Cyclomen (Danazol)

CYCLOMEN®

Sanofi

Danazol

Pituitary Gonadotropin Inhibitor

Action And Clinical 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: 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 gonadotrophic 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 97% of patients receiving 800 mg danazol daily and in 75% of 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 danazol’s suppressive effect on the gonadal steroid action and were found in 75% of 116 patients.

After institution of therapy with danazol, patients have one additional menstrual period and then become anovulatory and amenorrheic, though some patients have occasional spotting 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 longer.

Generally danazol’s action 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, however, normal menstrual patterns return within 2 months following discontinuation of therapy.

Indications And Clinical Uses: Endometriosis: The treatment of endometriosis characterized by dysmenorrhea, pelvic pain, infertility, induration of the cul de sac, or dyspareunia.

Primary Menorrhagia: The short-term (up to 6 months) hormonal management of severe primary menorrhagia (excessive menstrual bleeding at the time of expected menses in a regularly cycling women), as determined by history, physical examination, and laboratory studies. Organic pathology (such as polyps, fibroids, and genital neoplasia), abnormalities of blood coagulation (thrombocytopenia, von Willebrand’s disease) and endocrine disorders (hypothyroidism), any of which may be the cause of secondary menorrhagia, should be excluded before initiating treatment.

Fibrocystic Breast Disease: The symptomatic relief of 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.

Contra-Indications: 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.

Manufacturers’ Warnings In Clinical States: Pregnancy: 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, denazol should be initiated during menstruation and an effective nonhormonal 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.

Lactation: 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 9 months is limited. 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.

Extremely rare cases of serious adverse events and death have been reported in individual patients who were taking danazol; however, a causal relationship 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.

Precautions: In view of its pharmacology, known interactions and side effects, particular care should be observed in using danazol in those 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; a history of thrombosis or thromboembolic disease; a history of marked or persistent androgenic reaction to previous gonadal steroid therapy; migraine (see below for further precautions on several of these conditions). Danazol may cause erratic results in thyroid function tests. Patients who are taking danazol have shown the uncommon combination of low or low normal serum thyroxine, much reduced thyroxine binding globulin and normal free thyroxine index. In men and women a dose of 600 mg danazol daily for 15 days has been shown to have no significant effect on basal levels of TSH or on its response to thyrotrophin releasing hormone. The finding of normal thyroid stimulating hormone levels and free thyroxine index during danazol therapy indicates that patients are euthyroid. It is believed that the abnormality of thyroid function tests is due to an androgen-like reduction in thyroxine binding globulin rather than a true decrease in thyroid function or interference with the pituitary thyroid axis.

Changes in plasma levels of several other proteins have been observed during danazol administration. Pre-albumin, C1-esterase inhibitor, haptoglobins, transferrin, antithrombin III, prothrombin and plasminogen were all shown to increase following administration of danazol. The concentrations of T4 binding globulin, pregnancy zone protein and sex hormone binding globulin decreased to one-third or less on administration of danazol. The plasma estradiol content fell correspondingly. The clinical significance of these changes has not yet been determined. A temporary alteration of lipoproteins in the form of decreased high density lipoproteins and possibly increased low density lipoproteins has been reported in some patients during danazol therapy. Prescribers should consider the possible risk of atherosclerosis and coronary artery disease versus the benefit of therapy.

Since hepatic dysfunction has been reported in patients treated with danazol, periodic liver function tests should be performed (see Adverse Effects).

Fatal cases of fulminant hepatitis have been reported in 3 patients while on danazol therapy. One of these patients was shown to have an infection with hepatitis B virus while the symptoms and clinical course of the other 2 patients were consistent with non A – non B hepatitis.

If faced with continuing abnormalities of biochemical tests and/or their corresponding clinical manifestations, the possible risks should be carefully weighed against the potential benefits and discontinuation of danazol treatment should be considered.

It may be prudent to continue nonhormonal contraception after danazol treatment for fibrocystic breast disease until a menstrual period that is normal in amount of flow and duration has occurred.

Drug Interactions: 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.

Danazol is less likely to be effective in patients who have metrorrhagia in addition to menorrhagia (irregular as well as heavy menses).

Pregnancy: See Contraindications.

Lactation: See Contraindications.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions: The lowest dose of 200 mg daily, which is indicated for the treatment of menorrhagia (see Dosage), has clinically demonstrated a significantly lower incidence of side effects than that associated with higher doses used in the treatment of endometriosis. One should however, be aware that any of the following adverse effects can occur: acne, edema, mild hirsutism, decrease in breast size, deepening of the voice, oiliness of the skin or hair, weight gain, and rarely, clitoral hypertrophy. Also hypoestrogenic manifestations such as flushing, sweating, vaginitis including itching, dryness, burning and vaginal bleeding, nervousness, and emotional lability have been reported.

Hepatic dysfunction, as evidenced by reversible elevated serum enzymes has been reported. Jaundice has been reported rarely. It is recommended that patients receiving danazol be monitored for hepatic dysfunction by laboratory tests and clinical observation (see Precautions). Rare occurrences of benign hepatic adenomata, malignant hepatic tumor and peliosis hepatis have also been observed with long-term use. Rare cases of pancreatitis have been reported.

Although the following reactions have also been reported, a causal relationship to the administration of danazol has neither been confirmed nor refuted: Allergic: urticaria, pruritus, rarely nasal congestion.

Skin and Mucous Membranes: 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.

Gastrointestinal: nausea, vomiting, constipation, gastroenteritis and rarely pancreatitis.

Genitourinary: hematuria, prolonged post-therapy amenorrhea, disturbance of the menstrual cycle, intermenstrual spotting and/or prolonged anovulation.

Musculoskeletal: 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.

Cardiovascular: 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.

CNS: 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-Barr syndrome.

Ophthalmic: visual disturbances such as blurring of vision, difficulty in focusing, difficulty in wearing contact lenses and need for temporary alteration in refractive correction.

Hematologic: an increase in red cell and platelet count, leukopenia, thrombocytopenia and rarely eosinophilia, reversible erythrocytosis, leukocytosis, polycythemia, thrombophlebitis.

Other: hyperglucagonemia, increased insulin requirements in diabetic patients, decreased HDL cholesterol levels, decreased 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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 and the patient should be kept under observation in case of any delayed reactions.

Dosage And Administration: 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 nonhormonal 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.

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, but may be extended to 9 months, if necessary. Shorter courses of therapy have been used as adjuncts to surgery. After termination of therapy, if symptoms recur, treatment can be reinstated.

Primary Menorrhagia: A course of 200 to 400 mg of danazol daily in divided doses for up to 6 months. 200 mg is usually sufficient to reduce menstrual blood flow to acceptable limits. If no improvement is observed after 2 or 3 cycles, treatment should be discontinued and the patient should be reassessed for the cause of the excess bleeding.

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.

Availability And Storage: 50 mg: Each orange and white capsule contains: danazol 50 mg. Nonmedicinal ingredients: cornstarch, D and C Yellow #10, FD and C Red #3, gelatin, lactose, magnesium stearate, talc and titanium dioxide.
100 mg: Each yellow capsule contains: danazol 100 mg. Nonmedicinal ingredients: cornstarch, D and C Yellow #10, FD and C Yellow #6, gelatin, lactose, magnesium stearate, talc and titanium dioxide.
200 mg: Each orange capsule contains: danazol 200 mg. Nonmedicinal ingredients: cornstarch, D and C Yellow #10, FD and C Red #3, gelatin, lactose, magnesium stearate, talc and titanium dioxide.

CYCLOMEN® Sanofi Danazol Pituitary Gonadotropin Inhibitor

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