Danazol

Black Box Warnings

Contraindicated in pregnancy

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

Peliosis hepatitis and benign hepatic adenoma have been observed with long-term use

Benign intracranial hypertension (pseudotumor cerebri) has been reported

Contraindications

Pregnancy, breastfeeding

Porphyria

Undiagnosed abnormal genital bleeding

Severe liver/renal/cardiac disease,

Hypersensitivity

Cautions

Breast cancer

Epilepsy

Migraine

Cardiac dysfunction

Renal impairment

Preliminary epidemiological evidence suggests that the use of danazol might increase the baseline risk of ovarian cancer in patients being treated for endometriosis

Use of Danazol in pregnancy is contraindicated. A sensitive test (e.g., beta subunit test if available) capable of determining early pregnancy is recommended immediately prior to start of therapy. Additionally a non-hormonal 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. (See PRECAUTIONS: Pregnancy, Teratogenic Effects.)

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

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 the drug 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.

A temporary alteration of lipoproteins in the form of decreased high density lipoproteins and possibly increased low density lipoproteins has been reported during Danazol therapy. These alterations may be marked, and prescribers should consider the potential impact on the risk of atherosclerosis and coronary artery disease in accordance with the potential benefit of the therapy to the patient.

Before initiating therapy of fibrocystic breast disease with Danazol, carcinoma of the breast should be excluded. However, nodularity, pain, tenderness due to fibrocystic breast disease may prevent recognition of underlying carcinoma before treatment is begun. Therefore, if any nodule persists or enlarges during treatment, carcinoma should be considered and ruled out.

Patients should be watched closely for signs of androgenic effects some of which may not be reversible even when drug administration is stopped.

DANOCRINE, brand of danazol, is a synthetic steroid derived from ethisterone. It is a white to pale yellow crystalline powder, practically insoluble or insoluble in water, and sparingly soluble in alcohol. Chemically, danazol is 17α-Pregna-2,4-dien-20-yno [2,3-d]isoxazol-17-ol. The molecular formula is C22H27NO2. It has a molecular weight of 337.46 and the following structural formula:

Danocrine capsules for oral administration contain 50 mg, 100 mg or 200 mg danazol.

Inactive Ingredients: Corn Starch, Lactose, Magnesium Stearate, Talc. Capsules 50 mg, 100 mg and 200 mg contain D&C Yellow #10, FD&C Red #40, Gelatin, Silicon Dioxide, Sodium Lauryl Sulfate, Titanium Dioxide. The 50 mg and 200 mg capsules also contain D&C Red #28.

Endometriosis

DANOCRINE is indicated for the treatment of endometriosis amenable to hormonal management.

Fibrocystic Breast Disease

Most cases of symptomatic fibrocystic breast disease may be treated by simple measures (e.g., padded brassieres and analgesics).

In infrequent patients, symptoms of pain and tenderness may be severe enough to warrant treatment by suppression of ovarian function. DANOCRINE is usually effective in decreasing nodularity, pain, and tenderness. It should be stressed to the patient that this treatment is not innocuous in that it involves considerable alterations of hormone levels and that recurrence of symptoms is very common after cessation of therapy.

Hereditary Angioedema

DANOCRINE is indicated for the prevention of attacks of angioedema of all types (cutaneous, abdominal, laryngeal) in males and females.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Usual Adult Dose for Endometriosis:

100 mg to 200 mg orally two times a day.

Severe cases of endometriosis may require an initial dosage of 400 mg orally two times a day.

To assure that the patient is not pregnant, therapy should be initiated during menstruation. If this is not possible, a sensitive pregnancy test that detects early pregnancy should be done to insure the patient is not pregnant. A non-hormonal birth control method is recommended.

Following an initial favorable response (amenorrhea develops), the dosage should be titrated to the minimum dose that suppresses disease activity.

Therapy should continue uninterrupted for 3 to 6 months. Administration of danazol up to 9 months may be necessary. Should symptoms recur, danazol treatment may be reinitiated.

Usual Adult Dose for Fibrocystic Breast Disease:

50 mg to 200 mg orally two times a day.

To assure that the patient is not pregnant, therapy should be initiated during menstruation. If this is not possible, a sensitive pregnancy test that detects early pregnancy should be done to insure the patient is not pregnant. A non- hormonal birth control method is recommended.

Resolution of pain and tenderness usually occurs following 1 to 3 months of therapy. Elimination of nodules often requires 4 to 6 months of uninterrupted therapy. Symptoms recur within one year in 50% of patients and therapy may be reinitiated if necessary.

Usual Adult Dose for Angioedema:

200 mg orally two to three times a day.

To assure a female patient is not pregnant, therapy should be initiated during menstruation. If this is not possible, a sensitive pregnancy test that detects early pregnancy should be done to insure the patient is not pregnant. A non- hormonal birth control method is recommended.

Following an initial favorable response (prevention of edematous episodes), attempts should be made at 1 to 3 month intervals to reduce the dosage to the minimum continuous dose that will prevent angioedema. Dosage reductions up to 50% per interval may be considered. Should angioedema recur, the daily dosage may be increased up to 200 mg.

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Undiagnosed abnormal genital bleeding.b f

• Markedly impaired hepatic, renal, or cardiac function.b f

• Known or suspected pregnancy.a b f (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Nursing women.b f

• Porphyria.b f (See Porphyria under Cautions.)

Warnings/Precautions

Warnings

May cause fetal harm; virilization of the external genitalia (e.g., clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, ambiguous genitalia, abnormal vaginal development, persistence of a urogenital sinus) of female fetus reported.a b f

Exclude pregnancy immediately prior to initiation of therapy.b f

Use nonhormonal method of contraception during therapy.b f

Avoid pregnancy during therapy.b f If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.b f

Serious and potentially life-threatening thromboembolism, thrombotic and thrombophlebitic events (e.g., sagittal sinus thrombosis, stroke) reported.b f

Peliosis hepatis and benign hepatic adenoma reported with prolonged use of high doses of androgens.a b f Such hepatic effects may not be apparent until complicated by acute, potentially life-threatening intra-abdominal hemorrhage.a b f Administer lowest effective dosage.b f

Elevated concentrations of hepatic enzymes (e.g., alkaline phosphatase, AST, ALT) and/or jaundice reported with dosages of ≥400 mg daily.a b f

Periodic liver function evaluation recommended.a b f

Pseudotumor cerebri (benign intracranial hypertension), manifested by papilledema, headache, nausea and vomiting, and/or visual disturbances, reported.a b f (See Pseudotumor Cerebri under Boxed Warnings.)

May alter serum lipoprotein concentrations; decreased HDL and increased LDL reported.b f Consider the increased risk of cardiovascular disease (e.g., atherosclerosis and CAD) versus the possible benefits of therapy.b f

Exclude breast cancer before initiating therapy for fibrocystic breast disease; breast nodularity, pain, and tenderness may prevent recognition of underlying carcinoma.b f If any nodule persists or enlarges during treatment, consider and rule out carcinoma.b f

Possible androgenic effects (e.g., weight gain, acne, seborrhea, hirsutism, edema, hair loss, voice change); may be irreversible.a b f Monitor patient closely.b f

General Precautions

May cause fluid retention; use caution in conditions adversely affected by fluid retention (e.g., epilepsy, migraine, cardiac or renal dysfunction).b f

May induce 5-aminolevulinate synthetase activity and porphyrin; possible exacerbation of manifestations of acute intermittent porphyria.b f Contraindicated in patients with porphyria.b f (See Contraindications under Cautions.)

Specific Populations

Category X.b f (See Contraindications and also Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Discontinue nursing because of potential risk to nursing infants.c f (See Contraindications under Cautions.)

Safety and efficacy not established.b f

Use not recommended in patients with severe hepatic impairment.b f (See Contraindications under Cautions.)

Use with caution in renal dysfunction.b f (See Fluid Retention under Cautions). Use not recommended in patients with severe renal impairment.b f (See Contraindications under Cautions.)

Common Adverse Effects

Mild hirsutism, decreased breast size, voice changes, sore throat, acne, increased oiliness of skin or hair, hair loss, weight gain, edema, flushing, sweating, nervousness, emotional lability, vaginitis, menstrual irregularities.a b f

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Risk of virilization in females.a Advise female patients to contact their clinician if they notice hoarseness, acne, or the growth of facial hair.b f

• Importance of informing clinicians of headache, nausea and vomiting, or visual disturbances.b f

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.b f

• Importance of women using nonhormonal contraceptive measures.b f

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.b f

• Importance of informing patients of other important precautionary information.b f (See Cautions.)

• If you have an allergy to danazol or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: An androgen-dependent tumor, genital cancer, heart disease, kidney disease, liver disease, or porphyria.
• If you have blood clots or have had blood clots in the past.
• If you have unexplained vaginal bleeding.
• If you are breast-feeding. Do not breast-feed while you take danazol.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take danazol with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Have your blood pressure checked often. Talk with your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take danazol.
• Do not take this medicine for longer than you were told by your doctor.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking danazol with your other drugs.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food. Always take with food or always take on an empty stomach.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Consult your pharmacist.

Applies to danazol: compounding powder, oral capsule

General

The most commonly reported side effects included acne, edema, and flushing.[Ref]

Dermatologic

Very common (10% or more): Acne (up to 13%)
Common (1% to 10%): Facial edema, hair loss, hirsutism/mild hirsutism, maculopapular rash, papular rash, petechial rash, purpuric rash, seborrhea, sun sensitivity/sun sensitive rash, sweating, vesicular rash
Uncommon (0.1% to 1%): Pruritus, urticaria
Very rare (less than 0.01%): Erythema multiforme, inflammatory erythematous nodules, skin pigmentation/skin pigmentation change, Stevens-Johnson syndrome
Frequency not reported: Exfoliative dermatitis, rash[Ref]

Musculoskeletal

Common (1% to 10%): Arthralgia, backache/back pain, extremity pain, fasciculation, joint lock-up, joint swelling, muscle cramps, muscle spasms, muscle tremors, neck pain, spasms/pains
Rare (0.01% to 0.1%): Benign intracranial hypertension, dizziness
Very rare (less than 0.01%): Carpal tunnel syndrome
Frequency not reported: Altered creatine phosphokinase, creatinine phosphokinase increased, joint pain, limb pain[Ref]

Genitourinary

Common (1% to 10%): Amenorrhea/persistent amenorrhea/prolonged posttherapy amenorrhea, alteration in cycle timing, menstrual disturbances, pelvic pain, spotting, vaginal dryness/irritation
Uncommon (0.1% to 1%): Breast size changes
Rare (0.01% to 0.1%): Hypertrophy of the clitoris
Very rare (less than 0.01%): Abnormalities in semen volume/viscosity/sperm count/motility, hematuria, testicular atrophy
Frequency not reported: Bartholin's cyst, nipple discharge[Ref]

Psychiatric

Common (1% to 10%): Anxiety, depression/depressed mood, emotional lability, irritability, libido changes, nervousness
Frequency not reported: Sleep disorders[Ref]

Gastrointestinal

Common (1% to 10%): Constipation, gastroenteritis, indigestion, nausea, vomiting
Rare (0.01% to 0.1%): Pancreatitis
Very rare (less than 0.01%): Epigastric pain
Frequency not reported: Bleeding gums[Ref]

Respiratory

Common (1% to 10%): Hoarseness, pitch deepening/instability, sore throat, voice change
Uncommon (0.1% to 1%): Nasal congestion
Very rare (less than 0.01%): Interstitial pneumonitis, pleuritic pain[Ref]

Metabolic

Common (1% to 10%): Appetite changes, increased insulin requirements (in patients with diabetes), weight gain
Rare (0.01% to 0.1%): Fluid retention
Frequency not reported: Abnormal glucagon, abnormal glucose tolerance, altered glucose tolerance, altered glucagon, decreased apolipoproteins AI and AII, decreased high density lipoprotein cholesterol, increased total cholesterol/low density lipoprotein cholesterol, induction of amino levulinic acid synthetase[Ref]

Cardiovascular

Common (1% to 10%): Edema, flushing
Rare (0.01% to 0.1%): Arterial thrombosis, blood pressure elevation, hypertension/hypertension exacerbation, palpitation/palpitation exacerbation, tachycardia/tachycardia exacerbation, thrombotic events
Frequency not reported: Myocardial infarction[Ref]

Nervous system

Common (1% to 10%): Headache
Rare (0.01% to 0.1%): Faintness, vertigo, tremor
Very rare (less than 0.01%): Epilepsy aggravation, migraine/migraine provocation
Frequency not reported: Benign intracranial hypertension, cerebrovascular thrombosis, convulsions, dizziness, Guillain-Barre syndrome, paresthesia, sagittal sinus thrombosis[Ref]

Other

Common (1% to 10%): Fever
Rare (0.01% to 0.1%): Fatigue, weakness
Frequency not reported: Altered plasma proteins, chills, fasciculation[Ref]

Hepatic

Uncommon (0.1% to 1%): Hepatic dysfunction
Rare (0.01% to 0.1%): Cholestatic jaundice, hepatic adenoma
Very rare (less than 0.01%): Malignant hepatic tumor, peliosis hepatitis
Frequency not reported: Benign hepatic adenomata, hepatic failure, hepatocellular focal nodular hyperplasia, hepatocellular injury, hepatocellular jaundice, increased AST, jaundice, serum transaminase level increases, reversible elevated serum enzymes[Ref]

Hematologic

Rare (0.01% to 0.1%): Increased platelet count, increased red cell count, leukopenia, polycythemia/reversible polycythemia, thrombocytopenia
Very rare (less than 0.01%): Eosinophilia/reversible eosinophilia, reversible erythrocytosis, splenic peliosis
Frequency not reported: Leukocytosis[Ref]

Ocular

Rare (0.01% to 0.1%): Blurred vision, difficulty wearing contact lenses, focusing difficulty, refraction disorders requiring correction
Frequency not reported: Cataracts[Ref]

Endocrine

Frequency not reported: Altered sex hormone binding globulin, blunted cyclical surges of luteinizing hormone (LH), decreased protein bound iodine, decreased thyroid binding globulin and T4, increased T3 uptake, no disturbance of thyroid stimulating hormone/free thyroxine index[Ref]

Oncologic

Frequency not reported: Malignant liver tumors[Ref]

Hypersensitivity

Frequency not reported: Hereditary angioedema[Ref]

Some side effects of danazol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

100 mg to 200 mg orally two times a day.

Severe cases of endometriosis may require an initial dosage of 400 mg orally two times a day.

To assure that the patient is not pregnant, therapy should be initiated during menstruation. If this is not possible, a sensitive pregnancy test that detects early pregnancy should be done to insure the patient is not pregnant. A non-hormonal birth control method is recommended.

Following an initial favorable response (amenorrhea develops), the dosage should be titrated to the minimum dose that suppresses disease activity.

Therapy should continue uninterrupted for 3 to 6 months. Administration of danazol up to 9 months may be necessary. Should symptoms recur, danazol treatment may be reinitiated.

The use of danazol is not recommended in patients with severe renal dysfunction. The normal dosage recommendation may be considered if the patient's renal dysfunction is mild to moderate. Monitoring of renal function is recommended.

Danazol has been assigned to pregnancy category X by the FDA. Animal (rat) studies using danazol at doses 7 to 15 times that of a corresponding human dosage on days 6 to 15 of gestation failed to reveal evidence of teratogenicity or embryotoxicity. Studies in rabbits during days 6 to 18 of gestation at doses 2 to 4 times that of a corresponding human dosage resulted in inhibition of fetal development. There are no controlled data in human pregnancy. Danazol use is considered contraindicated during pregnancy. Reversible oligospermia may occur in adult males after prolonged administration or excessive dosage. If this effect occurs, danazol can be discontinued and if restarted, a lower dosage should be utilized.

If therapy is not initiated during menstruation, a sensitive pregnancy test that detects early pregnancy should be done to determine that the patient is not pregnant. A non-hormonal contraceptive method should be used during danazol therapy. If pregnancy occurs during therapy, danazol should be discontinued. Patients should be advised of the possible risks to the fetus.

There are no data on the excretion of danazol into human milk. Breast-feeding is considered to be contraindicated by the manufacturer.