Information for the Patient
Cyclomen
Pharmacology
In women of reproductive age, the primary mode of action of danazol is believed to be by suppression of the pituitary-ovarian axis, and inhibition of the output of gonadotropins from the pituitary-gland.
Other mechanisms of action currently postulated to explain its effects are: inhibition of midcycle FSH and LH surges; inhibition of enzymes required for gonadal hormone synthesis; and competitive binding of danazol to steroid receptors at target organs.
Danazol may also inhibit cyclic AMP accumulation in granulosa and luteal cells in response to gonadotropic hormones. 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.
In postmenopausal women, danazol suppresses FSH and LH levels. It has a weak dose-related androgenic activity. Danazol is a weak androgen but antiandrogenic, progestogenic, antiprogestogenic, estrogenic and antiestrogenic actions have also been observed.
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 dosing. Absorption is affected by prandial state, being approximately doubled if danazol is taken just after, compared with 2 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.
Bioavailability studies indicate that blood levels do not increase proportionally with increases in the administered dose. When the dose is doubled, the increase in plasma levels is only about 35 to 40%.
When used for the treatment of endometriosis, danazol alters the endometrium so that it becomes inactive and atrophic. Danazol produces marked regression of ectopic endometrial tissue. Pre- and post-medication laparoscopy was done on 96 subjects. Complete or partial resolution of ectopic endometrial sites was found in 85 out of 88 patients (97%) receiving 800 mg danazol daily and in 6 out of 8 patients receiving 600 mg. This regression is due to the suppression of ovarian function which results in anovulation and associated amenorrhea. Changes in vaginal cytology and cervical mucus reflect the suppressive effect of danazol on gonadal steroid action and were found in 75% of 116 patients.
After institution of therapy with danazol, patients (generally) have one additional menstrual period and then become anovulatory and amenorrheic, though some patients have occasional spotting or bleeding for the duration of treatment. In cases where it has been examined, this bleeding was associated with an atrophic endometrium. On regimens of 200 to 600 mg daily for 3 to 6 months, highly effective relief of the signs and symptoms of endometriosis was obtained. Complete or partial relief of dysmenorrhea occurred in 94% (290/309) of patients, of pelvic pain in 85% (276/322), of dyspareunia in 84% (134/160) and of induration of the cul-de-sac in 79% (217/274). Dysmenorrhea and pelvic pain are usually relieved within the first few weeks of therapy; relief of dyspareunia and induration of the cul-de-sac take somewhat longer.
Generally, the action of danazol on hormonal regulation is reversible. Ovulation and predictable cyclical bleeding usually return within 60 to 90 days when danazol therapy is discontinued. Discontinuation results in a rebound in FSH and LH secretion with consequent increase in fecundity.
In the treatment of fibrocystic breast disease, the mode of action of danazol on the breasts is not known. Therapy with this drug lasting up to 6 months, however, results in relief of pain, tenderness and various degrees of regression of nodularity. An alteration or improvement of the pathological process at the tissue level has not been demonstrated.
Oligomenorrhea and amenorrhea occur in a dose-dependent manner in most patients. Generally, however, the action of danazol on hormonal regulation is reversible and normal menstrual patterns return within 2 months following discontinuation of therapy.
Indications
Endometriosis: Danazol is indicated for the treatment of endometriosis associated symptoms and/or 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.
Fibrocystic Breast Disease: The symptomatic relief of severe pain and tenderness associated with fibrocystic disease of the breast. Danazol should be used in those patients who do not obtain adequate relief through other therapeutic measures or in whom such measures are otherwise inadvisable.
Carcinoma of the breast should be excluded prior to commencing treatment.
The treatment course should be limited to three to six months maximum.
Precautions
Danazol may potentiate the effects of coumarin-type anticoagulants. In cases where such drugs are given concurrently with danazol, careful attention to and, if necessary, readjustment of their dosages is recommended.
Danazol can increase the plasma level of carbamazepine and may affect responsiveness to this agent and to phenytoin. A similar interaction with phenobarbital is likely.
Plasma concentrations of cyclosporine and tacrolimus, administered concurrently with danazol may be higher than expected, leading to an increase of the renal toxicity of these drugs. Elevated plasma glucagon levels have been reported in a few patients receiving danazol; diabetic patients on insulin or oral hypoglycemic agents may need to have the dosage of those agents increased appropriately in order to maintain euglycemia as danazol can cause insulin resistance.
Danazol can diminish the effectiveness of antihypertensive agents and likely interact with gonadal steroid therapy.
Danazol can increase the calcemic response to alpha calcidol in primary hypoparathyroidism.
Alteration in values for laboratory tests may occur during danazol therapy, including CPK, glucose tolerance, glucagon, thyroid-binding globulin, sex hormone binding globulin, other plasma proteins, lipid and lipoproteins and urinary 17-ketosteroids.
Ability to Drive and Use Machines: Danazol is unlikely to affect the ability to drive or use machines.
See Contraindications and Warnings.
Safety and effectiveness in children have not been established.
See Contraindications and Warnings.
Supplied
Each hard pink gelatin capsule, with “D50" on the cap and on the body contains: danazol 50 mg. Nonmedicinal ingredients: cornstarch, gelatin, lactose, magnesium stearate, red iron oxide, talc and titanium dioxide. Energy:<8 kJ (2 kcal). Bisulfite-, gluten-, sucrose- and tartrazine-free. Blisters of 100.
Each hard white gelatin capsule, with “D200" on the cap and on the body contains: danazol 200 mg. Nonmedicinal ingredients: cornstarch, gelatin, lactose, magnesium stearate, talc and titanium dioxide. Energy:<8 kJ (2 kcal). Bisulfite-, gluten-, sucrose- and tartrazine-free. Blisters of 100.
Each hard bicolor (grey cap/white body) gelatin capsule, with “D100" on the cap and on the body contains: danazol 100 mg. Nonmedicinal ingredients: black iron oxide, cornstarch, gelatin, lactose, magnesium stearate, talc and titanium dioxide. Energy:<8 kJ (2 kcal). Bisulfite-, gluten-, sucrose- and tartrazine-free. Blisters of 100.
Contraindications
In patients presenting with undiagnosed abnormal genital bleeding; genital neoplasia; markedly impaired hepatic, renal or cardiac function; pregnancy; lactation (breast-feeding); porphyria—danazol can induce ALA synthetase activity and should not be used in patients with known or suspected acute intermittent porphyria; known hypersensitivity to danazol; androgen-dependent tumor; active thrombosis or thromboembolic disease and history of such events.
Warnings
Danazol has the theoretical potential for androgenic effects in breast-fed infants and therefore either danazol therapy or breast-feeding should be discontinued.
Before initiating therapy of fibrocystic breast disease with danazol, carcinoma of the breast should be excluded.
Nodularity, pain and tenderness due to fibrocystic breast disease may prevent recognition of underlying carcinoma before treatment is begun. As evidenced during clinical trials with danazol, breast pain and tenderness are usually significantly relieved by the first month of treatment and eliminated in 2 to 3 months. Regression of nodularity may require up to 6 months of uninterrupted therapy. Therefore, if any nodule persists or enlarges during treatment, carcinoma should be considered and ruled out.
Attempts should be made to determine the lowest clinically effective dose. In view of the fact that some cases of endometriosis may be resistant to one specific form of hormone therapy and responsive to another, danazol may prove to be of benefit in such cases. There are some limited data in support of the use of danazol in therapy-resistant cases of this type.
Patients should be watched closely for signs of virilization. Some of these, in rare cases (such as deepening of voice, clitoral hypertrophy and more than minimal hirsutism), may not be reversible. In these cases, cessation of therapy should be considered in order to prevent further progression due to the risk of irreversible androgenic effects.
It should be stressed to the patient that danazol treatment involves considerable alterations of hormone levels which may be evidenced by such side effects as the occurrence of acne, weight gain, irregular menstrual patterns or amenorrhea, signs of virilization and that recurrence of the initial symptoms may occur following cessation of therapy.
Experience with danazol greater than 6 months is limited. 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. Therapy with other steroids alkylated at the 17 position has been associated with serious toxicity (cholestatic jaundice, peliosis hepatis). The physician therefore should be alerted to the possibility that similar toxicity may develop during therapy with danazol, especially when administration is continued beyond recommended time periods. Peliosis hepatitis and hepatic adenoma may be silent until complicated by acute potentially life-threatening intra-abdominal hemorrhage.
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.
Extremely rare cases of serious adverse events and death have been reported in individual patients who were taking danazol; however, a causal relation to the administration of danazol has neither been confirmed nor refuted. These included one case of acute leukemia, one fatal case of primary liver carcinoma, and a few cases of peliosis, hepatomas and the association of danazol with several cases of benign intracranial hypertension (pseudotumor cerebri), thromboembolism, thrombotic and thrombophlebitic events, including sagittal sinus thrombosis and life-threatening or fatal strokes.
Danazol may cause fetal harm when administered to a pregnant woman. Exposure to danazol in utero may result in androgenic effects on the female fetus, comprising to date clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia. A sensitive test (e.g., beta subunit test if available) capable of determining early pregnancy is recommended immediately prior to start of therapy. Additionally, danazol should be initiated during menstruation and an effective non-hormonal method of contraception should be used during therapy. If a patient becomes pregnant while taking danazol, administration of the drug should be discontinued and the patient should be apprised of the potential risk to the fetus.
Adverse Effects
hematuria, prolonged post-therapy amenorrhea, disturbance of the menstrual cycle, intermenstrual spotting and/or prolonged anovulation.
nausea, vomiting, constipation, gastroenteritis and rarely pancreatitis.
an increase in red cell and platelet count, thrombocytopenia, leukopenia and rarely eosinophilia, splenic peliosis, leukocytosis or polycythemia, thrombophlebitis.
muscle cramps or spasms sometimes with elevation of creatine phosphokinase levels, muscle or joint pain, joint lock-up, joint swelling, pain in back, neck or extremities, fasciculation, limb pain and rarely carpal tunnel syndrome.
headache, nervousness and emotional lability, dizziness and fainting, vertigo, depression, fatigue, paresthesias, chills, visual disturbances including visual hallucination followed by seizure, papilledema, retrobulbar neuritis, and rarely benign intracranial hypertension (pseudotumor cerebri), anxiety, sleep disorders, tremor, weakness, changes in appetite, aggravation of epilepsy, provocation of migraine and Guillain-Barré syndrome.
urticaria, pruritus, rarely nasal congestion.
hyperglucagonemia, increased insulin requirements in diabetic patients, decreased in HDL cholesterol affecting all subfractions levels, increased LDL cholesterol levels with variable changes in total cholesterol, decrease in apolipoproteins A1 and A11 (the clinical significance of these changes is not established), induction of aminolevulinic acid (ALA) synthetase, changes in libido, elevation in blood pressure, and rarely nipple discharge, cataracts, bleeding gums, fever, pelvic pain, epigastric and pleuritic pain, interstitial pneumonitis. Also, very rarely, reduction of spermatogenesis.
rashes (maculopapular, vesicular, papular, purpuric, petechial), acne, hyperpigmentation, hair loss, inflammatory erythematous nodules, altered skin pigmentation, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome and rarely sun sensitivity.
visual disturbances such as blurring of vision, difficulty in focusing, difficulty in wearing contact lenses and need for temporary alteration in refractive correction.
exacerbation of hypertension, palpitation, tachycardia; thrombotic events have also been observed, including sagittal sinus and cerebrovascular thrombosis as well as arterial thrombosis; cases of myocardial infarction have been reported.
Overdose
Available evidence suggests that acute overdosage would be unlikely to give rise to immediate serious reaction. Nonetheless, consideration should be given to removal of the drug by emesis or stomach pump, or to reduce the absorption of the drug by activated charcoal, and the patient should be kept under observation in case of any delayed reactions.
Dosage
Danazol is for oral administration only.
Danazol should be given as a continuous course, dosage being adjusted according to the severity of the condition and the patient's response. A reduction in dosage once a satisfactory response has been achieved may prove possible.
Therapy should begin during menstruation. Otherwise, appropriate tests should be performed to ensure that the patient is not pregnant while on danazol therapy. An effective non-hormonal method of contraception should be used during the complete course of treatment. Regular menstrual patterns, irregular menstrual patterns and amenorrhea each occur in approximately one-third of patients treated with 100 mg danazol. Irregular menstrual patterns and amenorrhea are observed more frequently with higher doses.
The treatment course should be limited to three to six months maximum.
Endometriosis: Clinical effectiveness has been achieved with total daily doses of danazol ranging from 200 to 800 mg in 2 to 4 divided doses and administered without interruption for 3 to 6 months.
If at the lower doses, an anovulatory and amenorrheic state is not achieved and if the symptomatology is not relieved in 30 to 60 days, the dose should be increased. In patients with severe presenting symptomatology, the usual starting dose is 800 mg daily. The maximum recommended daily dose is 800 mg. It is essential that therapy continue uninterrupted for 3 to 6 months. Shorter courses of therapy have been used as adjuncts to surgery. After termination of therapy, if symptoms recur, treatment can be reinstated.
Fibrocystic Breast Disease: The total daily dose of danazol ranges from 100 to 400 mg in two divided doses, depending on patient response. Pain and tenderness usually respond to treatment after 30 to 40 days. Nodularity usually does not begin to regress until 60 to 90 days after initiation of therapy. Treatment should continue uninterrupted until complete disappearance of symptoms or for 6 months, whichever occurs first. Clinical studies have demonstrated that approximately 50% of patients may show evidence of recurrence of symptoms within 1 year. In this event, treatment may be reinstated.
