Danocrine™

[Danazol]

Danocrine

Description / Properties

The pharmacological properties of danazol include: relatively marked affinity for androgen receptors, less marked affinity for progesterone receptors, and least affinity for estrogen receptors.

Danazol is a weak androgen but anti-androgenic, progestogenic, anti-progestogenic, estrogenic and anti-estrogenic actions have also been observed. It interferes with the synthesis of gonadal steroids, possibly by inhibiting cholesterol side chain cleavage enzyme and other enzymes of steroidogenesis.

Danazol may also inhibit cyclic AMP accumulation in granulosa and luteal cells in response to gonadotrophic hormones.

Inhibition of the mid-cycle surge of FSH and LH and reduction in LH pulsatility have been observed. Danazol can reduce the mean plasma levels of these gonadotrophins after the menopause.

A wide range of actions on plasma proteins including increasing prothrombin, plasminogen, antithrombin III, alpha-2 macroglobulin, C1 esterase inhibitor, erythropoietin and reducing fibrinogen, thyroid binding and sex hormone binding globulins has been observed. Danazol increases the proportion and concentration of testosterone carried unbound in the plasma.

The suppressive effects of danazol on the hypothalamic-pituitary-gonadal axis are reversible, cyclical activity reappearing normally within 60-90 days after therapy.

Following oral administration in healthy adult females, danazol displays dose dependent absorption, which approaches linearity over the dosage range 100 to 400 mg twice daily in multiple dosaging.

Absorption is affected by prandial state, being approximately doubled if danazol is taken just after, compared with two hours before, a meal.

The principal metabolites of danazol appear to be ethisterone and 17-hydroxymethylethisterone. The mean plasma elimination half-life of danazol is in the order of 24 hours.

Indications

Treatment of endometriosis-associated symptoms or/and to reduce the extent of endometriotic foci – danazol may be used either in conjunction with surgery or, as sole hormonal therapy, in patients not responding to other treatments; in benign fibrocystic breast disease for symptomatic relief of severe pain and tenderness – danazol should be used only in patients not responsive to other therapeutic measures or for whom such measures are inadvisable; hereditary angioedema.

Contraindication

Pregnancy, breast-feeding, markedly impaired hepatic, renal or cardiac function, porphyria, androgen-dependent tumor, undiagnosed abnormal genital bleeding, active thrombosis or thromboembolic disease and history of such events.

Drug Interactions

  • Acne, weight gain, increased appetite, seborrhea, hirsutism, hair loss, voice change.
  • Disturbance of the menstrual cycle, intermenstrual spotting, amenorrhea, flushing, vaginal dryness, vaginal irritation, changes in libido.
  • Increased insulin resistance, elevation of plasma glucagon and abnormal glucose tolerance. An increase in LDL cholesterol, a decrease in HDL cholesterol affecting all subfractions and a decrease in apolipoproteins AI and
  • AII has been reported. Other metabolic events include induction of aminolevulinic acid (ALA) synthetase and reduction in thyroid binding globulin and T4 with increased uptake of T3, but without disturbance of thyroid stimulating hormone or of free thyroxin index.
  • Rashes which may be maculopapular, petechial or purpuric and may be accompanied by fever. Facial edema and photosensitivity have also been reported.
  • Backache, muscle cramps, sometimes with elevation of creatine phosphokinase levels, muscle tremors, fasciculation, limb pain, joint pain and joint swelling.
  • Emotional lability, anxiety, depressed mood, nervousness, headache, nausea.

    Interactions with laboratory function tests: Danazol treatment may interfere with laboratory determination of testosterone or plasma proteins (see 5.1 pharmacodynamic properties and 4.8 undesirable effects).

    Side Effects

    Acne, weight gain, increased appetite, seborrhea, hirsutism, hair loss, voice change.

    Disturbance of the menstrual cycle, intermenstrual spotting, amenorrhea, flushing, vaginal dryness, vaginal irritation, changes in libido.

    Increased insulin resistance, elevation of plasma glucagon and abnormal glucose tolerance. An increase in LDL cholesterol, a decrease in HDL cholesterol affecting all subfractions and a decrease in apolipoproteins AI and AII has been reported. Other metabolic events include induction of aminolevulinic acid (ALA) synthetase and reduction in thyroid binding globulin and T4 with increased uptake of T3, but without disturbance of thyroid stimulating hormone or of free thyroxin index.

    Rashes which may be maculopapular, petechial or purpuric and may be accompanied by fever. Facial edema and photosensitivity have also been reported.

    Backache, muscle cramps, sometimes with elevation of creatine phosphokinase levels, muscle tremors, fasciculation, limb pain, joint pain and joint swelling.

    Emotional lability, anxiety, depressed mood, nervousness, headache, nausea.

    Warning and Precautions

    Danazol should be stopped if any clinically significant adverse event arises, and particularly if there is evidence of: virilization (failure to stop danazol increases the risk of irreversible androgenic effects), papilledema, headache, visual disturbances or other signs or symptoms of raised intracranial pressure, jaundice or other indication of significant hepatic disturbance, thrombosis or thromboembolism.

    While a course of therapy may need to be repeated, care should be observed, as no safety data are available in relation to repeated courses of treatment over time. The risk of long-term exposure to 17-alkylated steroids including benign hepatic adenomata, hepatic peliosis and hepatic carcinoma should be considered when danazol, which is chemically related to these compounds, is used.

    Data, from two case-control epidemiological studies, were pooled to examine the relationship between endometriosis, endometriosis treatments and ovarian cancer. These preliminary results suggest that the use of danazol might increase the baseline risk of ovarian cancer in endometriosis-treated patients.

    In view of its pharmacology, known interactions and side effects, particular care should be observed in using danazol in patients with: hepatic or renal disease, hypertension or other cardiovascular disease, any state which may be exacerbated by fluid retention, diabetes mellitus, polycythemia, epilepsy, lipoprotein disorder, history of marked or persistent androgenic reaction to previous gonadal steroid therapy, or migraine.

    Close clinical monitoring is advised in all patients.

    For long-term treatment (> 6 months) or repeated courses of treatment, biannual hepatic ultrasonography is recommended.

    Laboratory monitoring should also be considered including periodic measurement of hepatic function and hematological state.

    Before treatment initiation, the presence of hormone-dependent carcinoma should be excluded at least by careful clinical examination as well as if breast nodules persist or enlarge during danazol treatment.

    Danazol should be initiated during menstruation. An effective, nonhormonal method of contraception should be employed.

    The lowest effective dose of danazol should always be sought.

    Dosage

    Danazol is for oral administration only. The following dosage regimens are recommended and should be adjusted according to the condition being treated and the patient’s response.

    Endometriosis: the recommended dosage is 200 mg to 800 mg daily, a course of treatment lasting normally six months, although up to nine months may be necessary in some cases.

    Benign fibrocystic breast disease (chronic cystic mastitis, virginal breast hyperplasia, mazoplasia, mastodynia): dosage normally ranges from 100 mg to 400 mg daily in divided doses, a course of treatment normally lasting 3-6 months.

    Hereditary angioedema: an initial dosage of 200 mg two or three times a day is recommended. Following a favorable response, the lowest effective maintenance dose should be sought and reduction in dosage of up to 50 percent may be attempted at intervals of one to three months or longer depending on the patient's history and clinical response.

    Elderly: danazol is not recommended.

    Children: danazol is not recommended

    Presentations Available

  • 100mg: Yellow opaque capsule each containing danazol U.S.P. 100 mg
  • 200mg: Orange opaque capsule each containing danazol U.S.P. 200

    Jars of 30 capsules

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