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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
| Breastfeeding | Excreted in human breast milk (ethinyl estradiol and drospirenone). Reduced milk production and quality; potential for estrogenic effects in infant, including gynecomastia. M/P ratio not well established. Contraindicated during breastfeeding. |
| 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. |
■ 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 |
["Thrombophlebitis or thromboembolic disorders","Cerebrovascular or coronary artery disease","Known or suspected pregnancy","Undiagnosed abnormal uterine bleeding","Breast cancer or other estrogen-sensitive neoplasia","Hepatic adenoma or carcinoma","Active liver disease with abnormal liver function","Renal impairment with serum creatinine ≥1.7 mg/dL","Adrenal insufficiency","Diabetes with vascular involvement","Uncontrolled hypertension","Migraine with focal aura at any age"]
| 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…
| 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. |