ETHINYL ESTRADIOL AND NORELGESTROMIN
Clinical safety rating: avoid
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
Combination contraceptive: estrogen (ethinyl estradiol) suppresses gonadotropin release via negative feedback on pituitary; progestin (norelgestromin) thickens cervical mucus and inhibits ovulation.
| Metabolism | Ethinyl estradiol: CYP3A4; norelgestromin: CYP3A4, CYP1A1, and CYP2C9; norelgestromin is metabolized to norgestrel and other metabolites. |
| Excretion | Ethinyl estradiol and norelgestromin are excreted primarily via urine and feces. Ethinyl estradiol undergoes extensive metabolism; about 40% is excreted in urine and 60% in feces as glucuronide and sulfate conjugates. Norelgestromin is metabolized to norgestrel and other metabolites; approximately 45% is excreted in urine and 35% in feces. |
| Half-life | Ethinyl estradiol has a terminal elimination half-life of approximately 13-27 hours (mean ~17 hours). Norelgestromin has a terminal half-life of about 28 hours. These half-lives support once-weekly dosing of the transdermal system, achieving steady-state by the second application. |
| Protein binding | Ethinyl estradiol is approximately 97-98% bound to serum albumin, and induces sex hormone-binding globulin (SHBG). Norelgestromin is about 97% bound, primarily to albumin and SHBG. |
| Volume of Distribution | Ethinyl estradiol: Vd approximately 2.4-2.7 L/kg, indicating extensive tissue distribution. Norelgestromin: Vd approximately 1.6-2.0 L/kg, also indicating distribution into tissues. |
| Bioavailability | Transdermal route: Bioavailability is complete (100%) as the drug is absorbed directly into systemic circulation, avoiding first-pass metabolism. Oral bioavailability of ethinyl estradiol is typically 38-48% due to first-pass effect. |
| Onset of Action | Transdermal route: Onset of contraceptive effect occurs within 24-48 hours of first application. Ovulation suppression is achieved by day 7 of the first cycle if applied on time. |
| Duration of Action | Transdermal system: Each patch is worn for 7 days, maintaining effective hormone levels. After removal, hormone levels decline rapidly, and contraceptive protection is lost; thus, adherence to the 7-day schedule is critical. |
| Molecular Weight | Ethinyl estradiol: 296.4 Da; Norelgestromin: 327.5 Da |
One transdermal patch (releasing 0.035 mg ethinyl estradiol and 0.150 mg norelgestromin per 24 hours) applied once weekly for 3 weeks, followed by 1 week patch-free.
| Dosage form | FILM, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for mild-moderate renal impairment. Insufficient data for severe impairment (CrCl <30 mL/min); contraindicated in patients with acute renal failure or significant renal disease due to potential fluid retention. |
| Liver impairment | Contraindicated in Child-Pugh class B or C (moderate to severe hepatic impairment). Use with caution in class A (mild), with monitoring for signs of hepatic dysfunction. |
| Pediatric use | Approved post-menarche; dosing same as adult (one patch weekly for 3 weeks, then 1 week off). Adjust based on age and Tanner stage per clinical judgment. |
| Geriatric use | Not indicated for use after menopause. If used, consider increased risk of thromboembolism and cardiovascular events; monitor for adverse effects. |
| 1st trimester | Contraindicated due to risk of fetal harm; estrogen and progestin combination may cause congenital anomalies. |
| 2nd trimester | Contraindicated; use in second trimester is associated with increased risk of fetal abnormalities and pregnancy complications. |
| 3rd trimester | Contraindicated; use during third trimester may lead to placental disruption, fetal harm, and postpartum hemorrhage. |
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 | Both components cross the placenta. Norelgestromin and ethinyl estradiol reach fetal plasma concentrations approximately 10-20% of maternal levels. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events. Women over 35 who smoke should not use this product.
| Common Effects | osteoporosis prevention |
| Serious Effects |
Known or suspected pregnancyUndiagnosed abnormal uterine bleedingHistory of or current thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected carcinoma of the breast or endometriumHepatic adenoma or carcinoma, or active liver diseaseMajor surgery with prolonged immobilizationSevere hypertension (systolic ≥160 mm Hg or diastolic ≥100 mm Hg)Diabetes with vascular involvementHypersensitivity to any componentMigraine with focal neurological symptoms≥35 years of age and smoking ≥15 cigarettes per day
| Precautions | Thrombotic disorders (smoking, obesity, hypertension, age >35), Hepatic disease, Gallbladder disease, Hypertension, Carbohydrate and lipid effects, Headache, Bleeding irregularities, Ocular lesions |
Loading safety data…
| Breastfeeding |
| Ethinyl estradiol and norelgestromin are excreted in human milk. Estrogens can reduce milk production and composition. Norelgestromin is present in low amounts; however, use during breastfeeding is generally not recommended due to potential adverse effects on infant liver and reproductive development. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | First trimester: Limited data; no increased risk of major birth defects from inadvertent exposure. Second and third trimesters: Associated with feminization of male fetus, urogenital sinus malformations, and potential for cardiovascular and limb defects if used in early pregnancy. Contraindicated during pregnancy. |
| Fetal Monitoring | Monitor blood pressure, signs of thrombotic events, hepatic function, and fetal growth if unintentional exposure during early pregnancy. |
| Fertility Effects | Suppresses ovulation via inhibition of gonadotropins; reversible upon discontinuation. No long-term impact on fertility. |
| Food/Dietary |
| No specific food interactions; grapefruit juice may slightly increase estrogen levels but not considered clinically significant. Avoid concurrent St. John's wort (reduces efficacy). |
| Clinical Pearls | Monitor for breakthrough bleeding and amenorrhea; counsel on missed dose management (if >48 hours late, use backup contraception for 7 days). Advise that efficacy may be reduced with concurrent CYP3A4 inducers (e.g., rifampin, St. John's wort). Consider increased risk of venous thromboembolism, especially in smokers over 35. |
| Patient Advice | Apply patch once weekly for 3 weeks, then patch-free week for withdrawal bleed. · If patch detaches, reapply immediately; if >24 hours, start new cycle and use backup contraception for 7 days. · Do not cut or alter patch; do not apply to irritated or damaged skin. · Common side effects: nausea, breast tenderness, headache, and irregular bleeding. · Report signs of blood clot: leg pain/swelling, sudden chest pain, shortness of breath, vision changes. |