TRI-NORINYL 28-DAY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRI-NORINYL 28-DAY (TRI-NORINYL 28-DAY).
Combination oral contraceptive containing ethinyl estradiol and norethindrone. Suppresses gonadotropin (FSH and LH) release via negative feedback, inhibiting ovulation. Also increases viscosity of cervical mucus and alters endometrial lining to reduce implantation likelihood.
| Metabolism | Ethinyl estradiol primarily metabolized by CYP3A4 via hydroxylation. Norethindrone metabolized by CYP3A4 and CYP2C9. Both undergo conjugation (glucuronidation and sulfation). |
| Excretion | Renal: 40% as metabolites; Fecal: 50% as metabolites; Biliary: minor; unchanged ethinyl estradiol excreted in urine <5%, norethindrone <1%. |
| Half-life | Ethinyl estradiol: 17 ± 6 hours (terminal); Norethindrone: 10 ± 3 hours (terminal). Steady-state achieved after 7-14 days. |
| Protein binding | Ethinyl estradiol: 97-98% (albumin 70%, SHBG 30%); Norethindrone: 95-99% (albumin 61%, SHBG 38%). |
| Volume of Distribution | Ethinyl estradiol: 2.7-3.1 L/kg; Norethindrone: 4.8-5.3 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Oral: Ethinyl estradiol 38-48% (first-pass metabolism); Norethindrone 64-65% (first-pass metabolism). |
| Onset of Action | Oral: Contraceptive effect requires 7 days of continuous dosing (if starting not on day 1 of menses). No immediate effect. |
| Duration of Action | Oral: Contraceptive coverage persists for 24 hours per active pill; after last active pill, protection continues for 7 days (placebo period). |
One tablet orally once daily for 21 days, followed by one placebo tablet orally once daily for 7 days. Each active tablet contains 0.035 mg ethinyl estradiol and 0.5 mg norethindrone (7 days), 0.035 mg ethinyl estradiol and 1.0 mg norethindrone (9 days), and 0.035 mg ethinyl estradiol and 0.5 mg norethindrone (5 days).
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment required based on GFR. Contraindicated in patients with acute or chronic hepatic dysfunction with impaired renal function. |
| Liver impairment | Contraindicated in patients with acute or chronic hepatic disease (Child-Pugh class B or C). For Child-Pugh class A, use with caution and monitor liver function; no specific dose adjustment available. |
| Pediatric use | Not indicated for use before menarche. After menarche, standard adult dosing applies. |
| Geriatric use | Not indicated for use after menopause. No specific geriatric dose adjustment required if used off-label in perimenopausal women, but consider increased risk of cardiovascular events and venous thromboembolism. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRI-NORINYL 28-DAY (TRI-NORINYL 28-DAY).
| Breastfeeding | Small amounts of ethinyl estradiol and norethindrone excreted in breast milk. M/P ratio: ethinyl estradiol ~0.5; norethindrone ~0.6. May reduce milk production and quality. Use in breastfeeding is generally not recommended; alternative contraception advised for nursing mothers. |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy due to risk of fetal harm. First trimester: no increased risk of major malformations from combination oral contraceptives in most studies, but post-marketing reports of fetal abnormalities. Second and third trimesters: associated with increased risk of fetal genital tract abnormalities (e.g., hypospadias, vaginal adenosis) and possible carcinogenic effects. Use during pregnancy is not recommended; discontinue if pregnancy occurs. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular adverse events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years, and with the number of cigarettes smoked. Women who use combination oral contraceptives should be strongly advised not to smoke.
| Serious Effects |
["High risk of arterial or venous thrombotic events","Known or suspected pregnancy","Undiagnosed abnormal uterine bleeding","Current or history of breast cancer or other estrogen- or progestin-sensitive cancer","Hepatic impairment or active liver disease (including benign and malignant liver tumors)","Uncontrolled hypertension (blood pressure >160/100 mmHg)","Diabetes with vascular disease","Migraine with focal neurological symptoms (aura) or age over 35 with migraine","Known hypersensitivity to any component"]
| Precautions | ["Thrombotic disorders (thrombophlebitis, pulmonary embolism, stroke, myocardial infarction), especially in smokers and women over 35","Hepatic neoplasia (benign and malignant liver tumors)","Gallbladder disease (increased risk of gallstones)","Hypertension (may develop or worsen)","Carbohydrate metabolism effects (reduced glucose tolerance, insulin resistance)","Ocular lesions (retinal thrombosis, optic neuritis)"] |
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| Fetal Monitoring | Monitor for signs of pregnancy before initiation; perform pregnancy test if pregnancy suspected. During use, monitor for thrombotic events (e.g., DVT, PE), hypertension, liver dysfunction, and gallbladder disease. No specific fetal monitoring required if pregnancy ruled out. In case of accidental use during pregnancy, ultrasonography may be considered to assess fetal anatomy. |
| Fertility Effects | Suppresses ovulation as primary mechanism; fertility is transiently impaired during use. Return to normal fertility typically occurs within 1-3 months after discontinuation. No long-term adverse effects on fertility reported. Does not cause permanent infertility. |