DROSPIRENONE AND ETHINYL ESTRADIOL
Clinical safety rating: avoid
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
Drospirenone is a spironolactone analogue with anti-mineralocorticoid and anti-androgenic activity. It suppresses gonadotropin secretion, inhibiting ovulation. Ethinyl estradiol provides negative feedback on LH and FSH, preventing follicular development and ovulation.
| Metabolism | Drospirenone is extensively metabolized by CYP3A4, forming inactive metabolites. Ethinyl estradiol is metabolized by CYP3A4 and undergoes sulfation and glucuronidation. |
| Excretion | Drospirenone: ~40-50% renal (as glucuronide conjugates), ~50-60% fecal. Ethinyl estradiol: ~40% renal, ~60% fecal, primarily as glucuronide and sulfate conjugates. |
| Half-life | Drospirenone: approximately 30-35 hours (terminal), allowing once-daily dosing. Ethinyl estradiol: approximately 13-20 hours (terminal), supporting daily administration. |
| Protein binding | Drospirenone: 95-97% bound to albumin, not to sex hormone-binding globulin (SHBG). Ethinyl estradiol: approximately 97-98% bound to albumin and induces SHBG synthesis. |
| Volume of Distribution | Drospirenone: approximately 2.7 L/kg. Ethinyl estradiol: approximately 2.8 L/kg. Reflects extensive distribution into tissues, with a Vd of ~200 L for EE in a 70 kg adult. |
| Bioavailability | Oral: Drospirenone ~76% (absolute); Ethinyl estradiol ~55% (absolute) due to first-pass metabolism; both subject to interindividual variability. |
| Onset of Action | Oral: Contraceptive effect requires 7 days of continuous dosing to achieve sufficient ovarian suppression. Therapeutic effects (e.g., cycle control) may begin after 1-2 cycles. |
| Duration of Action | Contraceptive efficacy persists for 24 hours after each dose; missed dose guidelines reflect this. Steady-state reached within 7-10 days of daily dosing. |
One tablet (drospirenone 3 mg/ethinyl estradiol 0.02 mg or 0.03 mg) orally once daily for 21 days followed by 7 days of placebo, or 24 active tablets followed by 4 placebo tablets depending on formulation.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) due to risk of hyperkalemia. No dose adjustment required for mild-to-moderate impairment (eGFR 30-89). |
| Liver impairment | Contraindicated in Child-Pugh class B or C (moderate to severe hepatic impairment). Use with caution in Child-Pugh class A; consider alternative therapy. |
| Pediatric use | Approved for use only post-menarche. Dose same as adult: one tablet daily. No weight-based dosing; contraindicated in females with Tanner stage <4 or body weight <35 kg. |
| Geriatric use | Not indicated for use in postmenopausal women. Contraindicated in women over 35 years of age who smoke ≥15 cigarettes/day. Use lowest effective estrogen dose if prescribed off-label. |
| 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.
| FDA category | Positive |
| Breastfeeding | Contraindicated in breastfeeding. Drospirenone and ethinyl estradiol are excreted in human milk. M/P ratio for ethinyl estradiol is approximately 0.39. May reduce milk production and quality; potential adverse effects on infant development. |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy. First trimester: Increased risk of neural tube defects, cardiovascular anomalies, and limb reduction defects from ethinyl estradiol. Second and third trimesters: Potential for feminization of male fetus from antiandrogenic effects of drospirenone; risk of liver tumors and VACTERL associations. Postnatal effects: Possible long-term reproductive tract abnormalities. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day). Women over 35 who smoke should not use this product.
| Common Effects | Nausea Diarrhea Constipation Heartburn Indigestion Urine discoloration |
| Serious Effects |
Renal impairment (creatinine clearance <30 mL/min); hepatic impairment; adrenal insufficiency; known or suspected pregnancy; current or past thrombosis (venous or arterial); cerebrovascular or coronary artery disease; valvular heart disease with complications; thrombogenic arrhythmias; uncontrolled hypertension (BP >160/100 mm Hg); diabetes with vascular involvement; headaches with focal neurological symptoms; major surgery with prolonged immobilization; cigarette smoking in women over 35; hypersensitivity to any component; undiagnosed abnormal genital bleeding; known or suspected breast cancer; liver tumor (benign or malignant); use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir.
| Precautions |
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| Fetal Monitoring | Perform pregnancy test before initiation. Monitor blood pressure, liver function, and renal function periodically. Ultraound for fetal anomalies if inadvertent exposure. No specific maternal-fetal monitoring recommended due to contraindication. |
| Fertility Effects | Drospirenone and ethinyl estradiol are combined oral contraceptives; suppress ovulation and alter endometrial receptivity, impairing fertility. Return to baseline fertility typically occurs within one to three cycles after discontinuation. |
| Thrombotic disorders including venous thromboembolism, arterial thromboembolism, and stroke; cigarette smoking; hypertension; gallbladder disease; hepatic effects; drug-induced liver injury; hyperkalemia (due to drospirenone's anti-mineralocorticoid effect, especially in patients with renal/hepatic impairment or on potassium-sparing drugs); reduced bone mineral density; depression; ocular effects including retinal thrombosis; carbohydrate and lipid effects; hereditary angioedema; lactation; pregnancy; serious bleeding events; drug interactions. |