Thromboembolism, thrombotic and thrombophlebitic events, including sagittal sinus thrombosis and life-threatening or fatal strokes have been reported.
Use of danazol in pregnancy is contraindicated. A sensitive test (eg, beta subunit test if available) capable of determining early pregnancy is recommended immediately prior to start of therapy. Additionally, a nonhormonal method of contraception should be used during therapy. If a patient becomes pregnant while taking danazol, administration of the drug should be discontinued and the patient should be apprised of the potential risk to the fetus. Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.
Experience with long-term therapy with danazol is limited. Peliosis hepatis and benign hepatic adenoma have been observed with long-term use. Peliosis hepatis and hepatic adenoma may be silent until complicated by acute, potentially life-threatening intra-abdominal hemorrhage. The physician therefore should be alert to this possibility. Attempts should be made to determine the lowest dose that will provide adequate protection. If danazol was begun at a time of exacerbation of hereditary angioneurotic edema due to trauma, stress or other cause, periodic attempts to decrease or withdraw therapy should be considered.
Danazol has been associated with several cases of benign intracranial hypertension also known as pseudotumor cerebri. Early signs and symptoms of benign intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, the patients should be advised to discontinue danazol immediately and be referred to a neurologist for further diagnosis and care.
Hereditary angioedema; prophylaxis (alternate agent): Limited data available:
Short-term prophylaxis (for patient-specific triggers, medical and dental procedures):
Note: For planned procedures, on-demand therapy with C1-inhibitor concentrate is preferred; however, if not available, danazol may be considered if time allows adequate therapy before procedure or if patient uses danazol as long-term prophylaxis (HAIWG [Farkas 2017]; WAO/EAACI [Maurer 2018]):
Postpubescent Children and Adolescents: Oral: 2.5 to 10 mg/kg/day divided into 3 doses; maximum daily dose: 600 mg/day; begin at least 5 to 7 days prior and continue for 2 to 5 days post-procedure (HAIWG [Farkas 2017]; JTFPP [Zuraw 2013a]; US HAEA [Busse 2021]; WAO [Craig 2012]).
Long-term prophylaxis:
Note: Use is not recommended in children due to potential adverse effects on bone, growth, and sexual development (US HAEA [Busse 2021]). Danazol is not a preferred first-line agent; use should be reserved for situations when C1-inhibitor concentrate (first-line) are not available or patient preference for oral therapy (US HAEA [Busse 2021]; WAO/EAACI [Maurer 2018]):
Adolescents ≥16 years: Oral: Initial: 2.5 mg/kg/day; maximum initial daily dose: 50 mg/day; increase slowly every 2 weeks until symptoms controlled, or maximum tolerated or maximum recommended dose is reached; maximum daily dose: 5 mg/kg/day up to 200 mg/day. Once control is obtained, reduce interval to every other day or every third day; maximum dose: 100 mg/dose (HAIWG [Farkas 2017]; US HAEA [Busse 2021]; WAO [Craig 2012]; WAO/EAACI [Maurer 2018]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Use is contraindicated in patients with markedly impaired renal function.
Use is contraindicated in patients with markedly impaired hepatic function.
(For additional information see "Danazol: Drug information")
Endometriosis (alternative agent):
Note: For use as an alternative to other first-line therapies in patients with pain associated with endometriosis (ACOG 2010).
Initial:
Mild disease: Oral: 200 to 400 mg/day in 2 divided doses.
Moderate to severe disease or infertility due to endometriosis: Oral: 800 mg/day in 2 divided doses.
Dosage adjustment: Gradually reduce dosage to maintain amenorrhea.
Duration of therapy: Continue therapy uninterrupted for 3 to 6 months; may extend up to 9 months, if needed. If symptoms recur following discontinuation, may reinitiate treatment.
Hereditary angioedema attacks, prophylaxis (alternative agent):
Note: May be considered as an alternative to other first-line therapies for preprocedural (short-term) and long-term hereditary angioedema (HAE) attack prophylaxis. Danazol is not recommended for treatment of acute HAE attacks (WAO/EAACI [Maurer 2018]).
Preprocedural (short-term) prophylaxis (off-label dose): Oral: Initial: 2.5 to 10 mg/kg/day; adjust dose according to patient response (maximum: 600 mg/day) (WAO [Craig 2012]). Administer for 5 days before and for 2 to 3 days after procedure; frequent short courses may lead to adverse effects associated with long-term use (WAO/EAACI [Maurer 2018]).
Long-term prophylaxis: Oral: Initial: 100 to 200 mg once daily. After favorable initial response, decrease the dosage by 50% or less at intervals of 1 to 3 months or longer if the frequency of attacks dictates; if an attack occurs, increase the daily dosage by up to 200 mg/day. Usual dosage range: 100 mg every other day to 200 mg 3 times daily (WAO [Craig 2012]; WAO/EAACI [Maurer 2018]; manufacturer’s labeling). Note: Use the minimum effective dose; use of dosages >200 mg/day for an extended time is not recommended due to adverse effects (WAO [Craig 2012]; WAO/EAACI [Maurer 2018]).
Immune thrombocytopenia, refractory (off-label use):
Note: May be considered in patients whose symptoms are refractory to or who are unable to take other preferred agents (ACH [Neunert 2019]; Provan 2019).
Oral: 200 mg 2 to 4 times/day; approximate time to response is 3 to 6 months (Provan 2019) or 600 mg once daily for at least 6 months followed by 400 mg once daily for 3 months, then (if remission maintained) 200 mg once daily (Maloisel 2004).
Mastalgia, cyclic, severe (off-label use):
Note: For use in patients with severe or refractory cyclic breast pain associated with benign breast disorders (ACOG 2016).
Oral: 200 mg/day administered in 1 or 2 divided doses. Cyclic administration during the luteal phase of the menstrual cycle (days 14 to 28) may reduce the risk of adverse effects; if given continuously, initiate the first day of the menstrual cycle (ACOG 2016; O’Brien 1999). Usual dosage range: 100 to 200 mg/day; doses up to 400 mg/day have been studied but may be associated with a higher incidence of adverse effects (ACOG 2016; Döberl 1984; Hinton 1986; Kontostolis 1997; Mansel 1982; Tobiassen 1984).
Duration of therapy: 3 to 6 months (AGOG 2016). In some studies in patients receiving continuous (ie, not cyclic) therapy, the dose was tapered off prior to discontinuation (ACOG 2016; Döberl 1984).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling. Use is contraindicated in patients with markedly impaired renal function.
There are no dosage adjustments provided in the manufacturer's labeling. Use is contraindicated in patients with markedly impaired hepatic function.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 50 mg, 100 mg, 200 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Cyclomen: 50 mg, 100 mg, 200 mg
Oral: Administer consistently with regard to food.
Endometriosis: Initiate therapy during menstruation or ensure patient is not pregnant while on therapy.
Store at 20°C to 25°C (68°F to 77°F). Protect from light.
Treatment of endometriosis amenable to hormonal management; prevention of attacks of hereditary angioedema of all types (cutaneous, abdominal, laryngeal) (All indications: FDA approved in adults).
Danazol may be confused with Dantrium
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Acute myocardial infarction, edema, flushing, hypertension, palpitations, syncope, tachycardia
Dermatologic: Acne vulgaris, alopecia, diaphoresis, maculopapular rash, papular rash, pruritus, seborrhea, urticaria, vesicular eruption
Endocrine & metabolic: Amenorrhea (may continue post-therapy), change in libido, decreased glucose tolerance (and glucagon changes), decreased HDL cholesterol, decreased thyroxine binding globulin, hirsutism (mild), increased LDL cholesterol, increased thyroxine binding globulin, menstrual disease (altered timing of cycle, spotting), weight gain
Gastrointestinal: Constipation, gastroenteritis, nausea, vomiting
Genitourinary: Asthenospermia, breast atrophy, decreased ejaculate volume, hematuria, inhibition of spermatogenesis, spermatozoa disorder (changes in sperm count and semen viscosity), vaginal dryness, vaginal irritation
Hematologic & oncologic: Abnormal erythrocytes (increased), decreased sex hormone binding globulin, eosinophilia, increased sex hormone-binding globulin, leukocytosis, leukopenia, malignant neoplasm (after prolonged use), petechial rash, polycythemia, purpuric rash, thrombocythemia, thrombocytopenia
Hepatic: Cholestatic jaundice, hepatic adenoma, hepatic neoplasm (malignant; after prolonged use), increased liver enzymes, jaundice, peliosis hepatitis
Nervous system: Depression, dizziness, emotional lability, fatigue, headache, nervousness, paresthesia, sleep disorder, voice disorder (deepening of the voice, hoarseness, instability, sore throat)
Neuromuscular & skeletal: Ankylosing spondylitis, arthralgia, asthenia, back pain, increased creatine phosphokinase in blood specimen, joint swelling, limb pain, muscle cramps, muscle spasm, neck pain, tremor
Ophthalmic: Visual disturbance
Respiratory: Interstitial pneumonitis
<1%, postmarketing, and/or case reports: Anxiety, carpal tunnel syndrome, cataract, change in appetite, chills, clitoromegaly, erythema multiforme, fever, gingival hemorrhage, Guillain-Barre syndrome, hepatotoxicity (idiosyncratic) (Chalasani 2014), intracranial hypertension (Tan 2019), nasal congestion, nipple discharge, pancreatitis, pelvic pain, pseudotumor cerebri, purpuric disease (splenic peliosis), seizure, skin photosensitivity, Stevens-Johnson syndrome
Hypersensitivity to danazol or any component of the formulation; undiagnosed abnormal genital bleeding; pregnancy; breastfeeding; porphyria; markedly impaired hepatic, renal, or cardiac function; androgen-dependent tumor; active or history of thrombosis or thromboembolic disease
Canadian labeling: Additional contraindications (not in the US labeling): Genital neoplasia; concomitant administration with simvastatin.
Concerns related to adverse effects:
• Androgenic effects: May cause nonreversible androgenic effects.
• Blood lipid changes: Anabolic steroids may cause blood lipid changes (decreased high density lipoproteins and increased low density lipoproteins) with increased risk of arteriosclerosis and coronary artery disease.
• Hepatotoxicity: [US Boxed Warning]: Peliosis hepatis and benign hepatic adenoma have been reported with long-term use. Peliosis hepatis and hepatic adenoma may be silent until complicated by acute, potentially life-threatening intraabdominal hemorrhage. Use the lowest effective dose. If therapy was initiated at a time of exacerbation of hereditary angioneurotic edema due to trauma, stress or other cause, consider periodic attempts to decrease or withdraw therapy. Monitor liver function tests and monitor closely for potential hepatotoxicity during therapy. Use is contraindicated in patients with marked hepatic impairment.
• Intracranial hypertension: [US Boxed Warning]: Danazol is associated with cases of benign intracranial hypertension (also known as pseudotumor cerebri). Early signs and symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Monitor for symptoms; if symptoms occur, screen for papilledema. Discontinue immediately and refer for neurology care if papilledema is present.
• Thromboembolic events: [US Boxed Warning]: Thromboembolism, thrombotic, and thrombophlebitic events have been reported (including sagittal sinus thrombosis and life-threatening or fatal strokes).
Disease-related concerns:
• Cyclic breast pain (mastalgia) associated with benign breast disorders: Use is reserved for severe and refractory cases that have not responded to conservative measures and analgesics. Malignancy should be ruled out prior to therapy (ACOG 2016; Groen 2017).
• Diabetes: Use with caution in patients with diabetes mellitus; insulin requirements may be increased; monitor carefully.
• Edematous conditions: Use with caution in patients with conditions influenced by edema (eg, cardiovascular disease, migraine, seizure disorder, renal impairment); danazol may cause fluid retention.
• Porphyria: May cause exacerbations of acute intermittent porphyria; use is contraindicated in patients with porphyria.
Special populations:
• Pregnancy: [US Boxed Warning]: Danazol use is contraindicated in pregnancy. Pregnancy should be ruled out immediately prior to starting treatment using a sensitive test (eg, beta subunit test if available) capable of determining early pregnancy. A nonhormonal method of contraception should also be used during therapy. If a patient becomes pregnant during danazol treatment, discontinue danazol and apprise the patient of the potential risk to the fetus. Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.
Other warnings/precautions:
• Appropriate use: Endometriosis: Danazol is generally reserved for the treatment of pain associated with endometriosis when other agents are not available, due to its high incidence of adverse events (Dunselman 2014).
Due to irreversible androgenic side effects, danazol should be avoided in prepubescent pediatric patients and exposure in adolescents should be limited; in adolescents, assess risk versus benefit; monitor patients closely (Laufer 2008; US HAEA [Busse 2021]; WAO [Craig 2012]; Zuraw 2013b).
Inhibits CYP3A4 (weak)
Ajmaline: Androgens may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Atorvastatin: Danazol may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy
C1 inhibitors: Androgens may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
CarBAMazepine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the fluid-retaining effect of Androgens. Risk C: Monitor therapy
CycloSPORINE (Systemic): Androgens may enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Management: Consider avoiding concomitant use of androgens and cyclosporine. If concomitant use is unavoidable, monitor serum cyclosporine concentrations and for signs and symptoms of hepatotoxicity. Cyclosporine dose reductions may be required. Risk D: Consider therapy modification
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification
Lovastatin: Danazol may increase the serum concentration of Lovastatin. Management: Initiate immediate release lovastatin at a dose of 10 mg/day, and do not exceed 20 mg/day for immediate or extended release lovastatin, in patients receiving danazol. Monitor closely for signs of lovastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider therapy modification
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Red Yeast Rice: Danazol may increase the serum concentration of Red Yeast Rice. Management: Initiate red yeast rice at a dose equivalent to lovastatin 10 mg/day, and do not exceed 20 mg/day, in patients receiving danazol. Monitor closely for signs of lovastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider therapy modification
Simvastatin: Danazol may increase the serum concentration of Simvastatin. Risk X: Avoid combination
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
Tacrolimus (Systemic): Danazol may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Vitamin D Analogs: Danazol may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Androgens may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased effects of vitamin K antagonists if an androgen is initiated/dose increased, or decreased effects if androgen is discontinued/dose decreased. Significant reductions in vitamin K antagonist dose are likely required. Risk D: Consider therapy modification
Food delays time to peak levels. A high-fat meal increases plasma concentration and extent of availability.
Evaluate pregnancy status prior to use in patients who may become pregnant. A sensitive test capable of determining early pregnancy is recommended immediately prior to start of therapy (eg, beta subunit test, if available). A nonhormonal method of contraception should be used during therapy.
Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.
Use of danazol in pregnancy is contraindicated. If a patient becomes pregnant while taking danazol, administration of the drug should be discontinued, and the patient should be apprised of the potential risk to the fetus.
The use of danazol for the management of hereditary angioedema (HAE) in pregnancy that is not responsive to preferred therapy has been described in case reports (Altman 2006; Boulos 1994; González-Quevedo 2016; Milingos 2009). However, danazol is contraindicated during pregnancy; current guidelines recommend use of other agents in pregnant patients (WAO/EAACI [Maurer 2018]).
Liver and renal function tests (periodically); hematologic parameters; lipid panel. Signs and symptoms of intracranial hypertension (eg, papilledema, headache, nausea, vomiting), androgenic changes, and/or fluid retention; pregnancy status.
Hereditary angioedema, long-term prophylaxis: CBC, urinalysis, LFTs, and lipid profile (baseline, every 6 months while on therapy, and 6 months after discontinuation); liver ultrasound (baseline and annually); blood pressure (every 6 months); weight, signs of virilization (every 6 months) (US HAEA [Busse 2021]; WAO [Craig 2012]).
Suppresses pituitary output of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in regression and atrophy of normal and ectopic endometrial tissue; decreases rate of growth of abnormal breast tissue; reduces attacks associated with hereditary angioedema by increasing levels of C4 component of complement
Onset of action: Immune thrombocytopenia (off-label use): Initial response: 14 to 90 days; Peak response: 28 to 180 days (Neunert 2011)
Metabolism: Extensively hepatic, primarily to 2-hydroxymethyl danazol and ethisterone
Half-life elimination: 9.7 ± 3.29 hours (variable; up to 24 hours following long-term use for endometriosis)
Time to peak, serum: 4 hours (range: 2 to 8 hours)
Excretion: Urine and feces
Capsules (Danazol Oral)
50 mg (per each): $3.63
100 mg (per each): $5.44
200 mg (per each): $10.29
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