drospirenone and estetrol
Regulatory sources consulted
Approved indications
- Oral contraception after individual assessment of risk factors, particularly venous thromboembolism.
Contraindications
Absolute
- Current, previous, or high risk of venous or arterial thromboembolism; thrombophilia; major surgery with immobilization; migraine with aura; vascular diabetes, severe hypertension, or severe dyslipidemia.
- Severe liver disease, liver tumor, severe renal impairment, or acute renal failure.
- Sex-hormone-dependent tumor, undiagnosed vaginal bleeding, pregnancy, or hypersensitivity.
Clinical warnings
- Major warning · Every combined hormonal contraceptive increases venous and arterial thromboembolism risk. It is not known how the risk with estetrol/drospirenone compares with lower-risk combined contraceptives containing low-dose levonorgestrel. Discontinue if suspected or confirmed and before major surgery with immobilization as clinically planned. — CIMA/AEMPS, ficha técnica 1211547001
- Major warning · Drospirenone may cause hyperkalemia; monitor potassium when renal risk is present or potassium-raising medicines are used. — CIMA/AEMPS, ficha técnica 1211547001
Drug interactions
- HighEnzyme inducers such as rifampicin, carbamazepine, phenytoin, topiramate, or St John’s wort
Mechanism: They increase hormone clearance and may cause bleeding or contraceptive failure.
Recommendation: Use a barrier method during treatment and for 28 days afterward; for long-term use, choose a reliable nonhormonal method.
CIMA/AEMPS, ficha técnica 1211547001https://cima.aemps.es/cima/dochtml/ft/1211547001/FT_1211547001.html
- ModeratePotassium-raising medicines
Mechanism: They may increase drospirenone-related hyperkalemia risk.
Recommendation: Assess baseline potassium and monitor according to risk.
CIMA/AEMPS, ficha técnica 1211547001https://cima.aemps.es/cima/dochtml/ft/1211547001/FT_1211547001.html
- HighLamotrigineN03AX09
Mechanism: Oral contraceptives may decrease plasma and tissue lamotrigine concentrations.
Recommendation: Monitor clinical control and review antiseizure treatment when starting or stopping the contraceptive.
CIMA/AEMPS, ficha técnica 1211547001https://cima.aemps.es/cima/dochtml/ft/1211547001/FT_1211547001.html
- ModerateCyclosporineL04AD01
Mechanism: Oral contraceptives may increase plasma and tissue cyclosporine concentrations.
Recommendation: Monitor cyclosporine concentrations and toxicity and adjust with the clinical team if needed.
CIMA/AEMPS, ficha técnica 1211547001https://cima.aemps.es/cima/dochtml/ft/1211547001/FT_1211547001.html
Adverse events
Common (≥1%)
Breakthrough or vaginal bleeding · Headache · Acne · Dysmenorrhea
Rare but serious
Venous or arterial thromboembolism · Hyperkalemia · Liver tumor
Pregnancy and lactation
It is not indicated during pregnancy; discontinue if pregnancy occurs. It is not recommended while breastfeeding because it may reduce milk quantity and alter its composition; offer an alternative method until breastfeeding ends.
Recent literature (PubMed)
The spironolactone derivative drospirenone is combined with ethinylestradiol or estetrol in combined oral contraceptives. Formulations with 17-β-estradiol are used to treat climacteric symptoms. A drospirenone-only formulation has been introduced for contraception. Here, the pharmacological properties of drospirenone, the impact of the different formulations on metabolic and laboratory parameters, and the resulting clinical implications are reviewed. Ethinylestradiol, an inhibitor of CYP metabolic enzymes, changes the pharmacokinetics of drospirenone, leading to a higher drospirenone exposure with ethinylestradiol/drospirenone compared to the drospirenone-only preparation. In addition, several metabolic alterations have been described. The impact of estetrol is less pronounced, and for 17-β-estradiol/drospirenone and drospirenone-only, decreased triglyceride and cholesterol levels were observed. Ethinylestradiol induces various pro-coagulatory factors, leading to hypercoagulability. The effect is significantly reduced with estetrol, and no influence was observed with the drospirenone-only preparation. The anti-mineralocorticoid activity of drospirenone seems to positively counteract the renin-angiotensin-aldosterone-system-activating action of ethinylestradiol. There is no influence on blood pressure with ethinylestradiol/drospirenone and estetrol/drospirenone formulations, while in clinical trials, a reduction has been observed with 17-β-estradiol/drospirenone and drospirenone-only. Anti-aldosterone activity via non-renal mineralocorticoid receptors is associated with cardiovascular health, while interactions with parathyroid hormone signaling impact bone structure and vascular calcification. Though the clinical relevance is unclear for drospirenone, data in this context are reviewed. To sum up, the advantages of drospirenone in hormonal contraception and treatment of menopausal symptoms have been demonstrated for all the formulations described here. Combination wi
Estetrol (E4) is a native estrogen produced only by the fetal liver during pregnancy. E4 is the first new estrogen to be used in hormonal contraception since the introduction of oral contraceptives in 1960. Ethinyl estradiol, the most commonly used estrogen in oral contraceptives today, increases the risks of thromboembolism and has other significant hepatic impacts, which induce important drug-drug interactions. On the other hand, Phase 2 E4 characterization studies demonstrated that E4 has negligible impacts on liver, breast, and vascular endothelium due to its distinct tissue selectivity. Combined with drospirenone (DRSP), E4 offers an improved safety profile for oral contraception. This paper briefly highlights the unique pharmacokinetic and pharmacodynamic features of E4. The efficacy, safety, and tolerability results from the Phase 2 and 3 studies of the E4/DRSP pill are discussed to provide the reader with a thorough understanding of E4 and information to use when counseling potential users. The estetrol/drospirenone oral contraceptive is effective and well tolerated and provides good cycle control. In the future, estetrol may be the estrogen of choice if subsequent evidence verifies that it reduces the risks associated with current estrogens, such as venous thromboembolism and drug-drug interactions.