiers is presented in Table 1.

Table 1: Chemical and Drug Identifiers for Drospirenone

Identifier Type	Value	Source(s)
Generic Name	Drospirenone	1
DrugBank ID	DB01395	1
Drug Type	Small Molecule	1
CAS Number	67392-87-4	2
Molecular Formula	C24​H30​O3​	2
Molecular Weight	366.50 g/mol	3
IUPAC Name	(1R,2R,4R,10R,11S,14S,15S,16S,18S,19S)-10,14-dimethylspiro[hexacyclo[9.8.0.0$^{2,4}.0^{5,10}.0^{14,19}.0^{16,18}$]nonadec-5-ene-15,5'-oxolane]-2',7-dione	2
InChIKey	METQSPRSQINEEU-HXCATZOESA-N	2
UNII	N295J34A25	2
ChEBI ID	CHEBI:50838	2
Alternate Names	Dihydrospirorenone, 1,2-dihydro Spirorenone, ZK 30595	3

2.2 Discovery, Development, and Regulatory Timeline

The development of drospirenone represents a significant example of purpose-driven medicinal chemistry aimed at creating a progestin with a more favorable side-effect profile than its predecessors. Its origin lies not in the modification of existing progestins, but in a research program focused on developing aldosterone antagonists.[6] Synthesized by Wiechert and coworkers at the pharmaceutical company Schering AG, drospirenone is a close chemical analog of the diuretic spironolactone.[6] This lineage is fundamental to its unique properties. The researchers' goal was to design a molecule that would not only possess potent progestogenic activity for contraception but would also retain the beneficial antimineralocorticoid and antiandrogenic properties of its parent compound. This approach was a direct response to the known drawbacks of earlier oral contraceptives. Older progestins, often derived from testosterone, could exhibit residual androgenic activity, leading to side effects like acne and hirsutism. Concurrently, the estrogen component in combined oral contraceptives (COCs) can stimulate the renin-angiotensin-aldosterone system, causing sodium and water retention, which manifests as bloating, weight gain, and potential increases in blood pressure.[8] By starting with a spironolactone scaffold, the chemists engineered a molecule that could actively counteract these undesirable effects.

Drospirenone was patented in 1976 and was first introduced for medical use in 2000 by Schering AG as a component of the combined oral contraceptive Yasmin®.[6] It is often referred to as a "fourth-generation" progestin, distinguishing it from earlier classes based on its unique pharmacological profile.[9] The regulatory journey in the United States saw key milestones for its combination product with ethinyl estradiol, Yaz®. It was first approved by the FDA for contraception on March 16, 2006. This was followed by strategic expansions of its indications to include the treatment of symptoms of PMDD in October 2006 and the treatment of moderate acne vulgaris in January 2007.[11] This development trajectory highlights a shift from a simple contraceptive to a multi-indication therapeutic agent.

The drug's evolution has continued with the approval of new formulations, including a combination with the novel estrogen estetrol (Nextstellis) and, significantly, as a progestin-only pill (POP) under the brand name Slynd.[1] This demonstrates its versatility and ongoing relevance in hormonal therapy. However, this purpose-driven design has also created a pharmacological paradox. The very antimineralocorticoid and antiandrogenic properties that provide its clinical advantages are inextricably linked to its unique safety concerns—namely, the risk of hyperkalemia and a debated, but potentially increased, risk of venous thromboembolism. This central tension between benefit and risk has defined its clinical use, regulatory history, and public perception since its introduction.

III. Comprehensive Pharmacological Profile

3.1 Mechanism of Action: A Multi-Receptor Engagement

Drospirenone exerts its physiological effects through high-affinity binding to several steroid hormone receptors. Unlike many other synthetic progestins, its activity is not limited to the progesterone receptor. Its pharmacological profile is characterized by a triad of effects:

1. Progestogenic Activity: It is a potent agonist of the progesterone receptor (PR), which is the primary mechanism for its contraceptive and endometrial-protective effects.[9]
2. Antimineralocorticoid Activity: It functions as a competitive antagonist at the mineralocorticoid receptor (MR), blocking the action of aldosterone.[1]
3. Antiandrogenic Activity: It also acts as an antagonist at the androgen receptor (AR), inhibiting the effects of androgens like testosterone and dihydrotestosterone (DHT).[1]

Importantly, drospirenone lacks any clinically significant estrogenic, glucocorticoid, or anti-glucocorticoid activity, resulting in a highly specific and "clean" pharmacological profile.[8] Its relative binding affinities for these receptors underscore its potency; it binds with high affinity to the PR and MR, and with moderate affinity to the AR.[5]

3.2 Progestogenic and Antigonadotropic Effects

The principal contraceptive action of drospirenone stems from its potent progestogenic and resulting antigonadotropic effects. By activating progesterone receptors in the hypothalamus and pituitary gland, drospirenone provides negative feedback on the hypothalamic-pituitary-ovarian (HPO) axis.[9] This feedback suppresses the pulsatile release of gonadotropin-releasing hormone (GnRH) and, consequently, inhibits the secretion of the pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH).[1]

The suppression of the mid-cycle LH surge is the critical event that prevents follicular maturation and the release of an egg (ovulation).[1] This is the primary mechanism by which drospirenone prevents pregnancy. In addition to ovulation inhibition, drospirenone contributes to its contraceptive efficacy through secondary mechanisms. It alters the consistency and quantity of cervical mucus, making it thicker and more viscous, which impedes the passage of sperm into the upper reproductive tract. It also induces changes in the endometrium, making it atrophic and less receptive to the implantation of a fertilized egg.[1]

3.3 Antimineralocorticoid Activity

A defining feature of drospirenone is its antimineralocorticoid activity, a direct consequence of its structural similarity to spironolactone.[7] By competitively antagonizing the mineralocorticoid receptor in the distal tubules of the kidney, drospirenone blocks the physiological effects of aldosterone.[8] Aldosterone normally promotes the reabsorption of sodium and water and the excretion of potassium. By inhibiting this action, drospirenone promotes the excretion of sodium and water (natriuresis), resulting in a mild diuretic effect.[7] The antimineralocorticoid potency of a 3 mg to 4 mg dose of drospirenone is considered comparable to that of a 20 mg to 25 mg dose of spironolactone.[9]

This property has significant clinical relevance in the context of combined oral contraceptives. The estrogen component (particularly ethinyl estradiol) can stimulate the renin-angiotensin-aldosterone system (RAAS), leading to increased aldosterone levels. This can cause sodium and water retention, which manifests as common side effects like bloating, breast tenderness, and weight gain.[8] Drospirenone's intrinsic antimineralocorticoid activity directly counteracts this estrogen-induced effect, which can lead to a neutral or even slight decrease in body weight and blood pressure, and an overall improvement in tolerability for many users.[8]

3.4 Antiandrogenic Activity

Drospirenone exerts its antiandrogenic effects through a dual mechanism of action, making it particularly effective for managing conditions driven by excess androgens.

First, through its central antigonadotropic effect, the suppression of LH secretion leads to reduced androgen synthesis by the theca cells of the ovaries.1 This decreases the overall production of androgens like testosterone.

Second, drospirenone acts as a direct competitive antagonist at the androgen receptor in peripheral tissues, such as the sebaceous glands of the skin.1 It competes with potent androgens like DHT for receptor binding, thereby preventing the cellular signaling that leads to increased sebum production and hirsutism.1

This combination of central suppression of androgen production and peripheral blockade of androgen action is the pharmacological basis for its FDA-approved indication for the treatment of moderate acne vulgaris and its widespread off-label use for hirsutism in conditions like polycystic ovary syndrome (PCOS).[1] This "clean progestin" profile, devoid of the intrinsic androgenicity of some older progestins, allows drospirenone-containing products to be marketed not just on their contraceptive efficacy but also on their ability to improve quality of life by actively treating common and distressing hormonal symptoms. This translated directly into a superior side-effect profile for many users, which became a key clinical advantage and drove its rapid adoption.

IV. Pharmacokinetic Characteristics

4.1 Absorption

Following oral administration, drospirenone is rapidly and nearly completely absorbed from the gastrointestinal tract. Maximum plasma concentrations (Cmax​) are typically achieved within 1 to 2 hours post-ingestion.[1] The absolute bioavailability of drospirenone is high, ranging from 76% to 85%. This indicates that while absorption is extensive, the drug does undergo a degree of first-pass metabolism.[1] The presence of food can influence the rate, but not the overall extent, of absorption. Studies have shown that administration with food can increase the

Cmax​ by approximately 30% but does not significantly alter the total drug exposure as measured by the area under the curve (AUC).[8] This finding suggests that drospirenone can be taken with or without food without a clinically relevant impact on its contraceptive efficacy.

4.2 Distribution

Drospirenone is widely distributed throughout the body, with an apparent volume of distribution (Vd​) of approximately 3.7 to 4.2 L/kg.[1] It is extensively bound to plasma proteins, with about 95% to 97% of the circulating drug bound, primarily to serum albumin.[1] A crucial pharmacokinetic feature of drospirenone is its lack of binding to sex hormone-binding globulin (SHBG) and corticoid-binding globulin (CBG).[1] Many other sex steroids are significantly bound to SHBG, which acts as a reservoir and limits the amount of free, active drug. Because drospirenone does not bind to SHBG, a higher proportion of the total drug concentration, approximately 3-5%, exists as a free and pharmacologically active steroid in the circulation.[1] This characteristic may contribute to its high potency at target receptors.

4.3 Metabolism

Drospirenone undergoes extensive metabolism, primarily in the liver, into pharmacologically inactive metabolites.[1] The two major metabolites identified are the acid form of drospirenone (M11), which is formed by the opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate (M14).[1] While drospirenone largely avoids significant first-pass metabolism by the cytochrome P450 system, it is a substrate for subsequent oxidative metabolism mediated by the CYP3A4 isoenzyme.[1] This metabolic pathway is a critical point of vulnerability for clinically significant drug interactions.

4.4 Excretion

The elimination of drospirenone and its metabolites occurs via both renal and fecal routes. The drug is almost completely cleared from the body approximately 10 days after the last dose, with negligible amounts of unchanged drospirenone found in either the urine or feces.[1] The metabolites are excreted in the urine (38-47%) and feces (17-20%), largely as glucuronide and sulfate conjugates.[1] Drospirenone has a long terminal elimination half-life (

t1/2​), which is estimated to be between 30 and 33 hours.[1] The half-life for the excretion of its metabolites is even longer, at approximately 40 hours.[1] This long half-life supports stable, therapeutic plasma concentrations with once-daily dosing, a key factor for maintaining reliable contraceptive efficacy. However, it also implies that in cases of impaired clearance, such as in patients with renal or hepatic disease, the drug and its physiological effects will persist for a longer duration, potentially increasing the risk of adverse events like hyperkalemia.

V. Clinical Efficacy and Therapeutic Applications

5.1 FDA-Approved Indications

Drospirenone's unique pharmacological profile has led to its approval for several distinct clinical indications, moving beyond simple contraception to targeted hormonal therapy.

• Oral Contraception: The primary indication for drospirenone is the prevention of pregnancy. It is approved for this use in various formulations, including as a combined oral contraceptive (COC) with the estrogens ethinyl estradiol or estetrol, and as a progestin-only pill (POP).[1] Large-scale clinical trials have demonstrated its high contraceptive efficacy, with Pearl Indices (a measure of contraceptive failure rates) that are comparable to other established oral contraceptives.[18]
• Premenstrual Dysphoric Disorder (PMDD): Drospirenone, in combination with a low dose of ethinyl estradiol (e.g., Yaz), is specifically indicated for the treatment of symptoms of PMDD in women who elect to use an oral contraceptive for birth control.[1] PMDD is a severe form of premenstrual syndrome characterized by significant mood and physical symptoms. The efficacy of drospirenone in PMDD is attributed to its ability to suppress the cyclical hormonal fluctuations that trigger symptoms, while its antimineralocorticoid activity helps to alleviate physical symptoms like bloating and water retention.[8]
• Moderate Acne Vulgaris: The same low-dose combination formulation is approved for the treatment of moderate acne in women aged 14 years and older who have achieved menarche and also desire contraception.[1] This indication directly leverages drospirenone's antiandrogenic properties, which reduce sebum production by both centrally suppressing ovarian androgen synthesis and peripherally blocking androgen receptors in the skin.[1]

5.2 Specialized and Other Approved Applications

• Menopausal Hormone Therapy (MHT): In combination with estradiol (e.g., Angeliq), drospirenone is approved to treat moderate to severe vasomotor symptoms (hot flashes) and vulvovaginal atrophy associated with menopause.[1] In these formulations, the estrogen component addresses the symptoms of estrogen deficiency, while the drospirenone component provides essential endometrial protection, preventing the risk of estrogen-induced endometrial hyperplasia and cancer.[9] Studies have also shown that this combination can improve bone mineral density and reduce fracture risk in postmenopausal women.[9]
• Progestin-Only Pill (POP): Marketed as Slynd, the 4 mg drospirenone-only formulation provides an effective estrogen-free contraceptive option.[9] Unlike traditional POPs that primarily work by altering cervical mucus, drospirenone's potent antigonadotropic effect allows it to consistently suppress ovulation, providing a higher level of efficacy.[10] This makes it a suitable option for women with contraindications to estrogen, such as those with a history of VTE, certain types of migraine, or during lactation.

5.3 Evaluation of Off-Label Uses

The distinct pharmacology of drospirenone has led to its widespread and evidence-supported off-label use for various gynecological and endocrine disorders.

• Polycystic Ovary Syndrome (PCOS) and Hirsutism: Drospirenone-containing COCs are frequently used off-label as a first-line treatment for managing the symptoms of PCOS.[1] PCOS is characterized by hyperandrogenism, ovulatory dysfunction, and metabolic disturbances. Drospirenone is particularly well-suited for this condition. Its potent antiandrogenic activity directly targets the distressing symptoms of hirsutism (excessive male-pattern hair growth) and acne, while its progestogenic effect regulates the menstrual cycle and provides endometrial protection.[23] Clinical studies have demonstrated that treatment with drospirenone/ethinyl estradiol significantly improves hirsutism scores, reduces acne, and normalizes hormonal profiles by lowering LH and free testosterone levels.[23] Patient reviews often report positive experiences with symptom control, including weight management and mood stabilization.[26]
• Other Gynecological Conditions: Drospirenone is also used off-label for the treatment of other hormone-sensitive conditions, including menstrual irregularities, dysmenorrhea (painful menstruation), and endometriosis.[1]

The clinical journey of drospirenone illustrates a strategic evolution from a primary contraceptive to a targeted therapeutic agent. The initial approval for contraception was followed by leveraging its unique pharmacological profile to secure value-added indications for PMDD and acne. This, in turn, allowed clinicians to recognize its utility for managing the core symptoms of PCOS. This progression has solidified its position as a first-line option for women who not only require contraception but also have co-existing conditions like PCOS, PMDD, or acne, marking a significant shift in clinical practice toward more holistic and symptom-focused hormonal management.

VI. Formulations, Dosage, and Administration

6.1 Marketed Formulations and Strengths

Drospirenone is available in several oral tablet formulations, both alone and in combination with estrogens, tailored to different therapeutic needs. The specific formulation dictates the dosing schedule and approved indications.

• Combined Oral Contraceptives (COCs):
• 3 mg Drospirenone / 0.03 mg Ethinyl Estradiol: Marketed under brand names such as Yasmin, Ocella, Syeda, and Zarah. These products typically follow a 21-day cycle of active tablets followed by a 7-day hormone-free (inert tablet) interval.[27]
• 3 mg Drospirenone / 0.02 mg Ethinyl Estradiol: Marketed under brand names such as Yaz, Gianvi, and Loryna. These formulations utilize a 24-day cycle of active tablets followed by a shortened 4-day hormone-free interval.[27]
• Progestin-Only Pill (POP):
• 4 mg Drospirenone: Marketed as Slynd. This formulation also uses a 24-day active tablet regimen followed by 4 days of inert tablets.[9]
• Menopausal Hormone Therapy (MHT):
• 0.25 mg Drospirenone / 0.5 mg Estradiol or 0.5 mg Drospirenone / 1 mg Estradiol: Marketed as Angeliq, these formulations are taken continuously without a hormone-free interval.[9]
• Other Combinations: Newer formulations include a combination with the estrogen estetrol (Nextstellis) and versions that incorporate supplemental folic acid (levomefolate calcium) to reduce the risk of neural tube defects in the event of contraceptive failure and subsequent pregnancy.[1]

Table 2: Marketed Formulations and Strengths of Drospirenone-Containing Products

Brand Name(s)	Drospirenone Dose	Estrogen Component & Dose	Dosing Schedule (Active/Inert Days)	Primary Approved Indications
Yasmin, Ocella, Syeda	3 mg	Ethinyl Estradiol 0.03 mg	21 / 7	Contraception
Yaz, Gianvi, Loryna	3 mg	Ethinyl Estradiol 0.02 mg	24 / 4	Contraception, PMDD, Moderate Acne
Slynd	4 mg	None	24 / 4	Contraception (Progestin-Only)
Angeliq	0.25 mg or 0.5 mg	Estradiol 0.5 mg or 1 mg	Continuous	Menopausal Symptoms
Nextstellis	3 mg	Estetrol 14.2 mg	24 / 4	Contraception

6.2 Dosing Regimens by Indication

For contraception, PMDD, and acne, the standard administration is one tablet taken orally at the same time each day, following the sequential order directed on the blister pack.[28] Consistency is key to efficacy. Therapy is typically initiated on the first day of the menstrual cycle or the first Sunday following the onset of menses. When starting for the first time or switching from another method, a non-hormonal backup contraceptive (e.g., condoms) is recommended for the first 7 days of the first cycle to ensure protection.[15] The development of the 24/4 dosing regimen was a deliberate example of formulation engineering. The shorter 4-day hormone-free interval, compared to the traditional 7 days, leads to more stable hormone levels throughout the month. This greater hormonal stability is particularly beneficial for suppressing the cyclical symptoms of PMDD more effectively.[27]

6.3 Considerations in Special Populations

• Adolescents: Drospirenone-containing products are approved for use in post-menarchal females aged 14 years and older for contraception and the treatment of moderate acne.[15]
• Renal and Hepatic Impairment: Drospirenone is strictly contraindicated in patients with renal impairment, hepatic impairment, or adrenal insufficiency. The risk of hyperkalemia is significantly increased in these populations due to impaired drug and potassium clearance.[10]
• Postpartum Period: Due to the physiologically elevated risk of venous thromboembolism in the postpartum period, initiation of combined hormonal contraceptives containing drospirenone should be delayed for at least 4 weeks after delivery in women who are not breastfeeding.[15]

The availability of multiple formulations with varying estrogen doses, as well as an estrogen-free option, allows for a high degree of therapy individualization. A clinician can select the most appropriate product based on the patient's primary indication, age, cardiovascular risk factors, and sensitivity to estrogen, facilitating a more personalized and safer approach to hormonal therapy.

VII. Safety and Tolerability Profile

7.1 Adverse Drug Reactions

The safety and tolerability profile of drospirenone is well-characterized, with a range of common and serious adverse effects.

• Common Adverse Effects (Incidence ≥1%): The most frequently reported side effects are related to hormonal fluctuations and physiological adjustments to the medication. These include irregular uterine bleeding (intermenstrual bleeding or spotting), particularly during the first three months of use. Other common effects are headache (including migraine), breast pain or tenderness, nausea, mood changes (including depression and emotional lability), and weight gain.[9] Acne and dysmenorrhea (menstrual cramps) may also occur.[32]
• Serious and Less Common Adverse Effects: Although less frequent, several serious adverse events are associated with drospirenone use.
• Vascular Events: The most significant risks are venous and arterial thromboembolic events, including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), and stroke.[1]
• Metabolic Effects: Hyperkalemia (elevated serum potassium) is a unique risk associated with drospirenone due to its antimineralocorticoid activity.[1]
• Hepatobiliary Effects: Liver injury, jaundice, and in rare cases, benign or malignant liver tumors have been reported.[20]
• Cardiovascular Effects: An increase in blood pressure (hypertension) can occur.[20]
• Other: Gallbladder disease, new or worsening migraine headaches, and severe depression are other potential serious side effects.[20]

7.2 Special Warning: Thromboembolic Risk Analysis

All combined oral contraceptives are known to increase the risk of venous thromboembolism (VTE). However, drospirenone-containing products have been subject to intense scrutiny and debate due to post-marketing epidemiological studies suggesting a potentially higher risk of VTE compared to COCs containing older progestins, such as levonorgestrel.[1]

The U.S. Food and Drug Administration (FDA) has reviewed numerous studies on this topic, which have yielded conflicting results. Some studies suggested a 1.5- to 3-fold increase in the risk of VTE for women using drospirenone-containing COCs, while other studies, some with methodological limitations or financial ties to the manufacturer, found no significant difference in risk.[36] This ambiguity created a "contested risk" narrative. After extensive review and advisory committee meetings, the FDA concluded in 2012 that a higher risk may exist and mandated that the drug labels for all drospirenone-containing COCs be updated with a strengthened warning to reflect this potential increased risk.[35]

It is critical to contextualize this risk. The absolute risk of VTE in users of any COC remains low. The FDA estimates the risk to be approximately 10 in 10,000 women per year for drospirenone users, compared to about 6 in 10,000 for users of levonorgestrel-containing COCs.[35] For perspective, this risk is still substantially lower than the risk of VTE during pregnancy and the immediate postpartum period.[1] This entire saga serves as a case study in pharmacovigilance, highlighting the difficulty in quantifying small increases in the risk of rare events and demonstrating how scientific uncertainty can directly influence prescribing patterns and public perception.

7.3 Special Warning: Hyperkalemia Risk

A distinct and predictable risk associated with drospirenone is hyperkalemia, a direct result of its antimineralocorticoid activity.[1] By blocking aldosterone receptors, drospirenone can impair the body's ability to excrete potassium, leading to elevated serum levels. This risk is most pronounced in patients with underlying conditions that predispose them to hyperkalemia, such as renal impairment, hepatic impairment, or adrenal insufficiency.[10] The risk is also amplified in patients taking concomitant medications that can increase serum potassium.

While clinical trials have shown that elevations in potassium are often mild, transient, and resolve even with continued treatment, cases of persistent hyperkalemia requiring drug discontinuation have been reported.[9] Therefore, monitoring of serum potassium levels is recommended in high-risk patients, particularly during the first cycle of treatment.[9]

7.4 Contraindications and High-Risk Populations

Given its safety profile, drospirenone is contraindicated in several patient populations.

• Absolute Contraindications:
• Renal impairment, hepatic impairment, or adrenal insufficiency.[17]
• A high risk of, or existing, arterial or venous thrombotic diseases (e.g., history of DVT/PE, stroke, MI).[17]
• Undiagnosed abnormal uterine bleeding.[17]
• Presence or history of breast cancer or other progestin-sensitive cancers.[17]
• Liver tumors (benign or malignant) or active liver disease.[17]
• Co-administration with certain Hepatitis C drug combinations (e.g., ombitasvir/paritaprevir/ritonavir) due to risk of liver enzyme elevations.[17]
• High-Risk Populations (Use with Precaution):
• Women over 35 years of age who smoke cigarettes.[1]
• Uncontrolled hypertension or diabetes with vascular complications.[15]
• History of depression, as hormonal changes may exacerbate the condition.[15]
• Women with known hypercoagulable states or a strong family history of thromboembolism.[15]

VIII. Clinically Significant Interactions

The potential for drug interactions with drospirenone is a critical consideration for safe prescribing, stemming from both its pharmacodynamic effects on potassium and its pharmacokinetic metabolism.

8.1 Pharmacodynamic Interactions (Increased Hyperkalemia Risk)

The most clinically significant interactions are those that potentiate drospirenone's risk of causing hyperkalemia. Co-administration with other drugs that increase serum potassium can lead to additive effects and potentially life-threatening electrolyte imbalances. This creates a "silent risk," as the interacting drugs are extremely common, leading to a high potential for unintentional and dangerous co-prescriptions. For example, a patient might be prescribed drospirenone by a gynecologist, an ACE inhibitor for hypertension by a primary care physician, and take over-the-counter NSAIDs for pain, creating a combination that significantly elevates hyperkalemia risk. This underscores the necessity of comprehensive medication reconciliation. Key interacting drug classes include:

• Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Blockers (ARBs): (e.g., lisinopril, captopril, losartan). These agents can increase serum potassium and should be used with caution and monitoring.[10]
• Potassium-Sparing Diuretics: (e.g., spironolactone, amiloride, triamterene). Co-administration is generally not recommended. Use with spironolactone constitutes a therapeutic duplication, as both drugs act as mineralocorticoid receptor antagonists.[10]
• Aldosterone Antagonists: (e.g., eplerenone).[45]
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Chronic, daily use of NSAIDs (e.g., ibuprofen, naproxen) can impair renal function and potassium excretion, increasing the risk.[9]
• Potassium Supplements: Should be used with extreme caution and medical supervision.[10]

8.2 Pharmacokinetic Interactions (Altered Drospirenone Levels)

Drospirenone is a substrate of the hepatic enzyme CYP3A4, making it susceptible to interactions with drugs that induce or inhibit this enzyme.

• CYP3A4 Inducers: Potent inducers can significantly increase the metabolism of drospirenone, leading to lower systemic concentrations. This can reduce its efficacy, potentially resulting in breakthrough bleeding and contraceptive failure. Examples include certain anticonvulsants (e.g., carbamazepine, phenytoin, barbiturates) and the herbal supplement St. John's Wort. Use of a non-hormonal backup contraceptive method is strongly recommended during and for 28 days after discontinuing the inducer.[10]
• CYP3A4 Inhibitors: Strong inhibitors can decrease the metabolism of drospirenone, leading to higher plasma levels. This can increase the risk of dose-dependent side effects, particularly hyperkalemia. Examples include azole antifungals (e.g., ketoconazole) and certain protease inhibitors.[10]

8.3 Food and Supplement Interactions

• Grapefruit Juice: As a known inhibitor of intestinal CYP3A4, grapefruit juice can increase the absorption and plasma levels of drospirenone and should be avoided.[15]
• St. John's Wort: This herbal supplement is a potent inducer of CYP3A4 and should not be used concurrently with drospirenone-containing contraceptives due to the high risk of contraceptive failure.[45]

Table 3: Major Drug Interactions with Drospirenone and Management Recommendations

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Outcome	Recommended Management Strategy
ACE Inhibitors, ARBs, Potassium-Sparing Diuretics, Aldosterone Antagonists, NSAIDs (chronic use), Potassium Supplements	Pharmacodynamic (Additive Effect)	Hyperkalemia	Avoid combination if possible. If necessary, monitor serum potassium levels, especially during initiation. Counsel patient on symptoms of hyperkalemia. Contraindicated in patients with renal impairment.
CYP3A4 Inducers (e.g., Carbamazepine, Phenytoin, St. John's Wort)	Pharmacokinetic (Increased Metabolism)	Decreased drospirenone levels, breakthrough bleeding, contraceptive failure	Avoid combination. If unavoidable, advise patient to use a reliable non-hormonal backup contraceptive method during and for 28 days after discontinuation of the inducer.
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Itraconazole)	Pharmacokinetic (Decreased Metabolism)	Increased drospirenone levels, increased risk of adverse effects (especially hyperkalemia)	Monitor for adverse effects. Consider monitoring serum potassium in high-risk patients.
Grapefruit Juice	Pharmacokinetic (CYP3A4 Inhibition)	Increased drospirenone levels	Advise patient to avoid consumption of grapefruit and grapefruit juice.

IX. Clinical Evidence and Future Directions

9.1 Review of Pivotal Clinical Trials

The regulatory approval of drospirenone for contraception was supported by a series of large, multicenter Phase III clinical trials designed to establish its efficacy and safety. Key studies include CF111/301 and CF111/302 (conducted in Europe) and CF111/303 (conducted in the U.S.).[10] These trials evaluated drospirenone-only formulations (4 mg/day in a 24/4 regimen) in thousands of women.

The primary endpoint was contraceptive efficacy, measured by the Pearl Index (pregnancies per 100 woman-years of use). A pooled analysis of the two European studies involving 1,571 women and over 14,000 exposure cycles yielded an overall Pearl Index of 0.73, demonstrating contraceptive efficacy similar to established COCs.[19] The U.S. study (CF111/303) reported a slightly higher Pearl Index of 4.0 in the primary efficacy group (women ≤35 years old), which still falls within the accepted range for oral contraceptives.[10]

The safety data from these trials were crucial. No cases of VTE were reported in the clinical development program for the progestin-only pill.[10] Hyperkalemia was observed, but events were generally mild, isolated, and often returned to normal despite continued treatment. However, a small number of subjects did withdraw from the trials due to persistently elevated potassium levels.[9] A notable limitation of some trials, particularly the U.S. study, was a high rate of premature discontinuation (65% in CF111/303), with common reasons being lost to follow-up, withdrawal of consent, and adverse events like irregular bleeding.[10]

9.2 Emerging Research and Ongoing Clinical Trials

Current research on drospirenone is shifting from establishing its primary efficacy to exploring its unique pharmacological properties for specialized, niche applications in reproductive endocrinology and beyond. This suggests an evolution toward mechanism-based therapeutic expansion.

• Novel Applications:
• Emergency Contraception: A pilot study (NCT05675644) is actively investigating a single, high dose of drospirenone as a novel form of emergency contraception. This research aims to leverage its potent ovulation-inhibiting properties for a single-use application, potentially offering a new option for patients, including those with higher body mass index (BMI).[46]
• Controlled Ovarian Stimulation in PCOS: A clinical trial (NCT06608186) is evaluating whether drospirenone can be used to prevent a premature LH surge in women with PCOS who are undergoing assisted reproductive technology (ART) cycles. This repurposes its HPO-axis suppression from a contraceptive tool to one that could improve control and outcomes in fertility treatments.[47]
• Hidradenitis Suppurativa (HS): A completed study (NCT00722800) investigated the efficacy of a drospirenone-containing COC for treating HS, a chronic inflammatory skin disease with hormonal triggers. This explores the therapeutic potential of its antiandrogenic properties for a dermatological condition beyond moderate acne.[48]
• Bioequivalence Studies: As with many established drugs, ongoing trials (e.g., NCT06233058) continue to be conducted to compare the pharmacokinetic profiles of new generic formulations against the original reference brand-name products (e.g., Yasmin®) to ensure therapeutic equivalence.[49]

This trend in research suggests a potential "second life" for drospirenone. Having established its role as a mainstream contraceptive, researchers are now deconstructing its pharmacology to solve specific clinical problems. Success in these areas could significantly expand its therapeutic scope, solidifying its position as a uniquely versatile progestin in the armamentarium of reproductive endocrinologists, fertility specialists, and dermatologists.

X. Expert Synthesis and Conclusion

Drospirenone represents a significant and deliberate advancement in the field of synthetic progestins. Its development, rooted in the modification of an aldosterone antagonist, was a clear example of rational drug design aimed at overcoming the limitations of its predecessors. The resulting molecule possesses a unique and clinically valuable pharmacological profile, combining potent progestogenic activity with beneficial antimineralocorticoid and antiandrogenic effects. This has allowed drospirenone-containing products to evolve from simple contraceptives into targeted therapies for conditions such as premenstrual dysphoric disorder, moderate acne, and, through widespread off-label use, polycystic ovary syndrome. For many patients, this translates into improved symptom control, better tolerability, and enhanced quality of life compared to older hormonal options.

However, the clinical narrative of drospirenone is defined by a central pharmacological paradox: its greatest therapeutic strengths are inextricably linked to its most significant safety risks. The antimineralocorticoid activity that mitigates bloating and fluid retention is the same mechanism that creates a clear, predictable risk of hyperkalemia. Its unique progestogenic structure has been at the center of a protracted and complex regulatory debate regarding a potential, though not definitively proven, increase in the risk of venous thromboembolism.

Therefore, the place of drospirenone in modern pharmacotherapy is that of a highly effective but specialized tool that demands careful and informed clinical judgment. Its prescription cannot be routine; it requires a thorough, individualized risk-benefit analysis for each patient. This includes meticulous screening for contraindications, particularly renal, hepatic, and adrenal disease, as well as a detailed assessment of cardiovascular and thromboembolic risk factors. Furthermore, diligent review of all concomitant medications is paramount to avoid the potentially severe consequences of drug interactions, especially those that can precipitate hyperkalemia.

In conclusion, when used appropriately in a carefully selected patient population without contraindications, drospirenone remains a valuable and often superior therapeutic agent. Its ability to provide comprehensive symptom management in addition to contraception solidifies its important role in women's health. However, its safe and effective use is contingent upon the prescribing clinician's deep understanding of its unique benefits, its distinct risks, and the precise patient profiles for which it is best suited.

Works cited

1. Drospirenone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 22, 2025, https://go.drugbank.com/drugs/DB01395
2. Drospirenone | C24H30O3 | CID 68873 - PubChem, accessed August 22, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Drospirenone
3. Drospirenone | CAS 67392-87-4 | SCBT - Santa Cruz Biotechnology, accessed August 22, 2025, https://www.scbt.com/p/drospirenone-67392-87-4
4. Drospirenone - CAS Common Chemistry, accessed August 22, 2025, https://commonchemistry.cas.org/detail?ref=67392-87-4
5. Drospirenone (1,2-dihydro Spirorenone, ZK 30595, CAS Number: 67392-87-4), accessed August 22, 2025, https://www.caymanchem.com/product/23347/drospirenone
6. The History of Drospirenone - ResearchGate, accessed August 22, 2025, https://www.researchgate.net/publication/287855806_The_History_of_Drospirenone
7. go.drugbank.com, accessed August 22, 2025, https://go.drugbank.com/drugs/DB01395#:~:text=Drospirenone%20is%20an%20analog%20of,increases%20sodium%20and%20water%20excretion.&text=Studies%20in%20animals%20have%20demonstrated%20that%20drospirenone%20administration%20leads%20to%20antiandrogenic%20activity.
8. Drospirenone: Pharmacology and pharmacokinetics of a unique progestogen, accessed August 22, 2025, https://www.researchgate.net/publication/12300054_Drospirenone_Pharmacology_and_pharmacokinetics_of_a_unique_progestogen
9. Drospirenone - Wikipedia, accessed August 22, 2025, https://en.wikipedia.org/wiki/Drospirenone
10. Drospirenone (SLYND) National Drug Monograph March 2022 - VA.gov, accessed August 22, 2025, https://www.va.gov/formularyadvisor/DOC_PDF/MON_Drosperinone_SLYND_Mar2022.pdf
11. Yaz (drospirenone and ethinyl estradiol) FDA Approval History - Drugs.com, accessed August 22, 2025, https://www.drugs.com/history/yaz.html
12. go.drugbank.com, accessed August 22, 2025, https://go.drugbank.com/drugs/DB01395#:~:text=Off%2Dlabel%20uses%20for%20this,dysmenorrhea%2C%20hirsutism%2C%20and%20endometriosis.&text=Drospirenone%20inhibits%20the%20maturation%20of,effects%2C%20improving%20acne%20and%20hirsutism.
13. Pharmacological and metabolic effects of drospirenone as a progestin-only pill compared to combined formulations with estrogen - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9905034/
14. Pharmacology of Drospirenone ; Pharmacokinetics, Mechanism of Action, Uses, Effects, accessed August 22, 2025, https://www.youtube.com/watch?v=E1KPQyRS0dw
15. Drospirenone and ethinyl estradiol (oral route) - Side effects & dosage - Mayo Clinic, accessed August 22, 2025, https://www.mayoclinic.org/drugs-supplements/drospirenone-and-ethinyl-estradiol-oral-route/description/drg-20061917
16. Drospirenone (oral route) - Side effects & dosage - Mayo Clinic, accessed August 22, 2025, https://www.mayoclinic.org/drugs-supplements/drospirenone-oral-route/description/drg-20465072
17. This label may not be the latest approved by FDA. For current ..., accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021676s020lbl.pdf
18. Clinical Review - Drospirenone (Slynd) - NCBI Bookshelf, accessed August 22, 2025, https://www.ncbi.nlm.nih.gov/books/NBK606557/
19. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/31321765/
20. Drospirenone; Ethinyl Estradiol Tablets - Cleveland Clinic, accessed August 22, 2025, https://my.clevelandclinic.org/health/drugs/20645-drospirenone-ethinyl-estradiol-tablets
21. Drospirenone and estradiol (oral route) - Side effects & dosage - Mayo Clinic, accessed August 22, 2025, https://www.mayoclinic.org/drugs-supplements/drospirenone-and-estradiol-oral-route/description/drg-20063089
22. Table 4, Summary of Drug Plan Input and Clinical Expert Responses - Drospirenone (Slynd), accessed August 22, 2025, https://www.ncbi.nlm.nih.gov/books/NBK606557/table/tr8269868382080682_ch01_t04/?report=objectonly
23. Drospirenone for the Treatment of Hirsute Women with Polycystic ..., accessed August 22, 2025, https://www.researchgate.net/publication/8525986_Drospirenone_for_the_Treatment_of_Hirsute_Women_with_Polycystic_Ovary_Syndrome_A_Clinical_Endocrinological_Metabolic_Pilot_Study
24. Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome - PMC - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2504056/
25. A Review of Polycystic Ovary Syndrome Treatment - U.S. Pharmacist, accessed August 22, 2025, https://www.uspharmacist.com/article/a-review-of-polycystic-ovary-syndrome-treatment
26. Drospirenone/ethinyl estradiol for Polycystic Ovary Syndrome Reviews - Drugs.com, accessed August 22, 2025, https://www.drugs.com/comments/drospirenone-ethinyl-estradiol/for-polycystic-ovary-syndrome.html
27. Drospirenone/ Ethinyl Estradiol: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 22, 2025, https://www.rxlist.com/drospirenone__ethinyl_estradiol/generic-drug.htm
28. Yasmin, Yaz (drospirenone/ethinyl estradiol) dosing, indications ..., accessed August 22, 2025, https://reference.medscape.com/drug/yasmin-yaz-drospirenone-ethinyl-estradiol-342768
29. Drospirenone/ethinyl estradiol/levomefolate calcium Interactions - Drugs.com, accessed August 22, 2025, https://www.drugs.com/drug-interactions/drospirenone-ethinyl-estradiol-levomefolate-calcium.html
30. Drospirenone / Ethinyl Estradiol Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 22, 2025, https://www.drugs.com/dosage/drospirenone-ethinyl-estradiol.html
31. Drospirenone: Side Effects, Uses, Dosage, Interactions, Warnings, accessed August 22, 2025, https://www.rxlist.com/drospirenone/generic-drug.htm
32. Drospirenone tablets (contraception) - Cleveland Clinic, accessed August 22, 2025, https://my.clevelandclinic.org/health/drugs/21324-drospirenone-tablets
33. Drospirenone (Slynd): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 22, 2025, https://www.webmd.com/drugs/2/drug-177410/slynd-oral/details
34. Drospirenone / Ethinyl Estradiol Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 22, 2025, https://www.drugs.com/sfx/drospirenone-ethinyl-estradiol-side-effects.html
35. Yaz and Other Oral Contraceptives Will Carry a New Warning Label, accessed August 22, 2025, https://womensmentalhealth.org/posts/yaz-and-other-oral-contraceptives-will-carry-a-new-warning-label/
36. Are Some Birth Control Pills Too Risky? - National Center for Health ..., accessed August 22, 2025, https://www.center4research.org/birth-control-pills-risky/
37. Update on drospirenone-containing birth control pills a. FDA Drug Safety Communication, accessed August 22, 2025, https://www.drugoffice.gov.hk/eps/upload/eps_news/15205/ZH/1/Update%20on%20drospirenone-containing%20birth%20control%20pills.pdf
38. The association between drospirenone and hyperkalemia: a comparative-safety study, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3265420/
39. Drospirenone/Ethinyl estradiol: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 22, 2025, https://www.webmd.com/drugs/2/drug-21091-5115/drospirenone-ethinyl-estradiol-oral/ethinyl-estradiol-drospirenone-oral/details
40. The concomitant prescribing of ethinyl estradiol/drospirenone and potentially interacting drugs - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/17900437/
41. Slynd (drospirenone) dosing, indications, interactions, adverse ..., accessed August 22, 2025, https://reference.medscape.com/drug/slynd-drospirenone-100052
42. Drospirenone and spironolactone Interactions - Drugs.com, accessed August 22, 2025, https://www.drugs.com/drug-interactions/drospirenone-with-spironolactone-4018-0-2105-0.html
43. Drospirenone-Containing Birth Control Pills (Yaz, Yasmin, Ocella, Gianvi and their generics), accessed August 22, 2025, https://www.medovate.io/wp-content/uploads/2020/02/Yaz.pdf
44. Drug Interaction Report: drospirenone, spironolactone - Drugs.com, accessed August 22, 2025, https://www.drugs.com/interactions-check.php?drug_list=4018-0,2105-0&professional=1
45. Yaz interactions: Alcohol, medications, and other factors, accessed August 22, 2025, https://www.medicalnewstoday.com/articles/drugs-yaz-interactions
46. Study Details | Drospirenone-only Pill as Emergency Contraception ..., accessed August 22, 2025, https://clinicaltrials.gov/study/NCT05675644
47. Study Details | Can Drospirenone be Used to Prevent LH Surge in Controlled Ovarian Stimulation in PCOS?! | ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT06608186?term=AREA%5BConditionSearch%5D(%22Ovarian%20Disease%22)%20AND%20AREA%5BInterventionSearch%5D(%22mineralocorticoid%20receptor%20antagonists%22)&rank=6
48. A Study to Examine the Safety and Efficacy of Drospirenone and Ethinyl Estradiol (YAZ) Versus Placebo In HS | ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT00722800
49. Study Details | Drospirenone (3 mg) + Ethinyl Estradiol (0.03 mg) Tablets Relative to Yasmin, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT06233058