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. |
| Molecular Weight | Drospirenone: 366.49 Da; Ethinyl Estradiol: 296.40 Da |
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 | Contraindicated due to increased risk of cardiovascular and thromboembolic events. Use only if benefits outweigh risks and no alternative. |
| 2nd trimester | Contraindicated due to risk of thromboembolic events and fetal harm. Avoid use. |
| 3rd trimester | Contraindicated due to risk of thromboembolic events and potential fetal toxicity (androgenization of female fetuses). Avoid use. |
Clinical note
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
| FDA category | Positive |
| Placental transfer | Yes, both components cross the placenta; ethinyl estradiol extensively bound to fetal tissues. |
| Breastfeeding |
■ 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 |
PregnancyThrombophlebitis or thromboembolic disordersHistory of deep vein thrombosis or pulmonary embolismCerebrovascular or coronary artery diseaseKnown or suspected breast cancerEstrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior pill useHepatic adenoma or carcinomaKnown or suspected pregnancyUncontrolled hypertensionDiabetes with vascular involvementMigraine with auraMajor surgery with prolonged immobilizationSmoking and age >35Renal impairment (creatinine clearance <30 mL/min) (drospirenone component)Adrenal insufficiency (drospirenone component)
| Precautions | 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. |
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| Excreted in breast milk in small amounts; may reduce milk production and affect infant growth. Use only if necessary and monitor infant. |
| Lactation Rating | L3 (Moderately Safe) |
| 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. |
| 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. |
| Food/Dietary | Avoid high-potassium foods (e.g., bananas, oranges, spinach, avocados) in large amounts if you have kidney problems or take potassium-sparing diuretics. Grapefruit juice may increase estrogen levels; limit consumption. |
| Clinical Pearls | Monitor serum potassium during first cycle in patients with renal impairment or on potassium-sparing diuretics; drospirenone has antimineralocorticoid activity similar to a 25 mg dose of spironolactone. Contraindicated in patients with hyperkalemia or conditions predisposing to hyperkalemia. Increased risk of venous thromboembolism, especially in smokers over 35. Offer as a first-line option for women with acne or premenstrual dysphoric disorder due to antiandrogenic effects. |
| Patient Advice | Take one tablet daily at the same time; missed doses increase pregnancy risk. · Do not smoke while taking this medication, especially if over 35. · Report sudden severe headache, chest pain, shortness of breath, or leg swelling immediately. · Avoid potassium supplements and salt substitutes containing potassium without consulting your doctor. · Use back-up contraception if you miss a dose or have vomiting/diarrhea. |