COMMON TRADE NAME(S): ANDROCUR(r), ANDROCUR(r) Depot, APO-CYPROTERONE(r), GEN- CYPROTERONE(r), NOVO-CYPROTERONE(r)
hormonal agent
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Cyproterone is a steroidal antiandrogen which competitively inhibits the binding of androgens to the androgen receptor. Cyproterone also demonstrates endocrine activity and exerts a negative feedback on the hypothalamo- pituitary axis by inhibiting the secretion of luteinizing hormone (LH) leading to decreased production of testicular testosterone.1 Prostate cancer is primarily an androgen-dependent cancer and can be treated with surgical or medical castration. Luteinizing hormone releasing hormone agonists (LHRHa) suppress pituitary release of LH and result in medical castration. The initial stimulation of the pituitary caused by LHRHa produces an acute increase in the concentration of plasma testosterone accompanied by temporary worsening of symptoms (flare reaction). To avoid the flare reaction, antiandrogens should be given concurrently with the first administration of LHRHa. Antiandrogens are also used in combination with LHRHa to inhibit the effects of testicular and adrenal androgens (maximum androgen blockade). In some patients with metastatic prostate cancer (15-20%),2 antiandrogen withdrawal may lead to a paradoxical decrease in serum prostate-specific antigen level (antiandrogen withdrawal syndrome).3
| Oral Absorption | slow but complete, 3-4 h to peak plasma levels | |
| Distribution | accumulates in fatty tissue 4 | |
| cross blood brain barrier? | no information found | |
| volume of distribution 5 | 16.8 L/kg | |
| plasma protein binding 6 | 96% | |
| Metabolism | hepatic | |
| active metabolite(s) 4,7 | principal metabolite is 15 B -hydroxy-cyproterone acetate | |
| inactive metabolite(s) | unconjugated metabolites and glucuronidized metabolites | |
| Excretion | urine 3 | 33% mainly as unconjugated metabolites |
| feces 3 | 60% mainly as glucuronidized metabolites | |
| terminal half life | 38 h + 5 h depot 3 : 4 days | |
| clearance 5 | 2.8 mL/min/kg | |
Adapted from standard reference1 unless specified otherwise.
Primary uses: Other uses:
*Prostate cancer
*Health Canada approved indication
Contraindicated in patients with the following conditions1: a history of hypersensitivity reaction to cyproterone renal insufficiency active liver disease or hepatic impairment
Caution:
Impairment of carbohydrate metabolism 1
may occur. Parameters of carbohydrate metabolism, fasting blood glucose, and glucose tolerance tests should be monitored in all patients, particularly in diabetic patients.
Plasma lipid profile changes may occur, use with caution in patients with familial defects of lipoprotein metabolism7 or cardiac disease.1
Thrombosis: 1
Use with caution in patients with a history of thrombophlebitis or thromboembolism.
Fluid retention: 7
Use with caution in conditions that may be aggravated by fluid retention or cardiovascular disease.
Depression:
Due to an increased incidence of depression, use caution when treating patients with a history of depression.
Laboratory interactions: 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. Carcinogenicity: Possible pre-neoplastic liver lesions have occurred in animal models.1 Reports of hepatocellular carcinoma have occurred in patients receiving cyproterone; causality not established.1 Mutagenicity: Not mutagenic in Ames test.1 Positive and negative results regarding mutagenicity in mammalian in vitro mutation test.1 Not clastogenic in mammalian in vivo chromosome tests.1 Fertility: Sperm count and volume of ejaculate are reduced.1 Azoospermia, associated with atrophy of seminiferous tubules, typically occurs after 8 weeks of therapy.1 Production of abnormal spermatozoa may occur; the relationship to fertilization and embryo development is not known.1 Pregnancy: Not available in the United States, therefore FDA Pregnancy Category has not been assigned. Fetal chromosome abnormalities have been reported.1 The use of cyproterone during pregnancy may carry a risk of feminization of a male fetus.6 Studies in animals have shown evidence of fetal damage.8
Breastfeeding 9
is not recommended due to the potential secretion into breast milk.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.10 When placebo-controlled trials are available, adverse events are included if the incidence is
>
5% higher in the treatment group.
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| allergy/immunology | allergic reaction |
| auditory/hearing | unspecified ear disorder |
| blood/bone marrow/ febrile neutropenia | anemia including: hypochromic (<1%), hemolytic, and normocytic anemia |
| leukopenia, leukocytosis | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| thrombocytopenia | |
| cardiovascular (arrhythmia) | electrocardiogram changes (1%) 8 |
| tachycardia | |
| cardiovascular (general) | hypotension |
| severe cardiovascular effects (10%) 11 ; myocardial infarction (4%), 8 heart failure | |
| coagulation | beneficial effect on blood clotting factors; increased antithrombin III and fibrinolytic activity 8,11 ; increased risk of thrombosis when combined with estradiol |
| constitutional symptoms | fatigue; dose-related, 8 common during the first weeks of therapy, typically improves after the third month |
| hot flashes, increased sweating | |
| weight gain/loss | |
| dermatology/skin | extravasation hazard: none 12 |
| dry skin; secondary to reduced sebum production | |
| eczema, exfoliative dermatitis | |
| injection site reaction | |
| loss of body hair; transient, patchy, secondary to reduced sebum production | |
| photosensitivity reactions | |
| pruritis, rash | |
| skin discolouration | |
| endocrine | gynecomastia (6-13%), 8 breast tenderness, galactorrhea; typically reversible with discontinuation or dose reduction |
| benign breast nodular hyperplasia; typically subsides 1-3 months after discontinuation or dose reduction but permanent enlargement has been reported 6,8 | |
| impaired carbohydrate metabolism, diabetes mellitus | |
| gastrointestinal | emetogenic potential: rare 13 |
| anorexia | |
| constipation, diarrhea | |
| glossitis | |
| indigestion | |
| nausea and vomiting | |
| hepatobiliary/pancreas | hepatic dysfunction; see paragraph following the Side Effects table |
| pancreatitis | |
| lymphatics | edema (2%) 8 |
| metabolic/laboratory | changes in plasma lipid profile 7,8 |
| decreased cortisol | |
| decreased prothrombin | |
| decreased response to ACTH | |
| elevated creatinine | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| elevated fibrinogen | |
| elevated prolactin 8 | |
| elevated sodium | |
| hypercalcemia | |
| hyperglycemia | |
| negative nitrogen balance; typically occurs at the start of therapy but corrects within 3 months of continued therapy | |
| musculoskeletal | abnormal gait |
| osteoporosis; with prolonged use 8 | |
| weakness, myasthenia | |
| neurology | depression; dose-related, 8 typically occurs during the first 6-8 weeks of therapy, likely due to androgen deprivation |
| dizziness | |
| encephalopathy | |
| hemiplegia | |
| speech impairment | |
| syncope | |
| ocular/visual | optic atrophy (<1%), 6 optic neuritis |
| retinal vascular disorder, retinal vein thrombosis | |
| vision changes | |
| pain | headache; dose-related, 8 vascular headache |
| pulmonary | dyspnea, shortness of breath on exertion |
| hyperventilation | |
| increased cough | |
| pulmonary fibrosis, unspecified respiratory disorder | |
| renal/genitourinary | renal failure |
| urinary frequency | |
| secondary malignancy | bladder carcinoma |
| hepatocellular carcinoma; causality not established 4,6 | |
| sexual/reproductive function | abnormal spermatozoa; relationship to fertilization and embryo development unknown |
| decreased libido, impotence 7 ( < 100%) 8 ; typically reversible with discontinuation or dose reduction | |
| decreased sperm counts, azoospermia; typically occurs after 8 weeks of therapy, typically returns to previous levels in 3-5 months after stopping therapy, though 20 months has been reported | |
| decreased volume of ejaculate; reversible | |
| vascular | phlebitis |
| thrombosis, embolism (2%) 8 | |
Adapted from standard reference1 unless specified otherwise. Hepatic dysfunction (<1%) including elevated serum transaminase levels, jaundice, hepatitis, hepatic failure, and death have been reported with cyproterone.1,7 These toxicities are dose-related and typically occur several months after starting treatment.1 Appropriate liver function tests should be measured before1 and during therapy.8 Liver function tests should also be obtained at the first signs and symptoms suggestive of liver dysfunction; e.g., nausea, vomiting, abdominal pain, lack of appetite, pruritis, fatigue, dark urine, persistent anorexia, unexplained "flu-like" symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness.1 Withdrawal of therapy is indicated if hepatic abnormalities develop.1 Hepatotoxicity may be more frequent in patients receiving high-dose therapy for periods greater than several months.
1,6-8
Alcohol may theoretically reduce the antiandrogen effect of cyproterone when used for hypersexuality. The manufacturer recommends avoiding concomitant alcohol use; the clinical significance of theoretically reduced tumour control in prostate cancer is not known.
Tablets: Apotex supplies cyproterone as a 50 mg lactose-free tablet.14 Store at room temperature.1 Bayer Healthcare Pharmaceuticals supplies cyproterone as a 50 mg tablet.3 Selected non-medicinal ingredients: lactose.15 Store at room temperature.16 Genpharm supplies cyproterone as a 50 mg tablet. Selected non-medicinal ingredients: lactose. Store at room temperature.17 Novopharm supplies cyproterone as a 50 mg tablet. Selected non-medicinal ingredients: lactose. Store at room temperature.18 Injection: Bayer Healthcare Pharmaceuticals supplies cyproterone acetate depot solution as 3 mL ampoules of 100 mg/mL for IM injection. Selected non-medicinal ingredients: benzyl benzoate and castor oil.3 Store at room temperature.16
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.
Adults: BCCA usual dose noted in bold, italics
*
Oral:
200-300
mg PO in 2-3 divided doses
1,6,19
administer after meals
start treatment 5-7 days before administering LHRHa
after orchiectomy, a lower daily dose of 100-200 mg is recommended
increased risk of hepatotoxicity with long-term use; see paragraph following the Side Effects table
*Intramuscular: 300 mg IM for one dose weekly3 after orchiectomy, the cycle length should be increased to 2 weeks3 BCCA usual dose noted in bold, italics
*Because of their pharmacokinetic properties, cyproterone tablets and depot solution may be interchanged in the course of long- term treatment.3
Concurrent radiation: 10
no dose adjustment required
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression"
Dosage in renal failure: 1
contraindicated
Dosage in hepatic failure: 1
contraindicated
Dosage in dialysis:
no information found
Children:
no information found regarding the use of cyproterone in pediatric oncology
Apotex Inc. APO-CYPROTERONE(r) product monograph. Weston, Ontario; 9 March 2004.
Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the treatment of prostate cancer. European Urology 2007; 51(2):306- 314.
Berlex Canada Inc. ANDROCUR(r) and ANDROCUR DEPOT(r) product monograph. Pointe-Claire, Quebec; 20 November 2006.
USPDI(r) Drug Information for the Health Care Professional (database on the Internet). Cyproterone (Systemic). Thompson MICROMEDEX(r), 2007. Available at: www.micromedex.com. Accessed 27 March 2007.
Kuhnz W, Kulmann H, Fuhrmeister A. Investigation into the age-dependence of the pharmacokinetics of cyproterone acetate in healthy male volunteers. European Journal of Clinical Pharmacology 1997; 53(1):75-80.
MARTINDALE - The Complete Drug Reference (database on the Internet). Cyproterone acetate. Thomson MICROMEDEX(r), 2007. Available at: www.micromedex.com. Accessed 27 March 2007.
Rose BD editor. Cyproterone. www.uptodate.com ed. Waltham, Massachusetts: UpToDate 15.1; 2007.
DRUGDEX(r) Evaluations (database on the Internet). Cyproterone. Thomson MICROMEDEX(r), 2007. Available at: www.micromedex.com. Accessed 27 March 2007.
REPROTOX(r) (database on the Internet). Cyproterone. Thompson MICROMEDEX(r), Available at: www.micromedex.com. Accessed 27 March 2007.
Judy Sutherland MD. Personal communication. BCCA Genitourinary Tumour Group; 11 June 2007.
Goldenberg SL, Bruchovsky N. Use of cyproterone acetate in prostate cancer. Urologic Clinics of North America 1991; 18(1):111-122.
BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
B.C. Cancer Agency. SCNAUSEA Protocol Summary. Vancouver, British Columbia: BC Cancer Agency; May 1999.
Rajesh Sthankiya. Personal communication. Medical Services Associate, Apotex Canada; 9 April 2007.
Repchinsky C. ANDROCUR(r) monograph, Compendium of Pharmaceuticals and Specialties 2006. Ottawa: Canadian Pharmacists Association; 2006. p. 136-137.
Anne-Marie Hakem. Personal communication. Medical Services Associate, Bayer HealthCare Canada; 24 April 2007.
Genpharm. GEN-CYPROTERONE(r) product monograph. Compendium of Pharmaceutical Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2006. p. 929.
Novopharm. NOVO-CYPROTERONE(r) product monograph. Compendium of Pharmaceutical Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2006. p. 1482.
Mahler C, Verhelst J, Denis L. Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer. Clinical Pharmacokinetics 1998; 34(5):405-417.