Pharmacology
Cyproterone is a steroid which clinically demonstrates 2 distinct properties: antiandrogenic: cyproterone blocks the binding of dihydrotestosterone—the active metabolite of testosterone—to the specific receptors in the prostatic carcinoma cell. Progestogenic/antigonadotrophic: Cyproterone exerts a negative feed-back on the hypothalamo-pituitary axis, by inhibiting the secretion of LH leading to diminished production of testicular testosterone.
The absorption of cyproterone following oral administration is complete. Peak plasma levels are reached 3 to 4 hours after administration. Plasma levels fall rapidly during the first 24 hours as a result of tissue distribution and excretion, and plasma half-life was 38±5 hours.
Most of the cyproterone is excreted unchanged in the feces (60%) or urine (33%) within 72 hours.
Cyproterone is eliminated in the urine mainly in the form of unconjugated metabolites and in the bile via feces in the form of glucuronidized metabolites.
The principal metabolite identified was 15 β-hydroxy-cyproterone acetate.
Androcur Depot: Following i.m. administration, mean maximum blood levels are attained 3.4 days after injection. The mean elimination half-life was found to be 4 days.
Indications
For the palliative treatment of patients with advanced prostatic carcinoma.
Precautions
Thromboembolism: Clinical investigations have shown that when cyproterone is used alone it has a minor effect on blood clotting factors. However, when cyproterone was combined with ethinyl estradiol, changes were found in increased coagulation capability. There is an inherent risk for those patients with a history of thrombophlebitis or thromboembolism for recurrence of the disease. Cyproterone should be discontinued at the first sign of thrombophlebitis or thromboembolism. And, the patient should be carefully re-evaluated if manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular complications, retinal thrombosis or pulmonary embolism) occur.
Adrenocortical Function: Suppression of adrenocortical function tests have occurred in patients receiving high doses (100 mg/m2) of cyproterone.
Reduced response to endogenous ACTH was noted by metyrapone test; furthermore, reduced ACTH and cortisol blood levels determined by the Mattingly method were also found.
It is therefore recommended that adrenocortical function tests should be monitored periodically by serum cortisol assay.
Diabetes: Cyproterone may impair carbohydrate metabolism. Parameters of carbohydrate metabolism, fasting blood glucose and glucose tolerance test, should be examined carefully in all patients and particularly in all diabetics before and regularly during therapy with cyproterone.
Hematology: Hypochromic anemia has been observed rarely during therapy with cyproterone. Regular hematological assessment is recommended.
Nitrogen Balance: A negative nitrogen balance is usual at the start of therapy, but does generally correct itself within 3 months of continued therapy.
Metabolic Effects: Fluid retention, hypercalcemia and changes in plasma lipid profile may occur. Accordingly, cyproterone should be used with caution in patients with cardiac disease.
Skin: Cyproterone therapy may cause a reduction of sebum production leading to dryness of the skin, and transient patchy loss of body hair.
Concomitant Alcohol: Alcohol may reduce the antiandrogenic effect of cyproterone in hypersexuality. The relevance of this in prostatic carcinoma is not known, however, it would be prudent to inform the patients that the use of alcohol during cyproterone therapy is not advisable.
Physical Performance: Patients should be informed that fatigue and lassitude are common in the first few weeks of therapy, but usually becomes much less pronounced from the third month on.
Marked lassitude and asthenia necessitate special care when driving or operating machinery.
Supplied
Each ampul contains: cyproterone acetate 100 mg/mL in a castor oil solution. Nonmedicinal ingredients: benzyl benzoate and castor oil. Ampuls of 3 mL, boxes of 4.
Each white, round, flat-sided tablet with beveled edges, imprinted one side “BV” in a regular hexagon, other side scored, contains: cyproterone acetate 50 mg. Nonmedicinal ingredients: aerosil (colloidal silicic acid), cornstarch, lactose, magnesium stearate and polyvinylpyrrolidone. Gluten- and tartrazine-free. Bottles of 60.
Contraindications
Known hypersensitivity to the drug. Active liver disease and hepatic dysfunction. Renal insufficiency.
Warnings
Liver Function: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200 to 300 mg cyproterone. Most reported cases are in men with prostatic cancer. Toxicity is dose-related and develops usually, several months after treatment has begun. Liver function tests should be performed before treatment and whenever any symptoms or signs suggestive of hepatotoxicity occur. If hepatotoxicity is confirmed, cyproterone should normally be withdrawn, unless the hepatotoxicity can be explained by another cause, e.g., metastatic disease, in which case cyproterone should be continued only if the perceived benefit outweighs the risk.
Inhibition of Spermatogenesis: The sperm count and the volume of ejaculate are reduced at oral doses of 50 to 300 mg/day. Infertility is usual, and there may be azoospermia after 8 weeks of therapy, which is associated with atrophy of seminiferous tubules.
Follow-up examinations on discontinuation of therapy have shown these changes to be reversible.
Spermatogenesis usually reverts to its previous level about 3 to 5 months after stopping cyproterone, or in some patients, after up to 20 months. Production of abnormal spermatozoa during cyproterone therapy has been observed; their relationship to abnormal fertilization or malformed embryos is not known.
Gynecomastia: Benign nodules (hyperplasia) of the breast have been reported, these generally subside 1 to 3 months after discontinuation of therapy and/or after a reduction of dosage. The reduction of dosage should be weighed against the risk of inadequate tumor control.
Depression: Cyproterone therapy has occasionally been associated with an increased incidence of depressive mood changes, especially during the first 6 to 8 weeks of therapy. Similar mood changes have also been seen following surgical castration and are considered to be due to androgen deprivation. Patients with tendencies to depressive reaction should be carefully observed.
Antiandrogen Withdrawal Syndrome: In some patients with metastatic prostate cancer, antiandrogens (steroidal or nonsteroidal), may promote, rather than inhibit, the growth of prostate cancer. A decrease in PSA and/or clinical improvement following the discontinuation of antiandrogens have been reported. It is recommended that patients prescribed an antiandrogen, who have PSA progression, should have the antiandrogen discontinued immediately and be monitored for 6-8 weeks for a withdrawal response prior to any decision to proceed with other prostate cancer therapy.
Adverse Effects
increased fibrinogen, decreased prothrombin, thrombocytopenia, anemia, hemolytic anemia, hypochromic anemia, normocytic anemia, leukopenia and leukocytosis.
fatigue, lassitude, weakness, hot flashes, increased sweating, aphasia, coma, depression, dizziness, encephalopathy, hemiplegia, personality disorder, psychotic depression, abnormal gait and headache.
myasthenia, osteoporosis.
constipation, diarrhea, indigestion, anorexia, nausea, vomiting, cholestatic jaundice, cirrhosis of liver, hepatic coma, hepatitis, hepatoma, hepatomegaly, jaundice, liver carcinoma, liver failure, abnormal liver function test, liver necrosis, pancreatitis and glossitis.
enlarged uterine fibroids, uterine hemorrhage, increased urinary frequency, bladder carcinoma, kidney failure, hematuria, urate crystalluria, urine abnormality.
negative nitrogen balance, decreased response to ACTH, hyperglycemia, lowered cortisol, hypercalcemia, increased AST, increased ALT, increased creatinine, hypernatremia, edema, weight gain, weight loss and diabetes mellitus.
asthma, increased cough, dyspnea, hyperventilation, respiratory disorder, shortness of breath on effort, lung fibrosis.
ascites, allergic reaction, asthenia, chills, fetal chromosome abnormality, death, fever, hernia, malaise and injection site reaction.
Adverse reactions are rarely of sufficient severity to require dosage reduction or discontinuation of treatment.
If reactions are severe, it may be beneficial to reduce the dosage.
eczema, urticaria, erythema nodosum, exfoliative dermatitis, rash, maculopapular rash, dryness of the skin, pruritus, alopecia, hirsutism, skin discolouration, photosensitivity reactions and scleroderma.
ear disorder, optic atrophy, optic neuritis, abnormality of accommodation, abnormal vision, blindness and retinal disorder.
hypotension, tachycardia, heart failure, syncope, myocardial infarct, hemorrhage, cerebrovascular accident, cardiovascular disorder, retinal vascular disorder, embolus, pulmonary embolism, superficial and deep thrombophlebitis, thrombosis, retinal vein thrombosis, phlebitis, vascular headache and shock.
Overdose
There have been no reports of fatal overdosage in man with cyproterone. There are no specific antidotes and treatment should be symptomatic. If oral overdosage is discovered within 2 to 3 hours, gastric lavage can safely be used if indicated.
Dosage
Oral Tablets: The usual daily initial and maintenance dose is 4 to 6 tablets (200 to 300 mg) divided into 2 to 3 doses and taken after meals.
After orchiectomy a lower daily dose of 2 to 4 tablets (100 to 200 mg) is recommended.
Injectable: The usual initial and maintenance dose is one weekly i.m. injection of 3 mL (300 mg). For orchiectomized patients, the recommended dose is one i.m. injection of 3 mL (300 mg) every 2 weeks.
Oral or i.m depot therapy should not be discontinued when remission or improvement occurs.
Because of their pharmacokinetic properties, the oral and i.m. depot can be interchanged in the course of long-term treatment. The dosage may be reduced if side effects are intolerable but should be kept within the oral range of 100 to 300 mg daily (2 to 6 tablets) or i.m. injections of 300 mg (3 mL) at weekly intervals, or every 2 weeks.
