DROSPIRENONE, ETHINYL ESTRADIOL AND LEVOMEFOLATE CALCIUM
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Combination of drospirenone (a progestin with antimineralocorticoid and antiandrogenic activity), ethinyl estradiol (an estrogen), and levomefolate calcium (a folate supplement). Prevents ovulation by suppressing gonadotropins; increases cervical mucus viscosity, inhibiting sperm penetration; levomefolate provides folate to reduce neural tube defect risk.
| Metabolism | Ethinyl estradiol is metabolized primarily by CYP3A4; drospirenone is metabolized by CYP3A4 and to a minor extent by CYP1A1 and CYP2C9; levomefolate calcium is converted to active folate forms (5-methyltetrahydrofolate). |
| Excretion | Drospirenone: ~50% renal (as metabolites), ~40% fecal. Ethinyl estradiol: ~40% renal, ~60% fecal. Levomefolate calcium: ~70% renal (as folate metabolites), ~30% fecal. |
| Half-life | Drospirenone: ~30 hours (steady state achieved after 8 days). Ethinyl estradiol: ~13-17 hours (biphasic, terminal). Levomefolate calcium: ~4-6 hours (folate derivatives have longer retention). |
| Protein binding | Drospirenone: 95-97% (albumin, not SHBG). Ethinyl estradiol: 98% (albumin). Levomefolate calcium: ~60-70% (albumin and folate binding proteins). |
| Volume of Distribution | Drospirenone: 4.3 L/kg. Ethinyl estradiol: 2.8-3.4 L/kg. Levomefolate calcium: 0.6-1.0 L/kg (folate concentrates in tissues). |
| Bioavailability | Drospirenone: ~76% (oral). Ethinyl estradiol: ~45% (first-pass metabolism). Levomefolate calcium: ~90% (oral, as folate). |
| Onset of Action | Oral: contraceptive effect requires 7 days of consistent dosing. Folate levels increase within days; full effect on homocysteine in 2-4 weeks. |
| Duration of Action | Contraceptive effect persists for 24 hours; consistent daily dosing required. Folate levels decline after discontinuation within 1-2 weeks. |
| Molecular Weight | Drospirenone: 366.5 Da; Ethinyl estradiol: 296.4 Da; Levomefolate calcium: 497.5 Da. Combination average molecular weight not applicable. |
One tablet orally once daily for 28 days (21 active tablets containing drospirenone 3 mg, ethinyl estradiol 0.02 mg, and levomefolate calcium 0.451 mg, followed by 7 placebo tablets containing levomefolate calcium 0.451 mg).
| Dosage form | TABLET |
| Renal impairment | Contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or acute renal failure. For mild to moderate impairment (CrCl 30-49 mL/min), use with caution due to potential for hyperkalemia; consider monitoring serum potassium. |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh C). For mild to moderate impairment (Child-Pugh A or B), use with caution and monitor liver function. |
| Pediatric use | Safety and efficacy in pediatric patients below menarche have not been established. For post-menarche adolescents, dosing is the same as for adults. |
| Geriatric use | Not indicated for use in postmenopausal women due to lack of efficacy and potential risks. |
| 1st trimester | Contraindicated; use during the first trimester is associated with an increased risk of neural tube defects and other congenital anomalies due to levomefolate calcium being a folate analog, though folate itself is protective, the combination with drospirenone and ethinyl estradiol carries risks of cardiovascular and other malformations. |
| 2nd trimester | Contraindicated; may cause fetal harm. Use during the second trimester may be associated with adverse fetal outcomes, including potential androgenizing effects from progestin and estrogenic effects. |
| 3rd trimester | Contraindicated; use during the third trimester is associated with adverse fetal and neonatal outcomes, including potential withdrawal bleeding, and long-term effects from hormonal exposure. |
Clinical note
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
| Placental transfer | Drospirenone and ethinyl estradiol cross the placenta; levomefolate calcium also crosses. Evidence: significant placental transfer demonstrated for ethinyl estradiol and drospirenone. Levomefolate calcium is a folate derivative and crosses via folate receptors. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Risk increases with age (>35) and heavy smoking (≥15 cigarettes/day). Women over 35 should not use combination oral contraceptives if they smoke.
| Common Effects | osteoporosis prevention |
| Serious Effects |
PregnancyBreast cancer or history thereofEstrogen-dependent neoplasiaActive venous thromboembolic diseaseCerebrovascular or coronary artery diseaseUncontrolled hypertensionDiabetes with vascular involvementSevere hepatic disease or liver tumorsRenal impairment (e.g., creatinine clearance < 30 mL/min)Adrenal insufficiencyHypersensitivity to any componentUse with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir
| Precautions | Increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE), Increased risk of myocardial infarction and stroke in smokers, Increased blood pressure, Gallbladder disease, Hepatic neoplasia, Glucose intolerance, Fetal harm if used during pregnancy (should be discontinued immediately), Hereditary angioedema exacerbation, Chloasma may occur, Hyperkalemia risk due to drospirenone's antimineralocorticoid activity, especially in patients with renal impairment, hepatic disease, or adrenal insufficiency |
Loading safety data…
| Breastfeeding | Drospirenone and ethinyl estradiol are excreted in breast milk in small amounts; levomefolate calcium is likely excreted. Use during breastfeeding may reduce milk production and quality, and affect infant hormonal balance. Generally not recommended; alternative contraceptives preferred. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Pregnancy category X. First trimester: Major congenital malformations (neural tube defects, cardiovascular anomalies) due to ethinyl estradiol and drospirenone; levomefolate calcium may reduce risk if initiated periconceptionally but combination is contraindicated. Second and third trimesters: Fetal harm, including feminization of male fetus (antiandrogenic effect of drospirenone) and potential estrogenic effects; metabolic acidosis from drospirenone-induced hyperkalemia. Avoid use in pregnancy. |
| Fetal Monitoring | If inadvertent exposure during pregnancy, monitor: fetal ultrasound for congenital anomalies, maternal serum potassium (due to drospirenone's antimineralocorticoid effect), and fetal growth. No routine monitoring for bleeding due to contraindication. |
| Fertility Effects | Suppresses ovulation via combined estrogen-progestin mechanism. Rapid return to ovulation upon discontinuation. Levomefolate calcium supports folate levels for fetal neural tube development. No known permanent negative effects on fertility. |
| Food/Dietary | No specific food interactions. Grapefruit juice may slightly increase ethinyl estradiol levels but not clinically significant. Avoid high-potassium foods (e.g., bananas, oranges, salt substitutes) only if renal impairment or concomitant use of potassium-sparing diuretics. Take with or without food. |
| Clinical Pearls | Contains drospirenone (a spironolactone analog with antimineralocorticoid activity), ethinyl estradiol, and levomefolate calcium (the calcium salt of the active metabolite of folic acid). The folate component is intended to reduce the risk of neural tube defects in case of pregnancy. Monitor serum potassium in women with renal impairment, hepatic disease, or adrenal insufficiency due to drospirenone's potassium-sparing effects. The risk of venous thromboembolism (VTE) is increased, especially in smokers over 35. Discontinue 4 weeks before elective surgery with prolonged immobilization. |
| Patient Advice | Take one tablet daily at the same time, in the order indicated on the blister pack. · Do not smoke cigarettes; smoking increases the risk of serious cardiovascular side effects, especially if you are over 35. · This medication does not protect against HIV or other sexually transmitted diseases. · If you miss a dose, follow the instructions in the package insert; use backup contraception if needed. · Contact your healthcare provider immediately if you experience leg pain/swelling, sudden shortness of breath, chest pain, severe headache, vision changes, or jaundice. |