Danazol

INDICATIONS AND USAGE Endometriosis. Danazol capsules are indicated for the treatment of endometriosis amenable to hormonal management. Hereditary Angioedema. Danazol capsules are indicated for the prevention of attacks of angioedema of all types (cutaneous, abdominal, laryngeal) in males and females.

DOSAGE AND ADMINISTRATION 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 capsules (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. Hereditary Angioedema. The dosage requirements for continuous treatment of hereditary angioedema with danazol capsules 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.

CONTRAINDICATIONS Danazol capsules 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 capsules can induce ALA synthetase activity and hence porphyrin metabolism. 6. Androgen-dependent tumor. 7. Active thrombosis or thromboembolic disease and history of such events. 8. Hypersensitivity to danazol.

ADVERSE REACTIONS 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 are menstrual disturbances including spotting, alteration of the timing of the cycle and amenorrhea. Although cyclical bleeding and ovulation usually return within 60 to 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, hepatic adenoma, hepatocellular injury, hepatocellular jaundice and hepatic failure 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 and splenic peliosis; 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 and erythema multiforme; other: increased insulin requirements in diabetic patients, change in libido, myocardial infarction, palpitation, tachycardia, elevation in blood pressure, interstitial pneumonitis, and rarely, cataracts, bleeding gums, fever, pelvic pain, nipple discharge. Malignant liver tumors have been reported in rare instances, after long-term use. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions: 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. Danazol can cause insulin resistance. Caution should be exercised when used with antidiabetic drugs. Danazol may raise the plasma levels of cyclosporin and tacrolimus, leading to an increase of the renal toxicity of these drugs. Monitoring of systemic concentrations of these drugs and appropriate dose adjustments may be needed when used concomitantly with danazol. Danazol can increase the calcemic response to synthetic vitamin D analogs in primary hypoparathyroidism. The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with statins such as simvastatin, atorvastatin and lovastatin. Caution should be exercised if used concomitantly. Consult the product labeling for statin drugs for specific information on dose restrictions in presence of danazol.

DESCRIPTION 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 C 22 H 27 NO 2 . It has a molecular weight of 337.46 and the following structural formula: Danazol capsules for oral administration contain 50 mg, 100 mg or 200 mg danazol. Inactive Ingredients: anhydrous lactose, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulfate, talc. Capsule shells for 200 mg danazol contain D&C Yellow #10, FD&C Red #40, D&C Red #28, gelatin, and titanium dioxide. Capsule shells for 50 mg and 100 mg danazol contain D&C Yellow # 10, FD&C Red # 40, gelatin, and titanium dioxide. The capsule imprinting ink contains: shellac glaze in ethanol, iron oxide black, n-butyl alcohol, propylene glycol, ethanol, methanol, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, and D&C Yellow No. 10 Aluminum Lake. Danazol Molecular Structure

HOW SUPPLIED Danazol Capsules USP, 100 mg are available as maize opaque/maize opaque capsules imprinted with logo "LANNETT" on the cap and "1368" on the body and are supplied in: Bottles of 30 (NDC 71205-861-30) Bottles of 60 (NDC 71205-861-60) Bottles of 90 (NDC 71205-861-90) Bottles of 100 (NDC 71205-861-00) Bottles of 120 (NDC 71205-861-72) Bottles of 500 (NDC 71205-861-55) Danazol Capsules USP, 200 mg are available as orange opaque/orange opaque capsules imprinted with logo "LANNETT" on the cap and "1369" on the body and are supplied in: Bottles of 30 (NDC 71205-862-30) Bottles of 60 (NDC 71205-862-60) Bottles of 90 (NDC 71205-862-90) Bottles of 100 (NDC 71205-862-00) Bottles of 120 (NDC 71205-862-72) Bottles of 500 (NDC 71205-862-55) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed container with a child-resistant closure as defined in the USP. Distributed by: Lannett Company, Inc. Philadelphia, PA 19136 Repackaged and Relabeled by: Proficient Rx LP Thousand Oaks, CA 91320 CIB70495E Rev. 04/20