ZOVIA 1/35E-21
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZOVIA 1/35E-21 (ZOVIA 1/35E-21).
Combination estrogen-progestin contraceptive; suppresses gonadotropin release, inhibits ovulation, alters cervical mucus and endometrial lining.
| Metabolism | Ethinyl estradiol and norethindrone are metabolized primarily via CYP3A4; undergoes sulfate and glucuronide conjugation. |
| Excretion | Renal (approximately 40% as parent drug and metabolites; 20-40% as metabolites; 15-20% as unchanged drug), fecal (30-50% via bile as metabolites), and less than 2% in breast milk. |
| Half-life | Norethindrone: 5-12 hours (terminal elimination half-life, approximately 8 hours). Ethinyl estradiol: biphasic with terminal half-life of 10-20 hours (mean 15 hours). Clinical context: Steady state reached in 5-7 days. |
| Protein binding | Norethindrone: 61% bound to albumin, 36% bound to SHBG (sex hormone-binding globulin); Ethinyl estradiol: 97% bound, primarily to albumin (98%) and SHBG (2%). |
| Volume of Distribution | Norethindrone: 3.6 ± 0.8 L/kg; Ethinyl estradiol: 2.7-5.9 L/kg (mean approximately 3.5 L/kg). Indicates extensive tissue distribution. |
| Bioavailability | Oral: norethindrone 50-80% (mean 65%) due to first-pass metabolism; ethinyl estradiol 38-48% (mean 45%) due to first-pass conjugation in gut wall and liver. |
| Onset of Action | 7 days of consistent daily dosing for contraceptive effect (follicle suppression requires at least 7 days). |
| Duration of Action | 1 month (21 days active pills followed by 7 placebo days; contraceptive protection maintained during placebo week if all active pills taken correctly). |
| Molecular Weight | Ethinyl estradiol: 296.41 Da; Norethindrone: 298.42 Da; average ~297 Da |
| Action Class | Oral Contraceptive; Estrogen-Progestin Combination |
One tablet orally once daily at the same time each day for 21 days, followed by 7 placebo tablets (if included in the pack) or a 7-day pill-free interval. Each tablet contains ethinyl estradiol 0.035 mg and norethindrone 1 mg.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure due to potential for adverse effects from estrogen component. |
| Liver impairment | Contraindicated in hepatic impairment classified as Child-Pugh class B or C (moderate to severe). In mild hepatic impairment (Child-Pugh A), use with caution and monitor hepatic function; consider alternative contraception. |
| Pediatric use | Safety and efficacy established in post-menarchal females. Dosing is same as adults: one tablet orally once daily for 21 days followed by 7 days off. Not indicated for use before menarche. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dosing recommendations; use alternative therapies for contraception or hormone replacement in geriatric population. |
| 1st trimester | Contraindicated. Risk of fetal harm. Combination oral contraceptives are not recommended during pregnancy. Epidemiologic studies have not revealed an increased risk of birth defects in women who inadvertently used oral contraceptives in early pregnancy, but use is not indicated. |
| 2nd trimester | Contraindicated. Pregnancy should be excluded before initiation. No therapeutic indication during pregnancy. |
| 3rd trimester | Contraindicated. No indication for use. May affect fetal development later in pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for ZOVIA 1/35E-21 (ZOVIA 1/35E-21).
| Placental transfer | Yes, steroid hormones (ethinyl estradiol and norethindrone) cross the placenta. Evidence from animal and human studies indicates placental transfer. |
| Breastfeeding | Combination oral contraceptives are not recommended during breastfeeding as they may reduce milk production and composition. Small amounts of steroids pass into breast milk. Use alternative contraception during lactation. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination hormonal contraceptives. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women >35 years who smoke should not use.
| Common Effects | Nausea, Vomiting, Headache, Breast tenderness, Breakthrough bleeding or spotting, Weight changes, Mood changes (depression, irritability), Acne, Chloasma (melasma), Decreased libido |
| Serious Effects | Venous thromboembolism (deep vein thrombosis, pulmonary embolism), Arterial thromboembolism (myocardial infarction, stroke), Hepatic adenoma or hepatocellular carcinoma, Hypertension, Gallbladder disease, Thrombotic thrombocytopenic purpura (TTP), Hemolytic uremic syndrome (HUS), Optic neuritis or retinal thrombosis, Cerebrovascular accident |
Thrombophlebitis or thromboembolic disordersHistory of deep-vein thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected carcinoma of the breastCarcinoma of the endometrium or other estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior pill useHepatic adenoma or carcinomaKnown or suspected pregnancyActive liver disease, provided liver function has not returned to normalHypersensitivity to any component
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| Lactation Rating | L4 (Possibly Hazardous) – Contraindicated in early postpartum period; use alternative methods. |
| Teratogenic Risk | FDA Pregnancy Category X. Contraindicated in pregnancy. First trimester: risk of cardiovascular defects, limb reduction defects, and neural tube defects. Second/third trimesters: associated with fetal adrenal suppression, masculinization of female fetuses, and other virilization effects. Use in pregnancy may cause irreversible harm. |
| Fetal Monitoring | Pregnancy test before initiation; rule out pregnancy. Monitor blood pressure, liver function, and signs of thromboembolism. Fetal assessment if inadvertent exposure occurs. |
| Fertility Effects | Reversible suppression of ovulation. After discontinuation, fertility returns promptly; no permanent adverse effects on female fertility. In males, no significant impact. |
| Precautions | Increased risk of venous thromboembolism, Myocardial infarction, Stroke, Hepatic neoplasia, Gallbladder disease, Hypertension, Carbohydrate/lipid effects, Ocular lesions (retinal thrombosis), Possible increased risk of breast cancer |
| Food/Dietary | Grapefruit juice may increase ethinyl estradiol levels; limit intake. St. John's wort (herbal supplement) induces CYP3A4 and reduces contraceptive efficacy; avoid concurrent use. No significant interactions with other foods. |
| Clinical Pearls | Contains ethinyl estradiol 35 mcg and norethindrone 1 mg. Monophasic combination oral contraceptive. Prescribe 21-day regimen: one tablet daily for 21 days, then 7 days off. Efficacy comparable to other COCs with Pearl Index ~0.1-0.9. Norethindrone has mild androgenic activity, may benefit women with acne. Avoid in patients with migraine with aura, hypertension, thromboembolic history, or smoking >35 years old. Monitor for breakthrough bleeding, especially in first 3 cycles. If a pill is missed, take as soon as remembered; if 2 or more missed, use backup contraception. Interaction with CYP3A4 inducers (e.g., rifampin, St. John's wort) reduces efficacy. |
| Patient Advice | Take one pill daily at same time each day for 21 days, then no pills for 7 days; withdrawal bleeding occurs during the 7-day break. · If you miss one pill, take it as soon as remembered and the next pill at regular time (may take two pills in one day). If you miss two or more pills, take one missed pill and discard others, use backup contraception for 7 days, and continue pack. · Common side effects: nausea, headache, breast tenderness, spotting; these often improve after 2-3 cycles. · Smoking increases risk of serious cardiovascular events; avoid smoking, especially if over 35. · Grapefruit juice may increase estrogen levels; avoid large amounts. St. John's wort reduces efficacy; use alternative contraception if taking. · Use backup contraception (condoms) for first 7 days of starting or if dosing error. |