Indications:
Treatment of symptomatic relief of endometriosis cases and/or reducing ectopic foci.
Danazol can be combined with surgical treatment or hormone therapy alone in patients who have not responded to other treatments or are intolerant/contraindicated to hormone therapy.
Prophylactic treatment of hereditary angioedema in men and women.
Benign breast diseases (benign fibroadenoma in women, benign breast enlargement in men).
Menorrhagia due to uterine dysfunction.
Treatment of endometrial thinning before surgery.
Administration and dosage:
Administration:
Danazol should not be taken with a fatty meal. In women, treatment shoud be begun on the first day of menstrual cycle, or when test results confirm that patient is not pregnant. Effective dose varies with patients, so the doctor will adjust dose according to each patient to get the lowest effective dose.
Dosage:
Mild endometriosis: 100 – 200 mg/time, twice daily continuously for 3 – 6 months, treatment up to 9 months if necessary. Continue treatment until menstrual bleeding stops.
Moderate and severe endometriosis: 400 mg/time, twice daily for 3 – 6 months, treatment up to 9 months if necessary. The dose may be adjusted gradually according to the patient’s response and tolerability.
Treatment before endometrial curettage: 400 – 800 mg divided into 4 times daily for 3 – 6 weeks.
Benign fibroadenoma: 50 – 200 mg/time, twice daily, adjust dose according to patient’s response, continuous treatment for 3 – 6 months.
Breast enlargement in men: 200 mg daily, take continuously, increase dose up to 400 mg divided into 4 times daily if there is no response after 2 months. Male adolescents and male adults: Initial dose is 400 mg divided into 4 times daily. Maximum dose is 800 mg daily. Treatment time is usually 6 months.
Hereditary angioedema: 200 mg/time, 2 – 3 times daily, depending on patient’s response. Once the appropriate dose is reached, the dose can be gradually reduced to 50% or less over 1 to 3 months. If an episode of acute angioedema occurs, increase the dose to 200 mg/day. During the dose adjustment time, patient must be closely monitored.
Treatment of menorrhagia due to dysfunction: Daily dose is 200 mg for a short time. After 3 months, recheck treatment.
Dosage in children: Although the use of danazol in children should be avoided due to many undesirable effects, in practice it is still used to treat gynecomastia in adolescent males at same dose as in adults. In children with hereditary angioedema, danazol is indicated when other therapies are not effective and in children with hereditary angioedema causing abdominal pain more than once a month, take the lowest effective dose, intermittent treatment regimen and need to be closely monitored. Long-term prophylactic dose is 50 – 200 mg daily (2.5 mg/kg/day) every other day or every 3 days. Short-term prophylactic dose is 300 mg daily (5 mg/kg/day), 5 days before surgery or dental procedure and 48 hours after surgery.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine afer use.
Contraindications:
Hypersenitivity to danazol or any excipients of the medicine.
Pregnant and lactating women.
Patients with abnormal vaginal bleeding (unknown cause).
Patients with liver failure, kidney failure, heart failure, patients with porphyrinuria.
Warnings and precautions for use:
Before prescribing danazol, a benefit-risk assessment should be made. The drug has moderate testosterone activity, so it can cause irreversible androgenic effects. Non-hormonal contraception methods should be used.
Because danazol can cause fluid retention, caution should be exercised in patients with a history of convulsions, migraine syndrome, edema, cardiovascular disease, liver and kidney disease.
Liver function tests should be performed periodically because danazol can cause liver dysfunction.
During treatment with danazol, it is necessary to periodically test about every 3 – 4 months for semen volume, consistency, sperm count and motility, especially in adolescents. Erectile dysfunction should be carefully monitored because danazol affects male hormones, which may not subside after discontinuation of the drug. For women, the drug can inhibit ovulation and decrease sex drive.
Long-term use of danazol may cause hepatoxicity, benign or malignant hepatocellular tumors may develop, but may not show symptoms until complications or exacerbations appear. Risk of life-threatening is caused by intra-abdominal bleeding.
Patients treated with danazol may have symptoms of pseudotumor cerebri, which should be checked regularly, discontinued immediately if symptoms occur, and referred to a neurologist for treatment.
Because danazol can cause disturbances in blood lipoproteins (decreased high-density lipoproteins, increased low-density lipoproteins), the increased risk of coronary artery disease should be taken into account when prescribing danazol therapy and weighing benefits and risks.
Breast cancer should be excluded before treatment with danazol in patients with fibrocystic breast. If the tumor increases in size, the patient needs to have tests to diagnose and exclude breast cancer.
Use caution when using danazol in patients with other endocrine-metabolic diseases such as diabetes, hypoparathyroidism, or people with low blood calcium.
This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase enzyme deficiency or glucose-galactose malabsorption should not take this medication.
Pregnancy and lactation:
Pregnancy:
Danazol may be harmful to the fetus. Androgenic effects on the female fetus may cause disorders such as clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received if mother take danazol during pregnancy. In addition, danazol can cause miscarriage. Women of childbearing age prescribed danazol should be counseled about the use of non-hormonal contraception methods and warned of the risk of fetal harm if pregnant during treatment. If a patient accidentally takes danazol during pregnancy, or becomes pregnant during treatment with danazol, the drug should be discontinued and the mother should be informed of the possible risk to the fetus.
Women of childbearing potential or using birth control methods should consult their doctor carefully before taking this medicine.
Lactation:
Since danazol excreted into breast milk and there is a risk of severe undesirable effects in lactating infants; therefore, discontinuing the drug or discontinuing lactation should be considered, depending on the mother’s need for danazol therapy.
Effects on ability to drive and operate machinery:
Danazol has no or negligible influence on the ability to drive and operate machines. However, because the drug can cause dizziness, fatigue, insomnia, headache, caution should be exercised when driving a vehicle or operating machinery if taking this medicine.
Interaction, incompatibilities of medicine:
Interaction with other medicinal products and other forms of interaction:
Avoid combination: With antidiabetics drugs (insulin, hypoglycaemic sulphonamides) because danazol causes diabetes. If this combination is required, the patient must be informed, patient must self-monitor blood glucose. Adjust dose of antidiabetic during and after danazol therapy.
Increase effect/toxicity: Danazol may increase effects of carbamazepine, cyclosporine, tacrolimus, HMG-CoA reductase inhibitors, vitamin K antagonists. If danazol is administered with statin, there is an increased risk of rhabdomyolysis.
Drug-food interactions: Food slows serum Cmax, fatty foods increase serum drug concentration.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); can not be estimated from the available data “Not known”.
Endocrine system:
Common: Androgenic (male hormone) effects such as: Increased hair growth, smaller breasts, voice changes, oily skin or hair, acne, hair loss, weight gain, edema.
Rare: Clitoris hypertrophy, testicular atrophy may occur. Reduce estrogen hormone effects such as: Hot flashes, sweating, nervousness, mood changes, vaginal dryness, itching, burning or bleeding.
Most of these ADRs reduce and disappear after discontinuing the drug, but some may not disappear after discontinuing the drug.
Genitourinary system:
Common: Menstrual cycle disorder (long menstrual cycle or amenorrhea) in most women treated with danazol, majority of these cases shall return to normal after discontinuing the drug for 2 – 3 months. However, there are also cases of permanent amenorrhea after discontinuing the drug.
Liver:
Common: Increased serum transaminases.
Uncommon: Jaundice, hepatitis.
Rare: Hepatocellular carcinoma, malignant liver tumor in case of long-term treatment. There may be blood stasis in the liver.
Central nervous system:
Common: Fatigue, depression, dizziness, mood changes.
Uncommon: Benign intracranial hypertension (pseudotumor cerebri) with symptoms of headache, vomiting or nausea, visual disorder.
Rare: Convulsion. In addition, patient may have Guillain – Barré syndrome.
Cardiovascular system:
Rare: Hypertension, tachycardia. In addition, thromboembolism may occur.
Skin:
Common: Allergic reactions such as urticaria, rash, itching, facial edema, photosensitivity reactions.
Rare: Fixed chromosomal erythema.
Musculoskeletal:
Not known: Muscle cramps or spasms; joint pain or swelling, stiffness; backache.
Hematology:
Rare: Thrombocytopenia, leukopenia, eosinophilia.
Guidance on handling ADR:
Danazol causes endocrine ADRs, which usually disappear after drug discontinuation, but in some cases the androgenic effects are irreversible. Therefore, signs of virilization need to be monitored. Danazol may cause liver failure, therefore periodic monitoring of liver function and transaminase is required in patients treated with danazol. In addition, cases of localized blood stasis in liver, benign liver tumor, hepatocellular carcinoma may occur, these ADRs are usually asymptomatic until potentially life-threatening complications such as intra-abdominal bleeding occur. Therefore, in the case of long-term treatment, it is necessary to monitor and detect these risks early.
Risk of pseudotumor cerebri may occur during danazol therapy with manifestations of headache, vomiting, nausea, visual disorder; ophthalmoscopy is needed, if there is edema of fundus, stop the drug and immediately refer to a neurologist for treatment.
If the tumor is enlarged in patients with breast fibroadenoma taking danazol therapy, further testing is needed to exclude breast cancer.
Overdose and management:
Overdose:
It is unlikely that an acute overdose may cause an immediate severe reaction.
Management:
Late reactions should be monitored. However, when using activated charcoal, drug absorption will be reduced.
Monitor closely for timely remedial measures.
Pharmacodynamics:
Pharmacotherapeutic group: Other sex hormones and modulators of the genital system.
ATC code: G03XA01.
Danazol is a synthetic derivative of ethinyl testosterone. Danazol inhibits the pituitary – ovarian axis, thus preventing gland and hypothalamus from secreting gonadotropin. Danazol inhibits sex steroid synthesis and binds to sex steroid receptors in cytoplasm of target tissues, leads to weak anti-estrogenic, anabolic and androgenic effects. The drug has weak metabolic and androgenic properties but has no estrogenic and progestogen effects. Androgenic activity related to dose. In addition, danazol also significantly reduced concentration of IgG, IgM, IgA as well as phospholipids and IgG autoimmune antibodies in patients with endometritis have increased autoimmune antibodies. Danazol dose not inhibit the release of corticotropin by pituitary gland and the release of cortisol by adrenal gland. Several studies have shown that in women, danazol inhibits mid-cycle FSH and LH secretion and reduces plasma estradiol and progesterone concentration. However, in some other studies, plasma concentrations of FSH, LH, estradiol, progesterone and prolactin were unchanged or changed insignificantly after taking danazol. In men treated with danazol, there was a decrease in FSH, LH, testosterone and dehydroepiandrosterone concentration.
In treatment of endometrial disease, danazol inhibits steroid synthesis in ovaries, thereby causing atrophy of normal and etopic endometrial tissue. Anovulation followed by amenorrhea occurs after 6 to 8 weeks of treatment. Danazol also reduces the rate of abnormal breast parenchymal growth.
In patients with hereditary angioedema treated with danazol, serum concentration of complement C1 esterase inhibitor increases 4.5 times and complement C4 increases 15 times compared with pre-treatment. In patients with factor VIII (hemophilia A) and factor IX (hemophilia B) deficiency, danazol increases factor VIII and factor IX concentration. In addition, danazol also increases alpha1-antitrypsin concentration in patients with this factor deficiency.
Patients with idiopathic thrombocytopenic purpura treated with danazol significantly reduced antiplatelet IgG antibodies, especially in patients who had failed splenectomy and other therapies (such as colchicine, periwinkle alkaloids, cortisteroids).
Pharmacokinetics:
Absorption: Danazol is well absorbed from the orally administration. In healthy women, taking danazol dose of 400 mg twice daily, in 2 days, peak plasma concentration is achived at about 140 – 460 nanogram/ml, averaging about 260 nanogram/ml, 2 hours after last dose. Bioavailability study showed that plasma plasma danazol concentration does not increase linearly with oral dose. When dose is doubled, danazol plasma concentration increases only 35 – 40%. Taking drug with high-fat meal (about 30 g fat) may increase bioavailability and Cmax by 3 – 4 times compared to taking it in fasted state. However, taking drug with meal increase time to reach Cmax by about 30 minutes.
Distribution, metabolism and elimination: Information on danazol distribution and elimination is limited. Danazol is mostly metabolised in liver to 2-hydroxymethylethiesterone which is an inactive metabolite.
Metabolites are excreted in urine and feces. Danazol half-file is about 3 – 6 hours after a single dose, but increase to 26 hours with repeated dosing. Danazol and its metabolites may undergo enterohepatic circulation.
