Danazol is a synthetic derivative of ethisterone (ethinyl testosterone) with weak androgenic and anabolic properties and no estrogenic or progestogenic activity.
Danazol is used for the palliative treatment of endometriosis in patients in whom alternative hormonal therapy is ineffective, intolerable, or contraindicated. Observation of the patient and analgesic therapy are usually adequate for patients with minimal symptoms or pelvic findings of endometriosis. Moderate endometriosis generally is treated conservatively with hormones, including estrogen and progestin (alone or in combination) or testosterone, while severe endometriosis generally requires surgery. When endometriosis is extensive, hormonal therapy may be administered prior to surgery, but danazol is not indicated when surgery alone is considered the treatment of choice. Uncontrolled clinical studies report symptomatic improvement, including relief of pain, in about 37-87% of patients with endometriosis who received danazol. Best results have occurred in patients with mild to moderate endometriosis. Resolution of endometrial lesions, as indicated by laparoscopy or laparotomy, has been reported to occur in 36-72% of patients receiving danazol. In most patients, endometriosis recurred within 8-12 months following discontinuance of the drug. Reports indicate that about 30-50% of previously infertile women with endometriosis are able to conceive within 6-8 months after danazol therapy, but this percentage is no greater than that expected following treatment with other hormones or surgery.
Danazol is used for the prophylactic treatment of all types (i.e., abdominal, cutaneous, laryngeal) of hereditary angioedema in males and females. In one well-controlled study in patients with hereditary angioedema, the number of attacks was substantially decreased during danazol therapy. However, long-term (i.e., exceeding 10 years) prophylaxis with danazol, even at low dosages, has been associated with adverse hepatic effects (e.g., hepatic adenomas). Because the adverse androgenic effects of the drug may be hazardous to children and pregnant women, some clinicians believe fibrinolytic inhibitors (e.g., aminocaproic acid) may be preferable to danazol when treating angioedema in these patients.
Danazol is used for the palliative treatment of fibrocystic breast disease in patients who are unresponsive to simple measures including the use of padded brassieres and/or analgesics. Danazol is usually effective in decreasing pain, tenderness, and nodularity; in most patients, breast pain and tenderness are substantially relieved during the first month of therapy and eliminated in 2-3 months, but elimination of nodularity usually requires 4-6 months of uninterrupted therapy. The patient should be warned that danazol therapy produces considerable alterations in hormone concentrations, and symptoms often recur following discontinuance of the drug; approximately 50% of patients may show evidence of recurrence of symptoms within 1 year after discontinuance of the drug.
In precocious puberty, danazol has been used to produce regression of secondary sexual characteristics† but the drug does not halt the progression of bone age and, therefore, it should not be used for this purpose.
Danazol has been used for the management of patients with idiopathic thrombocytopenic purpura (ITP)†. In patients with ITP, danazol produced a marked increase in platelet counts in most patients and can produce prolonged remissions; response did not appear to be affected by duration of disease or by previous failure of splenectomy or other therapies (e.g., colchicine, vinca alkaloids, corticosteroids). About 50% of patients with ITP who had unsatisfactory responses to colchicine or vinca alkaloids responded to danazol and about 30% of those who had an unsatisfactory response to corticosteroids responded to danazol. There is some evidence that efficacy of danazol in ITP may be reduced in young, unsplenectomized patients, particularly those who are female. Further study is needed to determine the role of danazol in the treatment of these conditions.
Because of their anabolic and androgenic effects on performance (ergogenic potential) and physique, androgens have been misused and abused by athletes, bodybuilders, weightlifters, and others, including high school- and college-aged individuals engaged in sports.193, 194 Following review of data from published literature and case reports in October 2016, the FDA concluded that misuse and abuse of androgens are associated with serious adverse cardiovascular, hepatic, endocrine, and mental health effects.193, 194
Serum testosterone concentrations should be evaluated in patients who may be misusing or abusing androgens (e.g., patients experiencing serious adverse cardiovascular or psychiatric effects); however, serum testosterone concentrations may be below or within the normal range in patients abusing synthetic derivatives of testosterone.135, 194
Danazol is administered orally. For the treatment of endometriosis and fibrocystic breast disease, administration of the drug should be initiated during menstruation; otherwise, appropriate laboratory tests should be performed to ensure that the patient is not pregnant. Attempts should be made to determine the lowest possible effective dosage of the drug.
For the palliative treatment of endometriosis in patients with moderate to severe disease or in patients who are infertile because of endometriosis, the usual initial dosage of danazol is 800 mg daily given in 2 divided doses. Amenorrhea and a rapid improvement in painful symptoms are best achieved at this dosage. Subsequent dosage may be gradually reduced, depending on the patient's therapeutic response, to a level sufficient to maintain amenorrhea.
For the treatment of endometriosis in patients with mild disease, the usual initial dosage is 200-400 mg daily given in 2 divided doses. Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response.
Danazol therapy for the treatment of endometriosis should continue uninterrupted for 3-6 months; however, therapy may be extended to 9 months, if necessary. If symptoms recur following discontinuance of therapy, treatment with danazol may be reinstituted.
For the symptomatic management of fibrocystic breast disease, the usual dosage of danazol is 100-400 mg daily given in 2 divided doses. Dosage should be individualized according to severity of the disease and the patient's response to treatment. Since ovulation may not be suppressed when danazol is administered at this dosage, an effective nonhormonal method of contraception is recommended during therapy with the drug. Regular menstrual patterns, irregular menstrual patterns, and amenorrhea each occur in approximately one-third of patients receiving danazol at a dosage of 100 mg daily. Irregular menstrual patterns and amenorrhea occur more frequently when higher dosages are used. In most patients, breast pain and tenderness are substantially relieved during the first month of therapy, and eliminated in 2-3 months, but elimination of nodularity usually requires 4-6 months of uninterrupted therapy. If symptoms recur following discontinuance of therapy, treatment with danazol may be reinstituted.
For the prophylactic treatment of hereditary angioedema, the usual initial dosage of danazol is 200 mg 2 or 3 times daily. After an initial response is obtained, as evidenced by prevention of episodes of edematous attacks, subsequent maintenance dosage should be determined by decreasing the dosage by 50% or less at intervals of 1-3 months or longer, depending on the frequency of attacks prior to initiation of danazol therapy. If an attack occurs during treatment with the drug, dosage may be increased by up to 200 mg daily. Dosage requirements for continuous prophylaxis should be individualized according to the patient's response to treatment. During the dosage adjustment phase, patients should be closely monitored, particularly if they have a history of airway involvement. If danazol therapy was initiated during exacerbation of angioedema resulting from trauma, stress, or other cause, periodic attempts to reduce dosage or withdraw therapy should be considered.
The most frequent adverse effects of danazol are androgenic effects, and include mild hirsutism, decreased breast size, voice changes (e.g., deepening, hoarseness, instability), sore throat, acne, increased oiliness of skin or hair, hair loss, weight gain, edema, and, rarely, clitoral hypertrophy or testicular atrophy. Adverse hypoestrogenic effects of the drug include flushing, sweating, nervousness, emotional lability, and vaginitis with itching, dryness, burning, and/or bleeding. Although these adverse effects usually subside following discontinuance of the drug, patients should be observed for signs of virilization because some adverse androgenic effects may not be reversible.
Glucose intolerance, increased insulin requirements in patients with diabetes mellitus and abnormalities in laboratory tests (e.g., serum creatine kinase [CK; creatine phosphokinase, CPK], oral glucose tolerance, glucagon, thyroxine-binding globulin, sex steroid binding globulin [sex hormone binding globulin, SHBG; testosterone-estradiol-binding globulin, TEBG], other plasma proteins, lipids and lipoproteins) also have been reported in patients receiving danazol; however, these effects have not been directly attributed to the drug.
Menstrual irregularities (e.g., spotting, alteration of menstrual cycle, amenorrhea) occur in most females receiving the drug. Amenorrhea occurs during danazol therapy in most females but menstruation usually resumes within 2-3 months following discontinuance of the drug; however, persistent amenorrhea has been reported rarely.
Hematuria also has been reported; however, this effect has not been directly attributed to the drug.
Like other 17-alkylated steroids, danazol may cause cholestatic jaundice, peliosis of the liver, and benign or (rarely) malignant hepatic adenoma following long-term administration of the drug. Hepatic dysfunction, as evidenced by elevated concentrations of hepatic enzymes (e.g., alkaline phosphatase, AST [SGOT], ALT [SGPT]) and/or by jaundice, has been reported in patients receiving danazol dosages of 400 mg or more daily.
Benign intracranial hypertension (pseudotumor cerebri), manifested as headache, papilledema, nausea and vomiting, and/or visual disturbances (e.g., diplopia), may occur in patients receiving danazol. In addition, anxiety, depression, dizziness, fainting, emotional lability, fatigue, Guillain-Barré syndrome, headache, nervousness, seizures, sleep disorders, syncope, paresthesias, tremor, and weakness have occurred during danazol therapy; however, these effects have not been directly attributed to the drug.
Increased blood pressure, thromboembolism, and thrombotic or thrombophlebitic events (e.g., sagittal sinus thrombosis, life-threatening or fatal stroke) have been reported in patients receiving danazol.
Dermatologic and Sensitivity Reactions
Allergic reactions, such as urticaria, pruritus, petechiae, rashes (e.g., maculopapular, vesicular, papular, purpuric), and erythema multiforme (including Stevens-Johnson syndrome), have occurred during danazol therapy. Photosensitivity also has been reported.
Gastroenteritis, changes in appetite, nausea, vomiting, constipation, and bleeding gums have been reported with danazol therapy; however, these effects have not been directly attributed to the drug.
Muscle cramps or spasms; joint pain or swelling; locked joints; pain in the back, neck, legs, or rarely, pelvis; and carpal tunnel syndrome (which may be secondary to fluid retention) have been reported in patients receiving danazol, although these effects have not been directly attributed to the drug.
Reversible erythrocytosis, leukocytosis, polycythemia, eosinophilia, leukopenia, thrombocytopenia, and increased erythrocyte and platelet counts have been reported with danazol therapy; however, these effects have not been directly attributed to the drug.
Visual disturbances, conjunctival edema, and rarely, cataracts have been reported with danazol therapy; however, these effects have not been directly attributed to the drug.
Serious adverse effects (e.g., increased aggression, antisocial behavior, manic episode, hostility, depression, changes in libido, increased risk of cardiovascular events, hepatotoxicity, testicular atrophy, sperm abnormalities) are associated with misuse and abuse of androgens.135, 193, 194
Manifestations of withdrawal (e.g., depressed mood, major depression, fatigue, cravings, restlessness, irritability, anorexia, insomnia, decreased libido, hypogonadotropic hypogonadism) may occur if androgens are discontinued abruptly or dosage is substantially reduced in physically dependent patients or in those taking supratherapeutic dosages of such drugs; withdrawal symptoms may persist for weeks or months.135
Fever, chills, and rarely, nasal congestion and pancreatitis also have been reported with danazol therapy; however, these effects have not been directly attributed to the drug.
Precautions and Contraindications
Because danazol may cause fluid retention, the drug should be used with caution in patients who may be adversely affected by this condition such as those with seizure disorders, migraine, or cardiac or renal dysfunction.
Periodic evaluations of liver function should be performed in all patients receiving danazol, since the drug may cause hepatic dysfunction.
Semen should be evaluated for volume, viscosity, and sperm count and motility every 3-4 months during danazol therapy, especially in adolescents.
Patients should be carefully monitored for signs of virilization, since some adverse androgenic effects may not subside after discontinuance of the drug.
Danazol has been associated with peliosis of the liver and benign or malignant hepatic adenoma, and such hepatic effects may not be apparent until complicated by acute, potentially life-threatening intra-abdominal hemorrha clinicians should be aware that such hepatotoxicity may develop during long-term administration of danazol.
Patients receiving danazol who develop signs and/or symptoms of pseudotumor cerebri (e.g., headache, nausea and vomiting, visual disturbances) should be examined for the presence of papilledema and informed to discontinue the drug immediately if any such manifestation is present; such patients should be referred to a neurologist for further evaluation and care.
Since substantial alterations in lipoprotein profiles (e.g., decreases in serum high-density lipoproteins, increases in serum low-density lipoproteins) have been reported in patients receiving danazol therapy, clinicians should consider the potential increased risk of cardiovascular disease (e.g., coronary artery disease, atherosclerosis) versus the possible benefits of therapy.
The possibility of carcinoma of the breast should be excluded before initiating danazol therapy in patients with fibrocystic breast disease. Nodularity, pain, and tenderness caused by fibrocystic breast disease may prevent recognition of underlying carcinoma before initiation of therapy. If any nodule persists or enlarges during danazol therapy, carcinoma should be considered and ruled out. Patients should be informed of the serious adverse effects associated with misuse and abuse of androgens.135
Danazol is contraindicated in pregnant or nursing women and in patients with abnormal genital bleeding of unknown etiology. The drug is also contraindicated in patients with markedly impaired hepatic, renal, or cardiac function and in those with porphyria.
Pregnancy, Fertility, and Lactation
Although there are no adequate and controlled studies to date in humans, danazol may cause fetal harm when administered to pregnant women. Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, ambiguous genitalia, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given danazol during pregnancy. Spontaneous abortions have also occurred in pregnant women who received the drug. Since the risks clearly outweigh the possible benefits in women who are or may become pregnant, danazol is contraindicated in such women. Women of childbearing age should be instructed to use an effective, nonhormonal method of contraception during danazol therapy and be informed of the potential hazard to the fetus should they become pregnant during therapy. In addition, a reliable pregnancy test (e.g., beta-subunit radioimmunoassay [RIA]) must be performed immediately prior to beginning danazol therapy. If the drug is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, administration of danazol should be discontinued, and the woman should be apprised of the potential risk to the fetus.
Although the effect of danazol on fertility in humans has not been conclusively determined, the drug suppresses ovulation at high dosages and decreases libido in women and produces a reversible oligospermia or azoospermia with no apparent change in libido in men; abnormalities in the volume and viscosity of semen and in sperm motility also may occur. Studies to further evaluate the effect of danazol on fertility are under way.
Because of the potential for serious adverse reactions to danazol in nursing infants, a decision should be made whether to discontinue nursing or not use the drug, taking into account the importance of the drug to the woman.
Danazol reportedly suppresses the pituitary-ovarian axis by inhibiting output of pituitary and hypothalamic gonadotropins. There is evidence that danazol directly inhibits the synthesis of sex steroids and binds to gonadal (sex) steroid receptors in the cytoplasm of target tissues and may thereby exhibit antiestrogen, anabolic, and weakly androgenic effects. The drug possesses weak androgenic and anabolic properties but exerts no estrogenic or progestogenic activity; androgenic activity is dose related. In addition, danazol has been shown to substantially decrease IgG, IgM, and IgA concentrations as well as phospholipid and IgG isotope autoantibodies in patients with endometriosis and associated elevations of autoantibodies, suggesting that this could be another mechanism by which the drug facilitates regression of this disorder. Danazol does not suppress normal pituitary release of corticotropin or adrenocortical release of cortisol.
When administered to women in some clinical studies, danazol suppressed the midcycle surge of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and decreased plasma estradiol and progesterone concentrations. However, other studies in women found little or no change in plasma concentrations of FSH, LH, estradiol, progesterone, and prolactin following administration of danazol. Regressive hypoestrogenic changes in the vaginal smear or in the pyknotic index of vaginal cytology, and reduced midcycle basal body temperatures have also been reported. Studies in men treated with danazol showed decreased plasma concentrations of FSH, LH, testosterone, and dihydroepiandrosterone. Investigators base claims of the antigonadotropic activity of danazol on these findings and on reports of decreased mean gonadal weight in animals treated with the drug.
In the treatment of endometriosis, suppression of ovarian steroidogenesis produces atrophy and involution of normal and ectopic endometrial tissue. Anovulation and resultant amenorrhea occur in most women after 6-8 weeks of danazol therapy. One study reported decreased sperm counts in males during danazol therapy, but another reported inconsistent changes in sperm production.
In one well-controlled study in patients with hereditary angioedema receiving danazol, serum levels of complement 1 (C1) esterase inhibitor were 4.5 times greater and C4 levels were 15 times greater than those prior to administration of the drug. In one study in several patients with factor VIII deficiency (hemophilia A) and in one patient with factor IX deficiency (hemophilia B), danazol produced substantial increases in plasma levels of factor VIII and IX, respectively. Danazol has also been shown to increase levels of alpha1-antitrypsin in deficient individuals. In a study in patients with idiopathic thrombocytopenic purpura, danazol caused a marked decrease in platelet-reactive IgG.
In one study in healthy women, oral administration of 400 mg of danazol twice daily for 2 days produced plasma danazol concentrations ranging from 140-460 ng/mL, with an average plasma concentration of 260 ng/mL 2 hours after the last dose. Bioavailability studies indicate that plasma danazol concentrations do not increase proportionally with increases in dose; doubling the dose results in a 35-40% increase in plasma concentrations. However, bioavailability and peak plasma concentrations of danazol increased by 3- to 4-fold, respectively, in healthy women who received 100- and 200-mg of danazol as single doses with a high-fat meal (more than 30 g of fat) compared with those who received the drug under fasting conditions. In addition, administration with food delayed mean time to reach peak plasma danazol concentrations by about 30 minutes.
Information regarding distribution and elimination of danazol is minimal. Danazol is metabolized to 2-hydroxymethylethisterone, which appears in the plasma in a concentration 5-10 times greater than that of the unchanged drug.
Danazol is a synthetic derivative of ethisterone (ethinyl testosterone). The drug occurs as a white to pale yellow, crystalline powder and is practically insoluble in water and sparingly soluble in alcohol.
Commercially available danazol capsules should be stored in well-closed containers at a temperature less than 40°C, preferably between 15-30°C.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 50 mg* | ||
100 mg* | Danazol Capsules | |||
200 mg* | Danazol Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
135. Abbvie. AndroGel® 1% (testosterone) topical gel prescribing information. North Chicago, IL; 2016 Oct.
193. Christou MA, Christou PA, Markozannes G et al. Effects of Anabolic Androgenic Steroids on the Reproductive System of Athletes and Recreational Users: A Systematic Review and Meta-Analysis. Sports Med . 2017; 47:1869-83. [PubMed 28258581]
194. Food and Drug Administration. Testosterone and other anabolic androgenic steroids (AAS): FDA statement - risks associated with abuse and dependence. Silver Spring, MD; 2016 Oct 25. From the FDA website. Accessed 2017 Apr 7. [Web]