DANAZOL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DANAZOL (DANAZOL).
Danazol is a synthetic androgen derived from ethisterone that suppresses pituitary-ovarian axis by inhibiting gonadotropin release, leading to decreased estrogen and progesterone levels. It also has weak androgenic and progestational activity.
| Metabolism | Primarily hepatic: undergoes oxidation and conjugation via CYP3A4, with metabolites excreted in urine and feces. |
| Excretion | Primarily hepatic metabolism; approximately 60% excreted in feces, 30% in urine as metabolites. |
| Half-life | Terminal elimination half-life is 4-4.5 hours; clinical context: requires multiple daily dosing to maintain therapeutic levels. |
| Protein binding | Highly protein bound: 97-99%, primarily to albumin. |
| Volume of Distribution | Approximately 1.5 L/kg; indicates extensive distribution into tissues, exceeding total body water. |
| Bioavailability | Oral bioavailability is approximately 100% due to extensive absorption, but first-pass metabolism reduces systemic availability to about 70-80%. |
| Onset of Action | Oral: 2-8 weeks for therapeutic effect in endometriosis; up to 3 months for fibrocystic breast disease. |
| Duration of Action | Duration varies with condition; relief persists for several months after discontinuation in endometriosis; symptoms may recur after stopping. |
| Molecular Weight | 337.46 |
300-600 mg orally twice daily; maximum 800 mg/day
| Dosage form | CAPSULE |
| Renal impairment | No adjustment required for GFR ≥10 mL/min; avoid use in GFR <10 mL/min due to fluid retention risk |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated |
| Pediatric use | 2-5 mg/kg/dose orally twice daily; maximum 400 mg/day |
| Geriatric use | Start at low end of adult dose, titrate cautiously due to increased risk of fluid retention and thromboembolism |
| 1st trimester | Danazol is contraindicated in the first trimester due to androgenic effects that can cause virilization of female fetus, including clitoral hypertrophy, labial fusion, and urogenital sinus abnormalities. Risk of pregnancy loss may also be increased. |
| 2nd trimester | Danazol is contraindicated in the second trimester because of continued risk of fetal virilization and potential adverse effects on fetal development. |
| 3rd trimester | Danazol is contraindicated in the third trimester due to risk of fetal virilization and potential suppression of fetal adrenal function. |
Clinical note
Comprehensive clinical and safety monograph for DANAZOL (DANAZOL).
| Placental transfer | Danazol crosses the placenta. Fetal concentrations are approximately 50% of maternal serum levels. Evidence from animal studies and human case reports confirm placental transfer and risk of fetal harm. |
| Breastfeeding | Danazol is excreted into breast milk. The effects on the nursing infant are unknown, but due to its androgenic nature, it is generally recommended to avoid breastfeeding during therapy or discontinue danazol if breastfeeding. If use is necessary, monitor infant for signs of virilization or other adverse effects. |
■ FDA Black Box Warning
Danazol may cause thrombotic events, including pulmonary embolism and thrombophlebitis. It is contraindicated in patients with a history of thrombosis.
| Serious Effects |
PregnancyBreastfeeding (unless benefit outweighs risk and infant monitored)Uncontrolled abnormal genital bleedingSeverely impaired hepatic functionSeverely impaired renal functionCardiac decompensation (including congestive heart failure)Hypercalcemia (in patients with metastatic breast cancer)
| Precautions | Hepatotoxicity (monitor LFTs), pseudotumor cerebri (benign intracranial hypertension), androgenic effects (hirsutism, acne, voice deepening), lipid changes (decreased HDL, increased LDL), thromboembolic events, and premature closure of epiphyses in children. |
| Food/Dietary | Take with food or milk to minimize gastrointestinal irritation. Avoid grapefruit juice as it may alter drug metabolism. Limit alcohol consumption due to increased risk of hepatotoxicity. |
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| Lactation Rating | Avoid |
| Teratogenic Risk | Danazol is contraindicated in pregnancy. First trimester exposure is associated with virilization of female fetus including clitoromegaly, labioscrotal fusion, and urogenital sinus abnormalities. Risk in second and third trimesters is also significant due to androgenic effects; fetal growth restriction and preterm birth may occur. No safe gestational period exists. |
| Fetal Monitoring | Monitor maternal liver function, lipid profile, and signs of androgenic effects. In pregnancy, if inadvertent exposure occurs, perform ultrasound for fetal anatomy and growth; assess for signs of virilization in female fetus. Evaluate infant for adrenal suppression if used near term. |
| Fertility Effects | Danazol suppresses ovulation via antigonadotropic effects and is used to treat endometriosis-associated infertility. Reversible suppression; ovulation typically returns within 8 weeks after discontinuation. May impair spermatogenesis in males. |
| Clinical Pearls | Monitor liver function tests; androgenic effects (acne, hirsutism, voice deepening) may occur; use with caution in patients with cardiac or renal impairment; may potentiate warfarin; effective for hereditary angioedema prophylaxis; check pregnancy test before initiation due to teratogenicity. |
| Patient Advice | Do not take if pregnant or planning pregnancy; use effective contraception. · Report symptoms of liver toxicity (jaundice, dark urine, abdominal pain) immediately. · Avoid alcohol as it may increase hepatotoxicity risk. · May cause weight gain, acne, or voice changes; report if bothersome. · Take with food to reduce GI upset. · Use sunscreen due to photosensitivity risk. · Do not discontinue abruptly; taper under medical supervision. |