CYCLAFEM 0.5/35
Clinical safety rating
cautionComprehensive clinical and safety monograph for CYCLAFEM 0.5/35 (CYCLAFEM 0.5/35).
Combination oral contraceptive containing norethindrone (progestin) and ethinyl estradiol (estrogen). Inhibits gonadotropin release, suppressing ovulation. Increases cervical mucus viscosity and alters endometrium, reducing sperm penetration and implantation.
| Metabolism | Norethindrone undergoes hepatic metabolism via reduction and hydroxylation followed by glucuronidation; ethinyl estradiol is metabolized primarily by CYP3A4 and undergoes first-pass metabolism with sulfation and glucuronidation in the gut wall and liver. |
| Excretion | Renal excretion accounts for approximately 50-60% of the dose (as metabolites), with 30-40% excreted in feces via biliary elimination. Unchanged drug is minimal in urine. |
| Half-life | Terminal elimination half-life of norethindrone is 5-14 hours (mean 7.6 hours); ethinyl estradiol half-life is 7-20 hours (mean ~13 hours). Steady-state is achieved within 5-7 days. |
| Protein binding | Norethindrone: ~97% bound to albumin and SHBG. Ethinyl estradiol: ~98% bound to albumin. |
| Volume of Distribution | Norethindrone: Vd ~4 L/kg (total body water and tissue distribution). Ethinyl estradiol: Vd ~2.5 L/kg. |
| Bioavailability | Oral bioavailability: norethindrone ~64% (due to first-pass metabolism); ethinyl estradiol ~45% (range 38-55%). |
| Onset of Action | Oral: 7 days of consecutive dosing required for contraceptive effect; immediate on first day of menstrual cycle. |
| Duration of Action | Duration of contraceptive effect is 24 hours with daily dosing; after discontinuation, ovulation may resume within 2-4 weeks. |
| Molecular Weight | 372.54 |
| Action Class | Oral contraceptive; antiandrogen |
One tablet (0.5 mg norethindrone/35 mcg ethinyl estradiol) orally once daily for 21 days, followed by 7 placebo days (or no tablets) per cycle.
| Dosage form | TABLET |
| Renal impairment | No specific dosage adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure due to potential adverse effects on renal function and hormonal balance. |
| Liver impairment | Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). For mild hepatic impairment (Child-Pugh class A), use with caution; no specific dose adjustment but monitor liver function tests. |
| Pediatric use | Not indicated for use before menarche. Post-menarche: same as adult dosing (one tablet daily per cycle) following standard contraceptive guidelines for adolescents. |
| Geriatric use | Not indicated for use in postmenopausal women due to lack of contraceptive need and increased risk of cardiovascular events and thromboembolism with estrogen-containing contraceptives. |
| 1st trimester | Contraindicated due to risk of fetal harm (cardiovascular defects, limb reduction). Increased risk of thromboembolism. |
| 2nd trimester | Not recommended. Continued use may increase risk of cholestasis and fetal abnormalities. |
| 3rd trimester | Contraindicated. Use in pregnancy can cause fetal adrenal suppression, feminization of male fetus, and other adverse effects. |
Clinical note
Comprehensive clinical and safety monograph for CYCLAFEM 0.5/35 (CYCLAFEM 0.5/35).
| Placental transfer | Easily crosses the placenta; reaches fetal circulation. |
| Breastfeeding | CYCLAFEM passes into breast milk and may decrease milk production and affect the nursing infant. Caution is advised; use only if clearly needed. |
| Lactation Rating | L3 (Moderately Safe) - Limited data suggest risk but benefits may outweigh in some cases. |
| Teratogenic Risk | FIRST TRIMESTER: Increased risk of neural tube defects, cardiovascular malformations, and orofacial clefts with inadvertent exposure; absolute risk estimated at 3-4% above baseline. SECOND TRIMESTER: No direct teratogenic risk, but continue to avoid use due to hormonal effects. THIRD TRIMESTER: Potential for adverse fetal outcomes including respiratory distress, neonatal jaundice, and hypoglycemia; use contraindicated throughout pregnancy. |
| Fetal Monitoring | Prior to initiation: Rule out pregnancy via sensitive hCG test. During use: Regular assessment for pregnancy symptoms; if pregnancy suspected, immediate discontinuation and confirmatory testing. Monitor for signs of pregnancy complications if inadvertent exposure occurs. |
| Fertility Effects | Reversible suppression of ovulation during use. Return to baseline fertility typically within 1-3 cycles after discontinuation. No evidence of long-term negative impact on fertility. Use may mask underlying fertility issues. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Risk increases with age and with heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this product.
| Common Effects | Nausea, Headache, Breast tenderness, Weight changes, Mood changes, Irregular menstrual bleeding, Decreased libido, Acne (initial worsening) |
| Serious Effects | Venous thromboembolism (deep vein thrombosis, pulmonary embolism), Arterial thromboembolism (myocardial infarction, stroke), Hepatic adenoma or hepatocellular carcinoma, Hypertension, Gallbladder disease, Depression, Hyperkalemia (due to cyproterone acetate's mineralocorticoid-like effect) |
Hypersensitivity to cyproterone acetate or ethinylestradiolKnown or suspected pregnancyBreast cancerHistory of thromboembolic disordersSevere hepatic impairmentUndiagnosed abnormal genital bleedingActive or history of arterial thrombosis
| Precautions | Increased risk of thromboembolic disorders (e.g., stroke, MI, DVT, PE), Increased risk of hepatic neoplasia (benign and malignant), Elevated blood pressure, Gallbladder disease, Carbohydrate and lipid metabolism effects, Ocular changes (retinal thrombosis), Depression, Headache/migraine, Hereditary angioedema exacerbation, Chloasma, Hepatic impairment, Pregnancy discontinuation, Lactation use |
| Food/Dietary | No specific food restrictions. Grapefruit juice may slightly increase estrogen levels but not clinically significant. Maintain a balanced diet for overall health. |
| Clinical Pearls | CYCLAFEM 0.5/35 (norethindrone 0.5 mg/ethinyl estradiol 35 mcg) is a monophasic combination oral contraceptive. The 0.5 mg norethindrone dose is lower than typical progestin doses, reducing androgenic side effects. Its lower estrogen content (35 mcg) still provides effective cycle control. It is a first-line option for patients desiring contraception with minimal hormonal exposure. Breakthrough bleeding may occur in the first few cycles, especially with missed pills. Contraindicated in patients with migraine with aura, thrombophilia, or history of estrogen-dependent neoplasia. |
| Patient Advice | Take one tablet daily at the same time each day, with or without food. · If you miss a pill, refer to the package insert instructions; use backup contraception if needed. · Side effects may include nausea, breast tenderness, or spotting, especially during the first few months. · Smoking increases risk of serious cardiovascular events while on this medication; avoid smoking. · This medication does not protect against sexually transmitted infections (STIs); use condoms for STI prevention. · Notify your healthcare provider before starting new medications, as some (e.g., rifampin, certain anticonvulsants) may reduce effectiveness. · Store at room temperature, away from moisture and heat. |
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