Danazol

What is Danazol?

Drug Reference Information

Dosage
Usual Adult Dose:
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.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.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.

Warnings
Danazol is contraindicated in patients with severe renal or hepatic dysfunction, acute intermittent porphyria, or in women who are suspected or known to be pregnant, who are nursing, or have undiagnosed abnormal genital bleeding.

Thromboembolic and thrombophlebotic events (including sagittal sinus thrombosis), some resulting in fatal strokes, have occurred.

Life-threatening peliosis hepatis and benign hepatic adenoma have occurred following prolonged danazol administration.

Benign intracranial hypertension (pseudotumor cerebri) has been reported.

The pituitary-suppressive actions of danazol are reversible. Ovulation and cyclic bleeding usually return in 2 to 3 months following discontinuation of danazol.

Side Effects
Cardiovascular side effects have included edema and congestive heart failure.Endocrine side effects have included the inhibition of estrogen synthesis, resulting in flushing, sweating, vaginal dryness and irritation, and reduction in breast size. During administration of danazol, endogenous testosterone synthesis and release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). Large doses of danazol may suppress spermatogenesis through inhibition of pituitary follicle stimulating hormone (FSH). Danazol may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged and there is no clinical evidence of thyroid dysfunction.Gastrointestinal side effects have included nausea and vomiting. Rare cases of pancreatitis have been reported.Genitourinary side effects have included oligospermia and decreased ejaculatory volume. Elderly male patients may experience prostatic enlargement resulting in urinary obstruction. Priapism and excessive stimulation may develop.

In female patients, the use of danazol may result in virilization including deepening voice, hirsutism, acne, clitomegaly (rare), and menstrual abnormalities. Discontinuation of medication at signs of mild virilization may prevent irreversible virilization.

Alterations in libido may occur (increased/decreased).Hematologic side effects have included thromboembolic and thrombophlebotic events (including sagittal sinus thrombosis), some resulting in fatal strokes, and increased red cell production.Metabolic side effects have included significant increases in low density lipoproteins (LDL) and decreases in high density lipoproteins (HDL). Decreased glucose tolerance requiring adjustments in hyperglycemic control has occurred.Other side effects in female patients have included virilization, including deepening voice, hirsutism, acne, clitomegaly (rare), and menstrual abnormalities, due the androgenic activity of danazol. Discontinuation of danazol at signs of mild virilization may prevent irreversible virilization. Reduction in breast size may occur due to decreased estrogen synthesis.Renal side effects have included the retention of nitrogen, sodium, potassium, chloride, water and phosphorus, and decreased urinary excretion of calcium.Oncologic side effects have included rare cases of hepatic neoplasms following prolonged use.Hepatic side effects have included life-threatening peliosis hepatitis and benign hepatic adenoma following prolonged danazol administration. Rare cases of hepatic neoplasms following prolonged use have been reported. Danazol can exacerbate acute intermittent porphyria. Serum transaminase levels may be increased.

Pregnancy
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.

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

Pharmacology
Pharmacology:

Danazol, a synthetic androgen, is derived from ethisterone.

Danazol inhibits pituitary release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) resulting in reduced gonadal (sex) steroid synthesis. Danazol may directly inhibit sex steroid synthesis and competitively inhibits sex steroid binding to intracellular target tissue receptors. Suppression of ovarian function induces endometrial inactivity and atrophy. Danazol decreases IgG, IgA, IgM, and autoantibodies levels in patients with endometriosis.

Danazol exerts weak dose-related androgenic activity. Androgenic activity induces normal growth and development of male sex organs, maintains secondary sex characteristics, and modulates the growth spurt of adolescence and eventual termination of linear growth.

Danazol increases serum concentrations of C1 esterase inhibitor (C1 IHN) which results in increased concentrations of the C4 component of the compliment system.

Danazol is FDA approved for treatment of endometriosis and fibrocystic breast disease. It is also indicated for use in prevention of attacks of hereditary angioedema.

Danazol has been used in treatment of gynecomastia, menorrhagia, and precocious puberty. It has also been used in female or male contraception, breast cancer, certain anemias (red cell aplasia and other deficient red cell production anemias) to enhance red cell production, as treatment in select coagulopathies (Antithrombin III deficiency or fibrinogen excess), in inflammatory responses (autoimmune hemolytic anemia, asthma, SLE) and to modulate growth failure (primary or secondary) or short stature associated with Turner’s syndrome.

Pharmacokinetics:

Danazol is available for oral administration.

Danazol is rapidly and almost completely absorbed. Peak levels occur within 2 hours. Bioavailability is increased when danazol is taken with food (especially fatty foods), however, the time to peak concentration is delayed approximately 30 minutes.

Dosage increases do not produce proportional increases in danazol serum concentrations. Doubling the dose increases serum concentrations only 35% to 40%.

The plasma protein binding of danazol is unknown.

The volume of distribution of danazol is unknown.

The apparent total body clearance is 710 L/hour.

The elimination half-life averages 9.44 hours.

Danazol is metabolized to various metabolites. Six metabolites have been identified. Ethisterone appears to be an active metabolite and possesses progestational and mildly androgenic activity. Danazol undergoes extensive enterohepatic circulation. Danazol is found primarily in the adrenals and kidneys. Danazol is excreted by the kidneys (50%) and to a lesser extent in the feces (36%).

There are no data on the pharmacokinetic disposition of danazol in patient with renal and/or hepatic dysfunction.

There are no data on the hemodialysis or peritoneal dialysis clearance of danazol.

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