NORDETTE-21
Clinical safety rating
cautionComprehensive clinical and safety monograph for NORDETTE-21 (NORDETTE-21).
Combination oral contraceptive containing ethinyl estradiol and levonorgestrel. Inhibits ovulation by suppressing gonadotropin release, increases viscosity of cervical mucus to prevent sperm penetration, and alters endometrial lining to reduce implantation likelihood.
| Metabolism | Ethinyl estradiol and levonorgestrel are metabolized primarily by CYP3A4. Ethinyl estradiol undergoes phase II conjugation (glucuronidation/sulfation). Levonorgestrel is reduced and conjugated. |
| Excretion | Renal: ~50% (as glucuronide and sulfate conjugates); Fecal: ~40% (enterohepatic recirculation); Biliary: <10% |
| Half-life | Ethinylestradiol: 13 ± 7 hours (terminal), clinically relevant for once-daily dosing; Levonorgestrel: 24 ± 6 hours (terminal), supporting steady-state after ~5 days |
| Protein binding | Ethinylestradiol: 98% bound to albumin; Levonorgestrel: 50% to SHBG, 50% to albumin |
| Volume of Distribution | Ethinylestradiol: 2.5-10 L/kg (extensive tissue distribution); Levonorgestrel: 1.5-4 L/kg (distributes to breast and uterine tissues) |
| Bioavailability | Oral: Ethinylestradiol 40-60% (first-pass metabolism); Levonorgestrel 90-100% (minimal first-pass) |
| Onset of Action | Oral: 24-48 hours for contraceptive effect (requires 7 consecutive days for reliable ovulation suppression) |
| Duration of Action | Contraceptive effect persists for 7 days after last active pill (placebo interval); meaning for missed pills: ≤7 days |
| Molecular Weight | 310.9 |
One tablet (0.15 mg levonorgestrel, 0.03 mg ethinyl estradiol) orally once daily for 21 days, followed by 7 days off.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Insufficient data for severe renal impairment (CrCl <30 mL/min); use is not recommended. |
| Liver impairment | Contraindicated in acute hepatic disease, hepatic adenomas, or severe hepatic impairment (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 available. |
| Pediatric use | Not indicated for use before menarche. For postmenarchal adolescents, same adult dosing (one tablet daily for 21 days) is used based on chronological age and physical development. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dose adjustment recommended for elderly patients if renal and hepatic function are normal, but alternative contraception should be considered due to increased risk of thromboembolism. |
| 1st trimester | Contraindicated due to risk of congenital anomalies; use only if benefit outweighs risk, with caution for cardiovascular effects. |
| 2nd trimester | Contraindicated; associated with fetal harm, including cardiovascular defects and limb reduction. |
| 3rd trimester | Contraindicated; may cause fetal feminization (male) or endocrine disruption; avoid use. |
Clinical note
Comprehensive clinical and safety monograph for NORDETTE-21 (NORDETTE-21).
| Placental transfer | Yes; crosses placenta; detected in fetal plasma at maternal levels. |
| Breastfeeding | Excreted in breast milk; may reduce milk production and composition. Use alternative method or discontinue drug. Monitor infant for jaundice and weight gain. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Trimester 1: No increased risk of major birth defects. Trimester 2-3: Possible risk of fetal harm (e.g., estrogenic effects on genital development) when used inadvertently. |
| Fetal Monitoring | Monitor blood pressure, weight gain, signs of thromboembolism. In pregnant patients inadvertently exposed, consider ultrasound for fetal genital development. |
| Fertility Effects | Use provides contraception; after discontinuation, fertility returns promptly with no permanent adverse effects. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular adverse events from combination oral contraceptives. Risk increases with age (especially >35 years) and with heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should use other contraception.
| Serious Effects |
Thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected breast carcinomaEstrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingPregnancyLiver tumor (benign or malignant) or active liver diseaseHypersensitivity to any component
| Precautions | Increased risk of thromboembolic disorders (e.g., DVT, PE, stroke, MI). Risk increased with smoking, hypertension, hyperlipidemia, diabetes, obesity, and age >35. Discontinue if jaundice, visual disturbances, or migraine develops. Monitor for hypertension, glucose intolerance, and depression. May affect lipid metabolism. Use with caution in women with a history of depression, migraine, or gallbladder disease. |
| Food/Dietary | No known significant food interactions. Grapefruit juice may slightly increase estrogen levels but not considered clinically relevant. Taking with food may reduce nausea. |
| Clinical Pearls | Nordette-21 (ethinyl estradiol/levonorgestrel) is a monophasic oral contraceptive. Monitor for thromboembolic events, especially in smokers over 35. Advise use of backup contraception if vomiting or severe diarrhea occurs. CYP3A4 inducers (e.g., rifampin) may reduce efficacy. Do not prescribe with certain anticonvulsants or St. John's wort. |
| Patient Advice | Take one tablet daily at the same time each day for 21 days, then 7 days off. · Use backup contraception (e.g., condoms) for the first 7 days of initial use. · If you miss a pill, follow the package instructions; use backup if needed. · Seek immediate medical attention for signs of blood clots, stroke, or liver problems. · Hormonal contraceptives do not protect against STDs, including HIV. · Notify your doctor if you become pregnant or plan to become pregnant. · Common side effects include nausea, breast tenderness, and breakthrough bleeding. |
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