NORGESTIMATE; ETHINYL ESTRADIOL
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Combination oral contraceptive containing norgestimate (a progestin) and ethinyl estradiol (an estrogen). The primary mechanism is suppression of gonadotropins (FSH and LH) via negative feedback on the hypothalamic-pituitary-ovarian axis, preventing ovulation. Additional effects include thickening cervical mucus (inhibiting sperm penetration) and altering endometrial receptivity.
| Metabolism | Norgestimate is extensively metabolized via first-pass metabolism in the liver, primarily to norelgestromin (active metabolite) and further to levonorgestrel. Ethinyl estradiol is metabolized via CYP3A4 in the liver and undergoes conjugation. Both undergo enterohepatic recirculation. |
| Excretion | Norgestimate metabolites are primarily excreted via urine (60-80%) and feces (35-49%) as glucuronide and sulfate conjugates; ethinyl estradiol is excreted in urine (40%) and feces (60%) as conjugates. |
| Half-life | Norgestimate: terminal half-life of norelgestromin (active metabolite) is 27.6 ± 7.8 hours; ethinyl estradiol: terminal half-life is 17.5 ± 6.3 hours. Steady state achieved within 14 days. |
| Protein binding | Norelgestromin: 99% bound primarily to albumin, less to SHBG; norgestrel (minor metabolite): 99% bound; ethinyl estradiol: 97-98% bound, mainly to albumin, with 20-30% binding to SHBG. |
| Volume of Distribution | Norelgestromin: 2.0-2.3 L/kg (large, indicating extensive tissue distribution); ethinyl estradiol: 2.3-3.8 L/kg (large, distributed to tissues). |
| Bioavailability | Oral: norgestimate is rapidly and completely absorbed, undergoes first-pass metabolism to active norelgestromin (bioavailability ≈ 60-70%); ethinyl estradiol bioavailability is 40-50% due to first-pass metabolism. |
| Onset of Action | Oral: contraceptive effect begins after 7 days of continuous use if started on day 1 of menstrual cycle; if started otherwise, additional contraception needed for 7 days. |
| Duration of Action | Oral: contraceptive protection lasts 24 hours per daily dose; hormone levels return to baseline within 5-7 days after discontinuation for norgestimate metabolites, 3-5 days for ethinyl estradiol. |
Oral, one tablet daily at the same time for 21 days, followed by 7 placebo tablets.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >= 30 mL/min; use is not recommended in patients with severe renal impairment (GFR < 30 mL/min). |
| Liver impairment | Contraindicated in severe hepatic disease (Child-Pugh class C). In mild to moderate disease (Child-Pugh class A or B), use with caution and monitor for adverse effects; no specific dose adjustment guidelines established. |
| Pediatric use | No FDA-approved indication in pediatric patients. Use is generally not recommended before menarche. |
| Geriatric use | Not indicated for postmenopausal women. No dose adjustment required in elderly women of reproductive age, but consider increased risk of thromboembolism and cardiovascular events. |
| 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 | Contraindicated in breastfeeding due to potential estrogen effects on milk production and composition. Ethinyl estradiol is excreted in breast milk (M/P ratio ~0.5-0.6). May reduce milk volume. Use alternative contraception. |
| Teratogenic Risk | First trimester: Limited data, no consistent evidence of major malformations from inadvertent exposure. Second and third trimesters: May increase risk of adverse fetal outcomes including cardiovascular malformations, preterm birth, low birth weight. Avoid use during pregnancy. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular adverse events from combination oral contraceptives. The risk increases with age and heavy smoking (≥15 cigarettes per day) and is substantial in women over 35 years of age. Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Common Effects | Headache Dizziness Breast tenderness Nausea Vaginal spotting Vomiting Abdominal cramp |
| Serious Effects |
["Known or suspected pregnancy","Current or past history of breast cancer or other estrogen-sensitive neoplasia","Undiagnosed abnormal uterine bleeding","Cigarette smoking in women over 35 years of age","History of thromboembolic disorders (deep vein thrombosis, pulmonary embolism, cerebrovascular accident, myocardial infarction) or known thrombophilias","Active or recent (within 1 year) arterial thromboembolic disease (e.g., stroke, MI)","Severe hypertension (sustained ≥160/100 mm Hg) or hypertension with vascular disease","Known liver disease (e.g., hepatitis, cirrhosis) or hepatic adenomas/carcinomas","Diabetes with nephropathy, retinopathy, neuropathy, or other vascular involvement","Major surgery with prolonged immobilization or current use of antiretroviral medications containing ombitasvir, paritaprevir, ritonavir, dasabuvir, or combinations (may cause liver enzyme elevations)","Hypersensitivity to any component"]
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| Fetal Monitoring | Monitor blood pressure, signs of thrombosis, and liver function. In pregnancy: assess fetal growth via ultrasound if inadvertent exposure occurs. |
| Fertility Effects | Suppresses ovulation via inhibition of gonadotropins. Fertility returns to normal upon discontinuation. No long-term impairment. |
| Precautions | ["Thromboembolic disorders: Increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). Discontinue if thrombotic events occur.","Cardiovascular disease: Increased risk of myocardial infarction and stroke, especially in smokers and women over 35.","Cervical cancer: Increased risk of cervical intraepithelial neoplasia; monitor for abnormal bleeding.","Liver disease: Discontinue if jaundice, cholestasis, or other liver dysfunction develops.","Hypertension: May cause or worsen hypertension; monitor blood pressure regularly.","Carbohydrate metabolism: May impair glucose tolerance; monitor diabetic patients.","Headache: May exacerbate migraine; discontinue if new or severe headache occurs.","Unscheduled bleeding: May occur, especially during first few cycles.","Depression: May worsen or cause depression; discontinue if severe."] |