Professional Drug Information > Danocrine

Danazol (Systemic)

VA CLASSIFICATION
Primary: HS109
Secondary: IM900

Commonly used brand name(s): Cyclomen; Danocrine.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Gonadotropin inhibitor—

angioedema (hereditary) prophylactic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Endometriosis (treatment)—Danazol is indicated for the treatment of pain and/or ^{02} infertility due to endometriosis. ^{{01} {12}}

Breast disease, fibrocystic (treatment)—Danazol is indicated for the treatment of fibrocystic breast disease in patients whose symptoms are not relieved by analgesics, the use of well-fitted bras, or other simple methods. ^{{01} {12}}

Angioedema, hereditary (prophylaxis)¹—Danazol is indicated for the prophylactic treatment of hereditary angioedema (cutaneous, abdominal, and laryngeal) in males and females, ^{01} including prior to surgery. ^{{08} {11}}

[Menorrhagia, primary (treatment)]—Danazol is indicated for short-term (up to 6 months) use in the treatment of severe primary menorrhagia at the time of expected menses in women with regular menstrual cycles. ^{12} Secondary menorrhagia manifest as abnormalities of blood coagulation (e.g., thrombocytopenia, von Willebrand's disease), endocrine disorders (e.g., hypothyroidism), or organic pathology (e.g., fibroids, genital neoplasia, polyps) should be ruled out prior to initiation of therapy. ^{12}

[Gynecomastia (treatment)]^1{15} or
[Puberty, precocious (treatment)]¹—Danazol is indicated for the treatment of gynecomastia and precocious puberty in females. ^{15}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Synthetic androgen.
Molecular weight—
    337.46 ^{{01} {06}}

Mechanism of action/Effect:

Gonadotropin inhibitor—Danazol suppresses the pituitary-ovarian axis ^{01} possibly by inhibiting the output of pituitary gonadotropins. ^{12} Danazol also depresses the preovulatory surge in output of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) ^{01} and therefore reduces ovarian estrogen production. Danazol also may directly inhibit ovarian steroidogenesis, bind to androgen, progesterone, and glucocorticoid receptors, bind to sex-hormone–binding globulin and corticosteroid-binding globulin, and increase the metabolic clearance rate of progesterone.

Endometriosis—As a consequence of suppression of ovarian function, both normal and ectopic endometrial tissues become inactive and atrophic. ^{{01} {12}} As a result, anovulation and associated amenorrhea occur. ^{12}

Fibrocystic breast disease—The exact mechanism of action is unknown, ^{12} but may be related to suppressed estrogenic stimulation as a result of decreased ovarian production of estrogen. A direct effect on steroid receptor sites in breast tissue also is possible. Disappearance of nodularity, relief of pain and tenderness, and possibly changes in the menstrual pattern result. ^{01}

Hereditary angioedema—Danazol corrects the underlying biochemical deficiency by increasing serum concentrations of the deficient C1 esterase inhibitor, resulting in increased serum concentrations of the C4 component of the complement system. ^{01}


Other actions/effects:

Danazol has weak androgenic effects ^{{01} {12}} and significantly decreases concentrations of immunoglobulins, IgA, IgG, and IgM, and also concentrations of phospholipids and IgG isotope autoantibodies in patients with endometriosis and associated elevations of autoantibodies. ^{01}

Absorption:

In studies in female volunteers, the mean time to peak concentration was delayed by food by approximately 30 minutes. ^{01}

Biotransformation:

Hepatic, to principal metabolites, ethisterone and 17-hydroxymethylethisterone. ^{12}

Half-life:

Elimination—Approximately 24 hours. ^{12}

Onset of action:

Endometriosis—Relief of dysmenorrhea and pelvic pain usually occurs within the first few weeks of therapy. ^{12}

Fibrocystic breast disease—Relief of breast pain and tenderness usually begins within 1 month. ^{{01} {09} {12}}

Peak serum concentration:

Following a 100-mg dose twice a day—200 to 800 nanograms per mL.

Following a 200-mg dose twice a day for 14 days—250 nanograms to 2 mcg per mL.

Time to peak effect:

Anovulation and amenorrhea—Usually occur after 6 to 8 weeks of therapy.

Fibrocystic breast disease—Breast pain and tenderness are usually eliminated after 2 to 3 months of therapy. Elimination of nodularity usually requires 4 to 6 months of uninterrupted therapy.

Duration of action:

Anovulation and amenorrhea—Ovulation and cyclic bleeding usually return within 60 to 90 days after therapy is withdrawn. ^{{01} {12}}

Fibrocystic breast disease—Symptoms return to some degree within 1 year after therapy is withdrawn in 50% of patients. ^{{01} {12}}

Elimination:
    Renal.


Precautions to Consider

Carcinogenicity

Studies to determine the carcinogenic potential of danazol have not been performed. ^{01}

Pregnancy/Reproduction

Pregnancy—
Danazol is contraindicated during pregnancy. ^{{01} {10}} Exposure to danazol in utero may result in androgenic effects (ambiguous genitalia, clitoral hypertrophy, labial fusion of the external genitalia, urogenital sinus defect, vaginal atresia) in the female fetus. ^{{01} {12}}

Unless abstinence is the chosen method, it is recommended that the patient use a form of nonhormonal contraception to prevent pregnancy during therapy. ^{{01} {12}} In patients treated for fibrocystic breast disease, nonhormonal contraception should be continued after danazol therapy until a menstrual period that is normal in amount of flow and duration has occurred. ^{12} If pregnancy occurs during therapy, danazol should be discontinued, and the patient should be made aware of the potential risk to the fetus. ^{{01} {12}}

Studies in pregnant rats administered danazol orally at doses of up to 250 mg per kg of body weight (mg/kg) per day (7 to 15 times the human dose) on days 6 through 15 of gestation did not show drug-induced embryotoxicity or teratogenicity or a difference in litter size, viability, or weight of offspring as compared with controls. However, studies in rabbits administered oral doses of 60 mg/kg per day (2 to 4 times the human dose) on days 6 through 18 of gestation showed inhibition in fetal development. ^{01}

FDA Pregnancy Category X. ^{01}

Breast-feeding

Nursing mothers should be advised to contact a physician before nursing infants. Use by nursing mothers is not recommended because of possible androgenic effects in the infant, such as precocious sexual development in males and virilization in females. ^{{10} {12} {13}}

Pediatrics

Caution is recommended in children and growing adolescents who are being treated for hereditary angioedema, because of possible androgenic effects, such as precocious sexual development in males and virilization in females. ^{11} Premature epiphyseal closure also may occur. ^{13}


Geriatrics


No information is available on the relationship of age to the effects of danazol in geriatric patients.

Treatment of geriatric male patients with androgens may cause increased risk of prostatic hyperplasia or prostatic carcinoma. ^{13}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Anticoagulants, coumarin- or indanedione-derivative^{01}{12}    (concurrent use with danazol may enhance effects of anticoagulants because of decreased hepatic synthesis of procoagulant factors, and may cause bleeding)


Antidiabetic agents, oral^{12} or
Insulin^{12}    (danazol may increase blood glucose concentrations and resistance to insulin ^{{11} {12}} due to changes in the metabolism of carbohydrates; ^{11} dosage adjustment of the antidiabetic agent or insulin may be necessary ^{12})


Carbamazepine^{01}{12}    (concurrent use may cause inhibition of carbamazepine metabolism, ^{07} resulting in increased plasma concentrations ^{{01} {07} {12}} and toxicity ^{01})


Cyclosporine^{12} or
» Tacrolimus^{12}    (danazol may increase plasma concentrations of cyclosporine and tacrolimus and may increase the risk of nephrotoxicity ^{{04} {12}})


Glucagon^{12}    (danazol may increase the plasma concentrations of glucagon ^{12})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Glucose tolerance test^{01}{12}    (results may be impaired)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT])^{14} or
Aspartate aminotransferase (AST [SGOT])^{14}    (values may be increased early in therapy and decreased toward baseline later in therapy; values generally return to baseline within one month following therapy ^{14})


Aldosase or
Creatine kinase (CK)^{01}{12}    (concentrations may be increased in the presence of muscle toxicity or rhabdomyolysis)


Androstenedione, serum^{01} or
Dehydroepiandrosterone (DHEA) sulfate^{01} or
Testosterone, free and total^{01}    (concentrations may be abnormal ^{01})


Blood pressure    (may be increased as a result of volume expansion ^{03})


Cholic acid, serum or
Cholic acid-to-chenodeoxycholic acid, serum ratio    (fasting concentrations may be increased during therapy but generally return to baseline within one month following therapy ^{14})


Delta aminolevulinic acid (ALA), urine^{01}{12}    (concentrations may be increased in response to induction of ALA dehydratase activity by danazol ^{{01} {12}})


Glucose, blood or
Lipoproteins, low-density^{01}{12}    (concentrations may be increased ^{{01} {12}})


Lipoproteins, high-density^{01}{12}    (concentrations may be decreased ^{{01} {12}})


Prothrombin time^{01}    (may be prolonged in patients taking coumarin- or indanedione-derivative anticoagulants ^{01})


Thyroid function tests^{01}    (total serum thyroxine [T ₄] may be decreased, and triiodothyroxine [T ₃] uptake may be increased; however, free T ₄ and thyroid-stimulating hormone [TSH] remain normal because of a concomitant decrease in thyroxine-binding globulin [TBG] ^{12})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiac function impairment, severe^{01}{12}
» Genital neoplasia^{12}
» Hepatic function impairment, severe^{01}{12}
» Porphyria^{01}{12}    (may be exacerbated ^{01})


» Renal function impairment, severe^{01}{12}
» Thromboembolic disease or thrombosis, active or history of^{12}
» Tumor, androgen-dependent^{12}
» Vaginal bleeding, undiagnosed, abnormal^{01}{12}
Risk-benefit should be considered when the following medical problems exist
Cardiac function impairment^{01}{12} or
Epilepsy^{01}{12} or
Migraine headaches^{01}{12} or
Renal function impairment^{01}{12}    (may be aggravated by fluid retention induced by danazol)


Diabetes mellitus^{12}    (possible impairment of glucose tolerance)


Sensitivity to anabolic steroids, androgens, or danazol

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Biopsy of cysts or
Mammography    (recommended prior to initiation of treatment for fibrocystic breast disease to rule out carcinoma; ^{{01} {12}} recommended during treatment if nodules persist or enlarge ^{{01} {12}})


» Hepatic function determinations^{01}{12}    (recommended at periodic intervals during therapy ^{12})


» Pregnancy test^{01}{12}    (recommended immediately prior to treatment of endometriosis or fibrocystic breast disease, if treatment is not started during menstruation or if the patient has irregular menstrual cycles ^{{01} {02} {12}})


Semen analysis    (recommended every 3 to 4 months, especially in adolescents, to assess motility, viscosity, volume, and total count of spermatozoa)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
In females
    
Amenorrhea (stopping of menstrual periods)^{01}{12}
    
breakthrough bleeding (heavier, irregular vaginal bleeding between regular menses)
    
decrease in breast size ^{10}{12}
    
irregular menstrual periods ^{01}{12}
    
spotting (lighter, irregular vaginal bleeding between regular menses)^{01}{12}
    
weight gain ^{{01}{08}{10}{12}}

Note: Amenorrhea occurs in most patients treated for endometriosis. ^{02} It also occurs in 50% of patients treated for fibrocystic breast disease with doses of 100 mg or more, although anovulation may not occur. Amenorrhea may be prolonged after danazol therapy is discontinued in any patient.
Breakthrough bleeding or spotting may occur in the first few months of therapy for endometriosis but does not necessarily indicate a lack of efficacy of the medication. ^{02}
Irregular menstrual periods occur in 25% of patients treated for fibrocystic breast disease, although anovulation may not occur.



Incidence less frequent
In both females and males
    
Peripheral edema (rapid weight gain; swelling of feet or lower legs)—dose-related^{01}
    
rhabdomyolysis (dark-colored urine; muscle cramps or spasms; unusual tiredness or weakness)
    
virilization (acne; oily hair; oily skin)^{01}—dose-related^{12}


Incidence rare
In both females and males
    
Adenoma, hepatocellular ^{01}{12}
    
bladder telangiectasia (blood in urine)
    
bleeding gums
    
carpal tunnel syndrome (burning, numbness, pain, or tingling in all fingers except smallest finger)^{01}{12}
    
cataracts (gradual blurring or loss of vision)
    
cholestatic jaundice —has occurred during long-term treatment with other 17-alkylated androgens^{02}{12}
    
discharge from nipple ^{01}{12}
    
eosinophilia (general feeling of illness; sudden coughing episodes)^{01}{12}
    
hepatic dysfunction (yellow eyes or skin)—with doses greater than 400 mg of danazol per day^{01}
    
intracranial hypertension, benign (decrease in vision; double vision; headache, severe; nausea; papilledema; vomiting)^{01}{12}
    
leukocytosis (chills; cough; eye pain; general feeling of illness; headache; sore throat; unusual tiredness)^{01}{12}
    
pancreatitis, acute (bloating and tenderness of abdomen; fast heartbeat; fever; nausea; pain in upper or middle abdomen, continuing, sudden, and severe; unusual tiredness; vomiting; yellow eyes or skin, transient)^{01}{12}
    
peliosis hepatis (dark-colored urine; fever; hives; light-colored stools; loss of appetite, continuing; nausea; purple- or red-colored spots on body or inside the mouth or nose; sore throat; vomiting)—has occurred during long-term treatment^{01}{12}
    
polyneuritis, acute idiopathic (numbness; tingling sensation or weakness in both legs, moving upward to both arms, trunk, and face)
    
skin rash
    
Stevens-Johnson syndrome (chest pain; cough; diarrhea; fever; general feeling of illness; joint pain; lesions on skin and inside the mouth or nose; muscle aches; sore throat; vomiting)^{01}{12}
    
thrombocytopenia (heavier menstrual periods; more frequent nosebleeds; unusual bruising or bleeding)^{01}{12}
    
thromboembolism or thrombotic and thrombophlebitic events including stroke (chest pain; complete or partial numbness or weakness on one side of body; cough; coughing up blood; difficulty in speaking; difficulty in swallowing; double vision; loss of muscle coordination; nausea; restlessness; shortness of breath; sweating; weakness)—may be life-threatening or fatal
or sagittal sinus thrombosis (extreme exhaustion; headache)^{01}{12}

Note: Hepatocellular adenoma and peliosis hepatis may be asymptomatic until acute, potentially life-threatening intra-abdominal hemorrhage occurs. ^{{01} {12}}
If benign intracranial hypertension is suspected, the patient should be monitored for papilledema. If confirmed, danazol use should be immediately discontinued and the patient referred to a neurologist for further evaluation and care. ^{01}


In females only
    
Virilization (enlarged clitoris; hoarseness or deepening of voice; unnatural hair growth)^{12}—dose-related^{10}

Note: Danazol should be discontinued if symptoms of virilization, which may not be reversible, occur to prevent further progression. ^{12}


In males only
    
Abnormalities in semen viscosity and volume, and in sperm count and motility —may occur during long-term therapy^{01}
    
testicular atrophy (decrease in size of testicles)




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
In both females and males
    
Hypoestrogenemia (flushing or redness of skin; mood or mental changes; nervousness; sweating)^{01}{12}


Incidence rare
In both females and males
    
Photosensitivity ^{01}{12}

In females only
    
Vaginitis (burning, dryness, or itching of vagina; vaginal bleeding)—hypoestrogenic effect^{01}{12}






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Danazol (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to anabolic steroids, androgens, or danazol

Pregnancy—Use is contraindicated during pregnancy because of possible androgenic effects in the female fetus





Breast-feeding—Use is usually not recommended, because of possible androgenic effects in the infant





Use in children—Caution is recommended because of possible androgenic effects

Other medications, especially coumarin- or indanedione-derivative anticoagulants or tacrolimus
Other medical problems, especially androgen-dependent tumor; genital neoplasia; porphyria; severe cardiac function impairment; severe hepatic function impairment; severe renal function impairment; thromboembolic disease or thrombosis, active or history of; or undiagnosed abnormal vaginal bleeding

Proper use of this medication
» Taking for full time of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

» Discontinuing therapy if symptoms of virilization (which may not be reversible) occur
Patients with diabetes: May alter blood glucose concentrations

» Possible photosensitivity reactions: caution during exposure to sun or when using sunlamps, tanning booths or beds

For treatment of endometriosis or fibrocystic breast disease
Possibility of amenorrhea or irregular menstrual periods; checking with physician if regular menstruation does not occur within 60 to 90 days after discontinuation of medication

Advisability of using nonhormonal forms of contraception during therapy; not using oral contraceptives

» Stopping medication and checking with physician if pregnancy is suspected


Side/adverse effects
Signs of potential side effects, especially:

• In both females and males—Peripheral edema; rhabdomyolysis; virilization; adenoma, hepatocellular; bladder telangiectasia; bleeding gums; carpal tunnel syndrome; cataracts; cholestatic jaundice; discharge from nipple; eosinophilia; hepatic dysfunction; intracranial hypertension, benign; leukocytosis; pancreatitis, acute; peliosis hepatis; polyneuritis, acute idiopathic; skin rash; Stevens-Johnson syndrome; thrombocytopenia; and thromboembolism or thrombotic and thrombophlebitic events


• In females only—Decrease in breast size, irregular menstrual periods, weight gain, and virilization


• In males only—Abnormalities in semen viscosity and volume, and in sperm count and motility and testicular atrophy



General Dosing Information
In the treatment of endometriosis and fibrocystic breast disease, it is recommended that therapy begin with the first day of the menstrual cycle after pregnancy has been ruled out. ^{{01} {02} {12}}

Development of amenorrhea is usually evidence of a clinical response to danazol in the treatment of endometriosis, although spotting or bleeding from the atrophic endometrium can still occur. ^{{01} {02} {12}}

In the treatment of endometriosis, therapy should be continued uninterrupted for 3 to 6 months, and may be continued for 9 months if necessary. ^{{01} {12}}

Dosage requirements for continuous treatment of hereditary angioedema should be individualized on the basis of the patient's clinical response. ^{01}

It is recommended that danazol treatment be discontinued if symptoms of virilization (which may not be reversible ^{01}) occur. ^{12}


Oral Dosage Forms

DANAZOL CAPSULES USP

Usual adult and adolescent dose
Endometriosis
Moderate to severe: Oral, 400 mg two times a day (beginning Day 1 of menstruation, if possible) ^{{01} {02} {12}} for at least three to six months, and may be continued for nine months if necessary. ^{{01} {12}}

Mild: Oral, 100 to 200 mg two times a day (beginning Day 1 of menstruation, if possible) ^{{01} {02}} for at least three to six months, and may be continued for nine months if necessary. ^{{01} {12}}

Note: If symptoms recur after discontinuation of therapy, therapy may be reinstituted. ^{{01} {12}}


Fibrocystic breast disease
Oral, 50 to 200 mg two times a day (beginning Day 1 of menstruation, if possible) ^{{01} {02} {12}} for six months or until the symptoms completely disappear, whichever comes first. ^{12}

Note: If symptoms recur within one year of discontinuation of therapy, therapy may be reinstituted. ^{{01} {12}}


Hereditary angioedema, prophylaxis of¹
Oral, initially 200 mg two or three times a day until the desired initial response is obtained; then the maintenance dosage is determined by decreasing the initial dosage by 50% or less at intervals of one to three months or longer, depending on the frequency of attacks prior to treatment. ^{01}

Note: Daily dosage may be increased by up to 200 mg if the condition is not controlled at lower doses. ^{{01} {08}}


[Primary menorrhagia]
Oral, 200 to 400 mg a day, in divided doses (beginning Day 1 of menstruation, if possible), for up to six months. ^{12}

Note: If no improvement is seen after two or three cycles, therapy should be discontinued and the cause of the excess bleeding reassessed. ^{12}



Usual adult prescribing limits
800 mg per day. ^{12}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg (Rx) [Danocrine^{01}][Generic]^{16}


100 mg (Rx) [Danocrine^{01}][Generic]^{16}


200 mg (Rx) [Danocrine^{01}][Generic]^{16}

Canada—


50 mg (Rx) [Cyclomen^{12}]


100 mg (Rx) [Cyclomen^{12}]


200 mg (Rx) [Cyclomen^{12}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), ^{01} unless otherwise specified by manufacturer. Store in a well-closed container. ^{05}

Revised: 06/09/1999

References

1. Danocrine (Sanofi). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2778-80.
   

2. Reviewers' consensus on monograph revision of 1986.
   

3. Facts & comparisons; 06/87. p. 116-116a.
   

4. Reviewers' consensus on Cyclosporine (Systemic) monograph revision of 05/18/86.
   

5. The United States pharmacopeia. The national formulary. USP 23rd revision (January 1, 1995). NF 18th ed. (January 1, 1995). Rockville, MD: The United States Pharmacopeial Convention Inc; 1994. p. 453.
   

6. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 208.
   

7. McInnes GT, Brodie MJ. Drug interactions that matter. A critical reappraisal. Drugs 1988; 36: 83-110.
   

8. Panel comment, 07/89.
   

9. Panel comment, 07/89.
   

10. Panel comment, 07/89.
    

11. Manufacturer comment, 07/89.
    

12. Cyclomen (Sanofi). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 34th ed. Ottawa: Canadian Pharmacists Association; 1999. p. 431-2.
    

13. Reviewers' consensus on monograph revision of 07/89.
    

14. Heikkinen J, et al. Serum bile acid concentrations as an indicator of liver dysfunction induced during danazol therapy. Fertil Steril 1988; 50(5): 761-5.
    

15. AMA Drug evaluations. 6th ed. Chicago: American Medical Association; September 1986.
    

16. Cardinale V, editor. 1999 drug topics red book. Montvale, NJ: Medical Economics Company Inc; 1999. p. 274.
    

Link to this page

Printable Version

Email Page