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Pronunciation

(DA na zole)

Index Terms

  • Danocrine

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 and luteinizing hormone that causes 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

Therapeutic: ~4 weeks

Time to Peak

Serum: Within 2-8 hours (median 4 hours)

Half-Life Elimination

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

Use: Labeled Indications

Treatment of endometriosis, fibrocystic breast disease, and hereditary angioedema

Contraindications

Hypersensitivity to danazol or any component of the formulation; undiagnosed genital bleeding; pregnancy; breast-feeding; porphyria; markedly impaired hepatic, renal, or cardiac function; androgen-dependent tumor; active or history of thrombosis or thromboembolic disease

Dosing: Adult

Endometriosis (females): Oral:

Mild disease: Initial: 200-400 mg/day in 2 divided doses

Moderate-to-severe disease: Initial: 800 mg/day in 2 divided doses

Maintenance: Mild-severe disease: Dosage should be individualized. Continue therapy uninterrupted for 3-6 months (up to 9 months).

Fibrocystic breast disease (females): Oral: Range: 100-400 mg/day in 2 divided doses. Pain and tenderness may be eliminated in 2-3 months; elimination of nodularity may require therapy for 4-6 months.

Hereditary angioedema (males/females): Oral: Initial: 200 mg 2-3 times/day; after favorable response, decrease the dosage by 50% or less at intervals of 1-3 months or longer if the frequency of attacks dictates. If an attack occurs, increase the dosage by up to 200 mg/day.

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. Symptoms may recur following discontinuation of therapy and treatment may need reinstated.

Storage

Store at controlled room temperature of 15°C to 30°C (59°F to 86°F).

Drug Interactions

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. Consider therapy modification

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); testosterone, androstenedione, 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.

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.

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 with increased risk of arteriosclerosis.

• Hepatic effects: [U.S. Boxed Warning]: Peliosis hepatis and benign hepatic adenoma have been reported with long-term use (may be complicated by acute intra-abdominal hemorrhage). Monitor closely for potential hepatotoxicity during therapy.

• Intracranial hypertension: [U.S. Boxed Warning]: May cause benign intracranial hypertension (pseudotumor cerebri); monitor for headache, nausea/vomiting, visual disturbances and/or papilledema.

• Thromboembolic events: [U.S. Boxed Warning]: Thromboembolism, thrombotic, and thrombophlebitic events have been reported (including 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); may cause fluid retention.

• Fibrocystic disease: Breast cancer should be ruled out prior to treatment for fibrocystic breast disease. Symptoms of pain and tenderness may recur following discontinuation of therapy. Ovulation may not be suppressed at doses used for fibrocystic disease therefore nonhormonal contraception is recommended.

• Hepatic impairment: Use with caution in patients with hepatic impairment; use is contraindicated with marked impairment.

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

Special populations:

• Pregnancy: [U.S. Boxed Warning]: Pregnancy must be ruled out prior to treatment; a nonhormonal method of contraception should be used during therapy.

Monitoring Parameters

Liver and renal function tests (periodically). Signs and symptoms of intracranial hypertension (papilledema, headache, nausea, vomiting), lipoproteins, androgenic changes

Pregnancy Risk Factor

X

Pregnancy Considerations

[U.S. Boxed Warning]: Pregnancy should be ruled out prior to treatment using a sensitive test (beta subunit test, if available). Nonhormonal contraception should be used during therapy. May cause androgenic effects to the female fetus; clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been reported. 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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