Source: Health Products and Food Branch (CA) Revision Year: 2021
Alcohol may reduce the antiandrogenic effect of ANDROCUR 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 ANDROCUR therapy is not advisable.
Patients should be informed that fatigue and lassitude are common in the first few weeks of therapy, but usually become much less pronounced from the third month on. Marked lassitude and asthenia necessitate special care when driving or operating machinery.
As with all oily solutions, ANDROCUR DEPOT must be injected strictly intramuscularly and very slowly. Pulmonary microembolism of oily solutions can in some cases lead to signs and symptoms such as cough, dyspnea, and chest pain. There may be other signs and symptoms including vasovagal reactions such as malaise, haemorrhages, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. Treatment is usually supportive, eg, by administration of oxygen.
Based on a retrospective meta-analysis, long-term combination therapy of ANDROCUR with either orchiectomy or a GnRH agonist as treatment of patients with advanced prostate cancer may result in a 5-year survival disadvantage compared to castration alone.
Cyproterone acetate showed a potential to initiate and/or promote liver tumor formation in rodents. Very rare cases of benign and malignant liver tumors have been observed in patients receiving ANDROCUR.
The occurrence of meningiomas (single and multiple) has been reported in association with long-term use (years) of cyproterone acetate at doses of 25 mg/day and above. The risk of meningioma increases with increasing cumulative doses of cyproterone acetate. In a retrospective cohort study using data from a primary care database, meningiomas were reported very rarely in patients treated with cyproterone acetate for prostate cancer after several months of treatment; in these cases, causality was not established. If a patient treated with ANDROCUR is diagnosed with a meningioma, treatment with cyproterone containing products, including ANDROCUR must be permanently stopped. Patients with prehistory or presence of meningioma should not be treated with ANDROCUR (see 2. CONTRAINDICATIONS).
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 has 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 to 8 weeks for a withdrawal response prior to any decision to proceed with other prostate cancer therapy.
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.
Suppression of adrenocortical function tests have occurred in patients receiving ANDROCUR and preclinical data also revealed a suppression of adrenal gland due to the administration of cyproterone acetate (see 16. NON-CLINICAL TOXICOLOGY).
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.
ANDROCUR may impair carbohydrate metabolism. Parameters of carbohydrate metabolism, fasting blood glucose, and glucose tolerance tests, should be examined carefully in all patients and particularly in all diabetics before and regularly during therapy with ANDROCUR.
Strict medical supervision is necessary if the patient suffers from diabetes, because the requirement for oral antidiabetics or insulin can change during ANDROCUR treatment.
Fluid retention, hypercalcemia and changes in plasma lipid profile may occur. Accordingly, ANDROCUR should be used with caution in patients with cardiac disease.
A negative nitrogen balance is usual at the start of therapy, but does generally correct itself within 3 months of continued therapy.
Hypochromic anemia has been observed rarely during therapy with ANDROCUR. Regular hematological assessment is recommended.
Clinical investigations have shown that when ANDROCUR is used alone it has a minor effect on blood clotting factors. However, when ANDROCUR was combined with ethinyl estradiol, changes were found in increased coagulation capability.
The occurrence of thromboembolic events has been reported in patients using ANDROCUR, although a causal relationship has not been established. Patients with previous arterial or venous thrombotic/thromboembolic events (eg, deep venous thrombosis, pulmonary embolism, myocardial infarction) or with a history of cerebrovascular accidents or with advanced malignancies are at increased risk of further thromboembolic events.
ANDROCUR should be discontinued at the first sign of thrombophlebitis or thromboembolism, and the patient should be carefully re-evaluated if manifestations of thrombotic disorder occur: thrombophlebitis, cerebrovascular complications, retinal thrombosis, or pulmonary embolism.
In patients with inoperable carcinoma of the prostate, presenting with a history of thromboembolic processes or suffering from sickle cell anemia or from severe diabetes with vascular changes, a careful risk:benefit evaluation must be carried out in each individual case before ANDROCUR is prescribed.
Direct hepatic toxicity, including jaundice, hepatitis, and acute hepatic failure has been observed in patients treated with ANDROCUR. At daily doses of 100 mg and above, cases with fatal outcome have also been reported. Most reported fatal cases were in men treated with cyproterone acetate for prostatic cancer. Hepatotoxicity is dose-related and develops, usually, a few weeks to several months after cyproterone treatment has begun. Liver function tests should be performed pretreatment, at regular intervals during treatment, and whenever any symptoms or signs suggestive of hepatotoxicity occur. If hepatotoxicity is confirmed, ANDROCUR should be withdrawn. Benefit and risk should be evaluated carefully if any drug(s) with known hepatotoxicity is to be used concurrently with ANDROCUR. ANDROCUR should not be used in patients with prior history or existing hepatic disease (see 2. CONTRAINDICATIONS).
In very rare cases, benign and malignant liver tumors which may lead to life-threatening intra-abdominal haemorrhage have been observed after the use of ANDROCUR. If severe upper abdominal complaints, liver enlargement, or signs of intra-abdominal haemorrhage occur, a liver tumor should be included in the differential-diagnostic considerations.
It is recommended that patients prescribed an antiandrogen, who have PSA progression, should have the antiandrogen discontinued immediately and be monitored for 6 to 8 weeks for a withdrawal response prior to any decision to proceed with other prostate cancer therapy.
With the potential for adrenal gland suppression, it is recommended that adrenocortical function tests should be monitored periodically by serum cortisol assay.
Parameters of carbohydrate metabolism, fasting blood glucose, and glucose tolerance tests, should be examined carefully in all patients and particularly in all diabetics before and regularly during therapy with ANDROCUR.
During treatment with ANDROCUR, serum electrolytes and complete blood counts should be performed regularly. Liver function tests should be performed pretreatment, at regular intervals during treatment, and whenever any symptoms or signs suggestive of hepatotoxicity occur.
ANDROCUR 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.
A sensation of shortness of breath was commonly reported in patients treated with 300 mg/day ANDROCUR. Patients with pre-existing pulmonary dysfunction are most likely to be affected.
The sperm count and the volume of ejaculate are reduced at oral doses of 50 to 300 mg per 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 ANDROCUR, or in some patients, after up to 20 months. Production of abnormal spermatozoa during ANDROCUR therapy has been observed; their relationship to abnormal fertilization or malformed embryos is not known.
ANDROCUR therapy may cause a reduction of sebum production leading to dryness of the skin and transient patchy loss of body hair.
Treatment with ANDROCUR is not indicated for use in women.
Treatment with ANDROCUR is not indicated for use in women.
ANDROCUR is not recommended for use in children and adolescents below 18 years of age.
ANDROCUR must not be given before the conclusion of puberty since an unfavorable influence on longitudinal growth and the still unstabilized axes of endocrine function cannot be ruled out.
The adverse events associated most frequently with the use of ANDROCUR are those related to the hormonal effects of the drug. These reactions usually disappear upon discontinuation of therapy or reduction of dose: decreased libido, breast enlargement, breast tenderness, benign nodular hyperplasia of the breast, galactorrhea, gynecomastia, abnormal spermatozoa, impotence, and inhibition of spermatogenesis.
The most serious adverse drug reactions (ADRs) in patients receiving ANDROCUR are hepatic toxicity, benign and malignant liver tumors which may lead to intra-abdominal hemorrhage, and thromboembolic events.
As with other antiandrogenic treatments, long-term androgen deprivation with ANDROCUR may lead to osteoporosis.
Other adverse events which have been reported are listed below:
Cardiovascular System: 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, shock, pulmonary oil microembolism, vasovagal reactions.
Gastrointestinal System: constipation, diarrhea, indigestion, anorexia, nausea, vomiting, cholestatic jaundice, cirrhosis of liver, hepatic coma, hepatitis, hepatoma, hepatomegaly, jaundice, liver carcinoma, liver failure (for further information see 7. WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic), abnormal liver function test, liver necrosis, pancreatitis, glossitis.
Hematology: increased fibrinogen, decreased prothrombin, thrombocytopenia, anemia (for further information see 7. WARNINGS AND PRECAUTIONS – Hematologic), hemolytic anemia, hypochromic anemia, normocytic anemia, leukopenia, leukocytosis.
Metabolism: negative nitrogen balance, decreased response to ACTH, hyperglycemia, lowered cortisol, hypercalcemia, increased SGOT, increased SGPT, increased creatinine, hypernatremia, edema, weight gain, weight loss, diabetes mellitus.
Musculoskeletal System: myasthenia, osteoporosis.
Central Nervous System: fatigue, lassitude, weakness, hot flashes, increased sweating, aphasia, coma, depression, dizziness, encephalopathy, hemiplegia, personality disorder, psychotic depression, abnormal gait, headache, temporary restlessness.
Meningiomas (single and multiple) have been reported in association with long-term use (several years) of ANDROCUR. In a retrospective cohort study using data from a primary care database, meningiomas were reported very rarely in patients treated with cyproterone acetate for prostate cancer after several months of treatment; in these cases, causality was not established (see 7. WARNINGS AND PRECAUTIONS – Carcinogenesis and Mutagenesis).
Respiratory System: asthma, increased cough, dyspnea, hyperventilation, respiratory disorder, shortness of breath on effort (see 7. WARNINGS AND PRECAUTIONS – Respiratory), lung fibrosis.
Skin: eczema, urticaria, erythema nodosum, exfoliative dermatitis, rash, maculopapular rash, dryness of the skin, pruritus, alopecia, hirsutism, skin discoloration, photosensitivity reactions, scleroderma.
Sensory System: ear disorder, optic atrophy, optic neuritis, abnormality of accommodation, abnormal vision, blindness, retinal disorder.
Urogenital System: enlarged uterine fibroids, uterine hemorrhage, increased urinary frequency, bladder carcinoma, kidney failure, hematuria, urate crystalluria, urine abnormality.
Other: ascites, allergic reaction, asthenia, chills, fetal chromosome abnormality, death, fever, hernia, malaise, 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.
The clinical trial data on which the original indication was authorized is not available.
The clinical trial data on which the original indication was authorized is not available.
The clinical trial data on which the original indication was authorized is not available.
Meningioma.
Although clinical interaction studies have not been performed, since this drug is metabolized by CYP3A4, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir, and other strong inhibitors of CYP3A4 inhibit the metabolism of cyproterone acetate. On the other hand, inducers of CYP3A4 such as rifampicin, phenytoin, and products containing St. John’s wort may reduce the levels of cyproterone acetate.
Based on in vitro inhibition studies, an inhibition of the cytochrome P450 enzymes CYP2C8, 2C9, 2C19, 3A4, and 2D6 is possible at high therapeutic cyproterone acetate doses of 300 mg daily. In addition, cyproterone acetate was also shown to increase the enzymatic activity of CYP1A2 and CYP2E1 in vitro. Caution should be exercised when ANDROCUR is to be co-administered with a substrate of the P450 enzymes.
The risk of statin-associated myopathy or rhabdomyolysis may be increased when those HMGCoA inhibitors (statins) which are primarily metabolized by CYP 3A4 are coadministered with high therapeutic cyproterone acetate doses, since they share the same metabolic pathway.
This information is not available for this drug product.
Interactions with other drugs have not been established.
Interactions with food have not been established.
Interactions with herbal products have not been established.
Interactions with laboratory test have not been established.
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