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Pronunciation

(DA na zole)

Index Terms

  • Danocrine
  • WIN-17757

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 50 mg, 100 mg, 200 mg

Pharmacologic Category

  • Androgen

Pharmacology

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

Metabolism

Extensively hepatic, primarily to 2-hydroxymethyl danazol and ethisterone

Excretion

Urine and feces

Onset of Action

Fibrocystic breast disease: Onset of pain/tenderness relief: 1 month (usually significantly relieved at 2 to 3 months); nodule elimination: 4 to 6 months

Immune thrombocytopenia (off-label use): Initial response: 14 to 90 days; Peak response: 28 to 180 days (Neunert 2011)

Time to Peak

Serum: 4 hours (range: 2 to 8 hours)

Half-Life Elimination

~10 hours (variable; up to 24 hours following long-term use for endometriosis)

Use: Labeled Indications

Endometriosis: Treatment of endometriosis amenable to hormonal management.

Fibrocystic breast disease: Management of symptoms (pain, tenderness, nodularity) of fibrocystic breast disease which are not reduced by simple measures (including padded brassieres and analgesics) and require suppression of ovarian function.

Hereditary angioedema: Prevention of attacks of angioedema of all types (cutaneous, abdominal, laryngeal) in males and females.

Contraindications

Hypersensitivity to danazol or any component of the formulation; undiagnosed abnormal genital bleeding; pregnancy; breast-feeding; 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

Dosing: Adult

Note: In females, begin treatment during menstruation:

Endometriosis (females): Oral:

Mild disease: Initial: 200 to 400 mg/day in 2 divided doses; gradually titrate dosage downward to maintain amenorrhea; continue (uninterrupted) for 3 to 6 months (may extend up to 9 months). If symptoms recur following discontinuation, may reinitiate treatment.

Moderate-to-severe disease or infertility: Initial: 800 mg/day in 2 divided doses; gradually titrate dosage downward to maintain amenorrhea; continue (uninterrupted) for 3 to 6 months (may extend up to 9 months). If symptoms recur following discontinuation, may reinitiate treatment.

Fibrocystic breast disease (females): Oral: Range: 100 to 400 mg/day in 2 divided doses. If symptoms recur following discontinuation, may reinitiate treatment.

Hereditary angioedema (males/females): Oral: Initial: 200 mg 2 to 3 times/day; 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 dosage by up to 200 mg/day.

Immune thrombocytopenia, refractory (off-label use): Oral: 200 mg 2 to 4 times/day (10 to 15 mg/kg/day in divided doses) (Provan 2010); initial response is observed at 14 to 90 days; may take up to 6 months for peak response (Neunert 2011; Provan 2010) 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 (Meloisel 2004).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Use is contraindicated in patients with markedly impaired renal function.

Dosing: Hepatic Impairment

Use is contraindicated in patients with markedly impaired hepatic function.

Administration

Endometriosis, fibrocystic breast disease: Initiate therapy during menstruation or ensure patient is not pregnant while on therapy.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Ajmaline: Androgens may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

C1 inhibitors: Androgens may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

CarBAMazepine: Danazol may decrease the metabolism of CarBAMazepine. Monitor therapy

Corticosteroids (Systemic): May enhance the fluid-retaining effect of Androgens. Monitor therapy

CycloSPORINE (Systemic): Androgens may enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

HMG-CoA Reductase Inhibitors: Danazol may increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Concurrent use of simvastatin with danazol is contraindicated. Initiate lovastatin at an adult maximum dose of 10 mg/day, and do not exceed 20 mg/day, when danazol is given concomitantly. Fluvastatin, pravastatin and rosuvastatin may pose lower risk. Exceptions: Fluvastatin; Pravastatin; Rosuvastatin. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

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. Consider therapy modification

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Simvastatin: Danazol may increase the serum concentration of Simvastatin. Avoid combination

Tacrolimus (Systemic): Danazol may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tacrolimus (Topical): Danazol may increase the serum concentration of Tacrolimus (Topical). Monitor therapy

Vitamin D Analogs: Danazol may enhance the hypercalcemic effect of Vitamin D Analogs. Exceptions: Calcipotriene. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Androgens may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Test Interactions

Estradiol (Kishino 2010); danazol may interfere with laboratory tests for testosterone, androstenedione, and dehydroepiandrosterone

Adverse Reactions

Frequency not defined.

Cardiovascular: Edema, flushing, hypertension, myocardial infarction, palpitations, syncope, tachycardia

Central nervous system: Depression, dizziness, emotional lability, fatigue, headache, nervousness, paresthesia, sleep disorder, voice disorder (deepening of the voice, hoarseness, instability, sore throat)

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: Abnormalities in semen viscosity, abnormalities in semen volume, abnormalities in sperm motility, breast atrophy, hematuria, inhibition of spermatogenesis, spermatozoa disorder (sperm count changes), vaginal dryness, vaginal irritation

Hematologic & oncologic: Change in creatine phosphokinase, decreased sex hormone binding globulin, eosinophilia, increased red blood cell count, increased sex hormone-binding globulin, leukocytosis, leukopenia, malignant neoplasm (after prolonged use), petechial rash, polycythemia, purpuric rash, secondary polycythemia (reversible), thrombocythemia, thrombocytopenia

Hepatic: Cholestatic jaundice, hepatic adenoma, hepatic neoplasm (malignant; after prolonged use), increased liver enzymes, jaundice, peliosis hepatitis

Neuromuscular & skeletal: Ankylosis, arthralgia, back pain, joint swelling, limb pain, muscle cramps, muscle spasm, neck pain, tremor, weakness

Ophthalmic: Visual disturbance

Respiratory: Interstitial pneumonitis

<1% (Limited to important or life-threatening): Anxiety, carpal tunnel syndrome, cataract, change in appetite, chills, clitoromegaly, convulsions, erythema multiforme, fever, gingival hemorrhage, Guillain-Barre syndrome, hepatotoxicity (idiosyncratic) (Chalasani 2014), nasal congestion, nipple discharge, pancreatitis, pelvic pain, pseudotumor cerebri, purpura (splenic peliosis), skin photosensitivity, Stevens-Johnson syndrome

ALERT: U.S. Boxed Warning

Thromboembolic events:

Thromboembolism, thrombotic and thrombophlebitic events, including sagittal sinus thrombosis and life-threatening or fatal strokes have been reported.

Pregnancy:

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, discontinue administration of the drug 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.

Hepatic effects:

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. Therefore, alert the physician 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.

Intracranial hypertension:

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. Screen patients with these symptoms for papilledema and, if present, advise the patients to discontinue danazol immediately and refer them to a neurologist for further diagnosis and care.

Warnings/Precautions

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. When used for hereditary angioneurotic edema, if danazol was initiated during an exacerbation 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:

• 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.

• Fibrocystic breast disease: Breast cancer should be ruled out prior to treatment for fibrocystic breast disease, and if fibrocystic nodules persist or enlarge during danazol treatment. The onset of relief of pain and tenderness is 1 month and symptoms are typically relieved within 2 to 3 months of treatment initiation; elimination of nodularity usually requires 4 to 6 months of continuous therapy. Symptoms of fibrocystic breast disease may recur within 1 year following discontinuation of therapy. Ovulation may not be suppressed at doses used for fibrocystic disease, therefore nonhormonal contraception is recommended.

• Porphyria: May cause exacerbations of acute intermittent porphyria; use is contraindicated in patients with porphyria.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Monitoring Parameters

Liver and renal function tests (periodically); hematologic parameters; lipid panel. Signs and symptoms of intracranial hypertension (papilledema, headache, nausea, vomiting), androgenic changes, and/or fluid retention.

Pregnancy Risk Factor

X

Pregnancy Considerations

[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. Therapy should be discontinued for 2 months prior to attempting pregnancy (Caballero 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, alopecia, nausea, emotional instability, acne, sexual dysfunction, or signs of virilization (in females a deep voice, facial hair, pimples, or period changes). Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on 1 side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, excessive weight gain, swelling of arm or leg, severe dizziness, passing out, severe headache, anxiety, mood changes, sudden vision changes, eye pain, eye irritation, lump in breast, or amenorrhea (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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