ENOVID-E 21
Clinical safety rating
cautionComprehensive clinical and safety monograph for ENOVID-E 21 (ENOVID-E 21).
Norethindrone is a progestin that suppresses gonadotropin release, inhibiting ovulation; mestranol is an estrogen that stabilizes endometrium and provides cycle control.
| Metabolism | Norethindrone: primarily hepatic via reduction and conjugation (CYP3A4 minor). Mestranol: demethylated to ethinyl estradiol; further metabolized by CYP3A4. |
| Excretion | 73% renal (45% as unchanged norethindrone, 20% as conjugates, 8% as other metabolites), 27% fecal via bile. Enterohepatic recirculation accounts for 15% of total clearance. |
| Half-life | Terminal elimination half-life: 27–36 hours (mean 30.8 h). Steady-state reached after 5–7 days. Clinical context: allows once-daily dosing with stable estrogenic effect. |
| Protein binding | Norethindrone: 61% bound to albumin, 36% to SHBG (sex hormone-binding globulin). Ethinylestradiol: 97–98% bound (mainly albumin). Total protein binding for norethindrone: 97%. |
| Volume of Distribution | Norethindrone: Vd 3.6–4.5 L/kg (mean 4.0 L/kg). Ethinylestradiol: Vd 2.5–3.6 L/kg (mean 3.1 L/kg). Clinical meaning: extensive distribution into tissues, including breast, adipose, and reproductive organs. |
| Bioavailability | Oral: norethindrone 50–73% (first-pass effect reduces absolute bioavailability); ethinylestradiol 38–48% (first-pass metabolism in gut wall and liver). |
| Onset of Action | Oral: contraceptive effect requires 7 consecutive days. For ovulation suppression, first cycle suppression begins within 2–3 days; full contraceptive protection after 7 days. Missed dose: within 12 hours, no additional protection needed. |
| Duration of Action | Contraceptive effect persists for 7 days after last dose. For cycle control, withdrawal bleed occurs 2–3 days after placebo. Extended use (e.g., 21-day active phase) allows 7-day hormone-free interval. |
| Molecular Weight | 428.45 |
One tablet (norethynodrel 2.5 mg, mestranol 0.1 mg) orally once daily for 21 consecutive days, followed by 7 days without medication. Repeat cycle.
| Dosage form | TABLET |
| Renal impairment | No specific guidelines; use with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to potential fluid retention. |
| Liver impairment | Contraindicated in severe hepatic disease (Child-Pugh class C). For mild to moderate impairment (Child-Pugh A or B), use with caution and monitor liver function; no specific dose adjustment established. |
| Pediatric use | Not approved for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | Not indicated for postmenopausal women; avoid use due to increased risk of thromboembolic events and cardiovascular disease. |
| 1st trimester | Contraindicated. High risk of fetal harm including cardiovascular and neural tube defects. Estrogen/progestin combinations are not recommended during pregnancy. |
| 2nd trimester | Contraindicated. May cause fetal harm; no therapeutic indication during pregnancy. |
| 3rd trimester | Contraindicated. Risk of fetal and neonatal adverse effects including jaundice and transient hormonal disturbances. |
Clinical note
Comprehensive clinical and safety monograph for ENOVID-E 21 (ENOVID-E 21).
| Placental transfer | Crosses placenta; fetal serum concentrations may be up to 50% of maternal levels. |
| Breastfeeding | Excreted in breast milk in small amounts. May reduce milk production and quality. Use only if clearly needed, with caution. |
| Lactation Rating | L3 (Moderately Safe) by Hale, but generally avoided due to hormonal effects. |
| Teratogenic Risk | First trimester: Increased risk of cardiovascular defects and neural tube defects; second and third trimesters: Risk of feminization of male fetus, urogenital abnormalities, and potential long-term metabolic effects. |
| Fetal Monitoring | Monitor fetal growth and development via ultrasound, assess for congenital anomalies, and evaluate maternal blood pressure, liver function, and glucose tolerance regularly. |
| Fertility Effects | May inhibit ovulation and cause endometrial changes that reduce implantation success. Return to normal fertility typically occurs within 1-3 months after discontinuation. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular side effects from oral contraceptive use. Risk increases with age and smoking ≥15 cigarettes per day. Women over 35 who smoke should not use this product.
| Serious Effects |
Known or suspected pregnancyHistory of thromboembolic disordersActive thrombophlebitisCerebrovascular or coronary artery diseaseKnown or suspected breast carcinomaUndiagnosed abnormal genital bleedingKnown hypersensitivity to componentsSevere hepatic impairment or liver tumor
| Precautions | Increased risk of thromboembolic disorders; discontinue if jaundice, visual disturbances, or migraine occurs; may cause fluid retention; monitor blood pressure; exacerbation of depression; liver enzyme alterations; glucose intolerance; cases of breakthrough bleeding; use with caution in patients with renal impairment. |
| Food/Dietary | No specific food restrictions. However, grapefruit juice may increase estrogen exposure and side effects; limit intake. Caffeine metabolism may be reduced, leading to increased caffeine effects. |
| Clinical Pearls | ENOVID-E 21 is a combined oral contraceptive containing mestranol and norethynodrel. It must be taken at the same time daily. Monitor for thromboembolic events, especially in smokers over 35. Use with caution in patients with history of depression, migraine, or liver disease. Breakthrough bleeding may occur in the first few cycles. |
| Patient Advice | Take one tablet daily at the same time, in the order directed. Do not skip doses. · Missed pills increase pregnancy risk; if one pill is missed, take it as soon as remembered, then continue. If two or more are missed, use backup contraception. · Common side effects include nausea, headache, breast tenderness, and irregular bleeding, which often improve after a few cycles. · Seek medical attention for signs of blood clot: sudden chest pain, shortness of breath, leg pain or swelling, vision changes, or severe headache. · Smoking while on this pill increases risk of serious cardiovascular side effects; avoid smoking. · This pill does not protect against HIV or other sexually transmitted infections; use condoms for STI prevention. |
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