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:

Danazol capsules for oral administration contain 200 mg Danazol.

Inactive Ingredients: Corn Starch, Lactose, Magnesium Stearate, Talc, D&C Yellow #10, D&C Red #28, FD&C Red #40, Gelatin, Silicon Dioxide, Sodium Lauryl Sulfate, Titanium Dioxide.

Endometriosis

Danazol 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. Danazol 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

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

Endometriosis

In moderate to severe disease, or in patients infertile due to endometriosis, a starting dose of 800 mg given in two divided doses is recommended. Amenorrhea and rapid response to painful symptoms is best achieved at this dosage level. Gradual downward titration to a dose sufficient to maintain amenorrhea may be considered depending upon patient response. For mild cases, an initial daily dose of 200 mg to 400 mg given in two divided doses is recommended and may be adjusted depending on patient response. Therapy should begin during menstruation. Otherwise, appropriate tests should be performed to ensure that the patient is not pregnant while on therapy with Danazol. (See CONTRAINDICATIONS and WARNINGS.) It is essential that therapy continue uninterrupted for 3 to 6 months but may be extended to 9 months if necessary. After termination of therapy, if symptoms recur, treatment can be reinstituted.

Fibrocystic Breast Disease

The total daily dosage of Danazol for fibrocystic breast disease ranges from 100 mg to 400 mg given in two divided doses depending upon patient response. Therapy should begin during menstruation. Otherwise, appropriate tests should be performed to ensure that the patient is not pregnant while on therapy with Danazol. A nonhormonal method of contraception is recommended when Danazol is administered at this dose, since ovulation may not be suppressed.

In most instances, breast pain and tenderness are significantly relieved by the first month and eliminated in 2 to 3 months. Usually elimination of nodularity requires 4 to 6 months of uninterrupted therapy. Regular menstrual patterns, irregular menstrual patterns, and amenorrhea each occur in approximately one-third of patients treated with 100 mg of Danazol. Irregular menstrual patterns and amenorrhea are observed more frequently with higher doses. Clinical studies have demonstrated that 50% of patients may show evidence of recurrence of symptoms within one year. In this event, treatment may be reinstated.

Hereditary Angioedema

The dosage requirements for continuous treatment of hereditary angioedema with Danazol should be individualized on the basis of the clinical response of the patient. It is recommended that the patient be started on 200 mg, two or three times a day. After a favorable initial response is obtained in terms of prevention of episodes of edematous attacks, the proper continuing dosage should be determined by decreasing the dosage by 50% or less at intervals of one to three months or longer if frequency of attacks prior to treatment dictates. If an attack occurs, the daily dosage may be increased by up to 200 mg. During the dose adjusting phase, close monitoring of the patient's response is indicated, particularly if the patient has a history of airway involvement.

Capsules of 200 mg (orange), bottles of 100 (NDC 0955-0306-20).

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

Caution: Federal law prohibits dispensing without prescription.

Manufactured for Sanofi-Synthelabo Inc. New York, NY 10016, by Nycomed Puerto Rico Inc. Barceloneta, Puerto Rico 00617. Issued August 1996. FDA revision date: 3/28/2001

The following events have been reported in association with the use of Danazol:

Androgen like effects include weight gain, acne and seborrhea. Mild hirsutism, edema, hair loss, voice change, which may take the form of hoarseness, sore throat or of instability or deepening of pitch, may occur and may persist after cessation of therapy. Hypertrophy of the clitoris is rare.

Other possible endocrine effects include menstrual disturbances in the form of spotting, alteration of the timing of the cycle and amenorrhea. Although cyclical bleeding and ovulation usually return within 60-90 days after discontinuation of therapy with Danazol, persistent amenorrhea has occasionally been reported.

Flushing, sweating, vaginal dryness and irritation and reduction in breast size, may reflect lowering of estrogen. Nervousness and emotional lability have been reported. In the male a modest reduction in spermatogenesis may be evident during treatment. Abnormalities in semen volume, viscosity, sperm count, and motility may occur in patients receiving long-term therapy.

Hepatic dysfunction, as evidenced by reversible elevated serum enzymes and/or jaundice, has been reported in patients receiving a daily dosage of Danazol of 400 mg or more. It is recommended that patients receiving Danazol be monitored for hepatic dysfunction by laboratory tests and clinical observation. Serious hepatic toxicity including cholestatic jaundice, peliosis hepatis, and hepatic adenoma have been reported. (See WARNINGS and PRECAUTIONS.)

Abnormalities in laboratory tests may occur during therapy with Danazol including CPK, glucose tolerance, glucagon, thyroid binding globulin, sex hormone binding globulin, other plasma proteins, lipids and lipoproteins.

The following reactions have been reported, a causal relationship to the administration of Danazol has neither been confirmed nor refuted; allergic: urticaria, pruritus and rarely, nasal congestion; CNS effects: headache, nervousness and emotional lability, dizziness and fainting, depression, fatigue, sleep disorders, tremor, paresthesias, weakness, visual disturbances, and rarely, benign intracranial hypertension, anxiety, changes in appetite, chills, and rarely convulsions, Guillain-Barre syndrome; gastrointestinal: gastroenteritis, nausea, vomiting, constipation, and rarely, pancreatitis; musculoskeletal: muscle cramps or spasms, or pains, joint pain, joint lockup, joint swelling, pain in back, neck, or extremities, and rarely, carpal tunnel syndrome which may be secondary to fluid retention; genitourinary: hematuria, prolonged posttherapy amenorrhea; hematologic: an increase in red cell and platelet count. Reversible erythrocytosis, leukocytosis or polycythemia may be provoked. Eosinophilia, leukopenia and thrombocytopenia have also been noted. Skin: rashes (maculopapular, vesicular, papular, purpuric, petechial), and rarely, sun sensitivity, Stevens-Johnson syndrome; other: increased insulin requirements in diabetic patients, change in libido, elevation in blood pressure, and rarely, cataracts, bleeding gums, fever, pelvic pain, nipple discharge. Malignant liver tumors have been reported in rare instances, after long-term use.

Prolongation of prothrombin time occurs in patients stabilized on warfarin. Therapy with Danazol may cause an increase in carbamazepine levels in patients taking both drugs.

Laboratory Tests: Danazol treatment may interfere with laboratory determinations of testosterone, androstenedione and dehydroepiandrosterone.

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.

Because Danazol may cause some degree of fluid retention, conditions that might be influenced by this factor, such as epilepsy, migraine, or cardiac or renal dysfunction, require careful observation.

Since hepatic dysfunction manifested by modest increases in serum transaminase levels has been reported in patients treated with Danazol, periodic liver function tests should be performed (see WARNINGS and ADVERSE REACTIONS).

Administration of Danazol has been reported to cause exacerbation of the manifestations of acute intermittent porphyria. (See CONTRAINDICATIONS.)

Carcinogenesis, Mutagenesis, Impairment of Fertility

No valid studies have been performed to assess the carcinogenicity of Danazol.

Pregnancy, Teratogenic Effects

(See CONTRAINDICATIONS.) Pregnancy Category X. Danazol administered orally to pregnant rats from the 6th through the 15th day of gestation at doses up to 250 mg/kg/day (7-15 times the human dose) did not result in drug-induced embryotoxicity or teratogenicity, nor difference in litter size, viability or weight of offspring compared to controls. In rabbits, the administration of Danazol on days 6-18 of gestation at doses of 60 mg/kg/day and above (2-4 times the human dose) resulted in inhibition of fetal development.

Nursing Mothers

(See CONTRAINDICATIONS.)

Pediatric Use

Safety and effectiveness in children have not been established.

No information provided.

Danazol should not be administered to patients with:

1. Undiagnosed abnormal genital bleeding.
2. Markedly impaired hepatic, renal, or cardiac function.
3. Pregnancy. (See WARNINGS.)
4. Breast feeding.
5. Porphyria-Danazol can induce ALA synthetase activity and hence porphyrin metabolism.

Danazol suppresses the pituitary-ovarian axis. This suppression is probably a combination of depressed hypothalamic-pituitary response to lowered estrogen production, the alteration of sex steroid metabolism, and interaction of Danazol with sex hormone receptors. The only other demonstrable hormonal effect is weak androgenic activity. Danazol depresses the output of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Recent evidence suggests a direct inhibitory effect at gonadal sites and a binding of Danazol to receptors of gonadal steroids at target organs. In addition, Danazol has been shown to significantly decrease IgG, IgM and IgA levels, as well as phospholipid and IgG isotope autoantibodies in patients with endometriosis and associated elevations of autoantibodies, suggesting this could be another mechanism by which it facilitates regression of the disease.

Bioavailability studies indicate that blood levels do not increase proportionally with increases in the administered dose. When the dose of Danazol is doubled the increase in plasma levels is only about 35% to 40%.

Separate single dosing of 100 mg and 200 mg capsules of Danazol to female volunteers showed that both the extent of availability and the maximum plasma concentration increased by three-to-four fold, respectively, following a meal ( > 30 grams of fat), when compared to the fasted state. Further, food also delayed mean time to peak concentration of Danazol by about 30 minutes.

In the treatment of endometriosis, Danazol alters the normal and ectopic endometrial tissue so that it becomes inactive and atrophic. Complete resolution of endometrial lesions occurs in the majority of cases.

Changes in vaginal cytology and cervical mucus reflect the suppressive effect of Danazol on the pituitary-ovarian axis.

In the treatment of fibrocystic breast disease, Danazol usually produces partial to complete disappearance of nodularity and complete relief of pain and tenderness. Changes in the menstrual pattern may occur.

Generally, the pituitary-suppressive action of Danazol is reversible. Ovulation and cyclic bleeding usually return within 60 to 90 days when therapy with Danazol is discontinued.

In the treatment of hereditary angioedema, Danazol at effective doses prevents attacks of the disease characterized by episodic edema of the abdominal viscera, extremities, face, and airway which may be disabling and, if the airway is involved, fatal. In addition, Danazol corrects partially or completely the primary biochemical abnormality of hereditary angioedema by increasing the levels of the deficient C1 esterase inhibitor (C1EI). As a result of this action the serum levels of the C4 component of the complement system are also increased.

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

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DANAZOL - ORAL

(DAY-nuh-zole)

COMMON BRAND NAME(S): Danocrine

WARNING: This drug must not be used during pregnancy because its use may result in birth defects. In females, treatment should begin during menstruation. Otherwise, an early pregnancy test is recommended before starting treatment. Use a reliable, non-hormonal birth control method (e.g., diaphragm, condoms) while taking this drug. Consult your doctor for details.

Danazol may rarely cause serious (sometimes fatal) blood clots, liver disease (e.g., peliosis hepatis, hepatic adenoma), and increased pressure on the brain (pseudotumor cerebri, benign intracranial hypertension). Tell your doctor immediately if you have: weakness on one side of the body, slurred speech, vision changes, confusion, sudden stomach/abdominal pain or swelling, dark urine, persistent nausea/vomiting, yellowing eyes/skin, swollen eyes, unusual headache.

USES: This medication is used to treat several conditions, including pelvic pain and infertility due to a uterus condition (endometriosis), breast pain and tenderness due to nodules (fibrocystic breast disease), and swelling of the abdomen/arms/face/airway due to a certain congenital disease (hereditary angioedema).

Danazol is an androgen similar to testosterone. In women, it works by preventing the ovaries from producing certain natural substances (hormones) that can make these conditions worse. In both men and women, it also works on the body's defense system (immune system) to correct the problems related to angioedema.

HOW TO USE: Take this medication by mouth with food, usually twice daily or as directed by your doctor.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Tell your doctor if your condition persists or worsens after 3 months.

SIDE EFFECTS: See also Warning section.

Weight gain, flushing, sweating, vaginal dryness/irritation, and decreased breast or testicle size may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: swelling of hands/feet, mental/mood changes (e.g., nervousness, depression).

Women may experience signs of masculinization (male characteristics) from danazol. To prevent these changes from becoming permanent, stop taking this medication and tell your doctor immediately if any of the following occur: hoarseness, deepening voice, sore throat, facial hair growth, new or worsening acne, enlarged clitoris.

Women often stop having regular menstrual periods while taking this medication. Menstrual periods usually return within 90 days of stopping the drug.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking danazol, tell your doctor or pharmacist if you are allergic to it; or to testosterone; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: abnormal vaginal bleeding of unknown cause, liver disease, kidney disease, heart disease, a certain blood disorder (porphyria).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high cholesterol levels (hypercholesterolemia), breast cancer, prostate cancer, seizure disorder, migraine headaches, diabetes, stroke.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Extreme caution is advised for use in children because they may be more sensitive to the effects of the drug, especially on bone growth and sexual development. Before starting treatment, consult a doctor with experience using this drug in children.

Caution is advised when using this drug in elderly men because they are at increased risk of developing enlarged prostate and prostate cancer with the use of androgen-like drugs.

This medication must not be used during pregnancy. It may harm the unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. (See also Warning section.)

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: "blood thinners" (e.g., warfarin), carbamazepine, certain statin-type drugs (lovastatin, simvastatin), cyclosporine, tacrolimus.

This medication may interfere with certain laboratory tests (including male hormone blood levels, glucose tolerance), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: yellowing eyes/skin, stomach/abdominal pain or swelling, dark urine.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature away from light and moisture. Different brands require different storage temperatures, so consult your pharmacist for more information. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.