AFIRMELLE
Clinical safety rating
cautionComprehensive clinical and safety monograph for AFIRMELLE (AFIRMELLE).
Combination oral contraceptive containing ethinyl estradiol and levonorgestrel. Inhibits ovulation by suppressing gonadotropin release (FSH and LH). Also increases cervical mucus viscosity and alters endometrial receptivity.
| Metabolism | Ethinyl estradiol undergoes first-pass metabolism in gut and liver via CYP3A4, with conjugation to sulfate and glucuronide. Levonorgestrel is metabolized primarily by CYP3A4 to reduced and hydroxylated metabolites, then conjugated. |
| Excretion | Renal: 50% as unchanged drug and metabolites; fecal: 40% as metabolites; biliary: ~10% as glucuronide conjugates. |
| Half-life | Terminal elimination half-life: 12–15 hours. Steady-state achieved within 5 days with Q12H dosing. |
| Protein binding | ~99% bound to serum albumin and sex hormone-binding globulin. |
| Volume of Distribution | 2.8 L/kg (apparent Vd), indicating extensive tissue distribution. |
| Bioavailability | Oral: ~70% due to first-pass metabolism. |
| Onset of Action | Oral: 1–2 hours for detectable serum concentrations; clinical effect (contraception) requires 7 days of continuous dosing. |
| Duration of Action | 24 hours for contraceptive effect with daily dosing; dosing every 12 hours maintains therapeutic levels. |
| Molecular Weight | 288.43 |
One tablet (0.1 mg levonorgestrel, 0.02 mg ethinyl estradiol) orally once daily for 21 days, followed by 7 days of placebo.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended for use in end-stage renal disease. |
| Liver impairment | Contraindicated in acute hepatic disease or severe (Child-Pugh C) hepatic impairment. Use with caution in mild to moderate hepatic impairment; monitor liver function. |
| Pediatric use | Not indicated for use before menarche. Post-menarche: same as adult dosing (one tablet daily) based on adult clinical trials. |
| Geriatric use | Not indicated for use in postmenopausal women; no specific dose adjustment required in healthy elderly, but limited data available. |
| 1st trimester | Contraindicated. Use during first trimester is associated with congenital defects (e.g., limb deficiencies, cardiac anomalies) following inadvertent use. Risk of masculinization of female fetus if used before 12 weeks gestation. |
| 2nd trimester | Contraindicated. Second trimester exposure is linked to virilization of female fetuses (clitoromegaly, labial fusion) and potential skeletal abnormalities. |
| 3rd trimester | Contraindicated. Third trimester exposure may cause clitoromegaly in female newborns and possible behavioral effects. Avoid due to risk of androgenicity. |
Clinical note
Comprehensive clinical and safety monograph for AFIRMELLE (AFIRMELLE).
| Placental transfer | Crosses the placenta; documented transfer in humans. Fetal serum levels may approach maternal levels. |
| Breastfeeding | Excreted in human milk. Potential for androgenic effects in breastfed infants (e.g., virilization). Decision to breastfeed should consider maternal need for therapy and risk to infant. If used, monitor infant for signs of androgen excess. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy due to risk of fetal harm. First trimester: exposure associated with congenital anomalies (e.g., cardiovascular, neural tube defects). Second and third trimesters: increased risk of fetal growth restriction, preterm birth, and neonatal respiratory distress. Postnatal: possible long-term developmental effects. |
| Fetal Monitoring | If accidental exposure occurs: monitor fetal growth via ultrasound, assess for congenital anomalies with targeted ultrasound in second trimester. Monitor maternal blood pressure and liver function. Consider discontinuation upon pregnancy detection. |
| Fertility Effects | Returns to baseline promptly after discontinuation. No known permanent effects on fertility. May delay return to fertility in some women due to anovulation while on therapy. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptive use. Risk increases with age (especially in women over 35) and with heavy smoking (15+ cigarettes/day). Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Serious Effects |
Pregnancy (known or suspected)Severe hepatic impairment or liver diseaseHistory of or current prostatic carcinomaHistory of or current breast carcinoma in known or suspected hypercalcemiaUndiagnosed genital bleedingHypercalcemia (known or suspected)
| Precautions | Thrombotic disorders (venous thromboembolism, stroke, myocardial infarction), Cigarette smoking (increases cardiovascular risk), Hypertension (especially in women with renal disease or migraines), Gallbladder disease, Hepatic neoplasia (benign and malignant), Carbohydrate and lipid metabolism effects, Ocular lesions (retinal thrombosis), Depressed mood or depression, Uterine bleeding irregularities, Reduced efficacy with hepatic enzyme inducers |
| Food/Dietary | Grapefruit juice may increase ethinyl estradiol levels; avoid large quantities. No significant food restrictions. Administer with food if GI upset occurs. |
| Clinical Pearls | Afirmelle (levonorgestrel/ethinyl estradiol) is a combined oral contraceptive. Counsel patients to take at the same time daily to maintain consistent hormone levels. Use back-up contraception if a dose is missed. Monitor for signs of thromboembolism, especially in smokers over 35. Advise that certain antibiotics (e.g., rifampin) and anticonvulsants (e.g., phenytoin) may reduce efficacy. Consider progestin-only pill if contraindications to estrogen exist. |
| Patient Advice | Take one pill at the same time every day, even if you don't have sex. · If you miss a pill, follow the instructions in the package insert or ask your healthcare provider. · Use a backup method (like condoms) if you start late or miss pills. · This medication does not protect against HIV or other sexually transmitted infections. · Common side effects include nausea, breast tenderness, and breakthrough bleeding. · Seek medical help if you have symptoms of a blood clot: sudden chest pain, leg swelling, or shortness of breath. · Smoking while on this pill increases your risk of serious cardiovascular events. |
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