Version May 2024
Hormone therapy for transgender females (assigned male at birth) (adjunct) (off-label use): Oral: 25 to 50 mg/day in combination with other appropriate agents; adjust dose with a goal of suppressing serum testosterone levels into the normal range for females (ie, <50 ng/dL) (ES [Hembree 2017]). Dosage range: 12.5 to 50 mg/day, the lowest effective dose is recommended (Angus 2019; Burinkul 2021; Cheung 2019; Even Zohar 2021; Tangpricha 2017; T'Sjoen 2020).
Paraphilia (off-label use): Males (Note: Avoid use if active pituitary pathology, hepatic failure, or thromboembolic disease):
Oral: Usual dose range: 50 to 200 mg/day; maximum dose: 600 mg/day (Guay 2009; Reilly 2000).
IM: 300 to 600 mg every 1 to 2 weeks (Guay 2009) or 400 to 700 mg once a week (Reilly 2000).
Prostate cancer, advanced, palliative treatment: Note: May interchange between oral and IM administration during chronic therapy; dosages should remain within usual ranges (oral: 100 to 300 mg daily; IM: 300 mg weekly or every 2 weeks).
Oral: 200 to 300 mg daily in 2 to 3 divided doses (maximum: 300 mg daily); following orchiectomy, reduce dose to 100 to 200 mg/day.
IM: 300 mg once weekly; reduce dose in orchiectomized patients to 300 mg once every 2 weeks.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution
Use is contraindicated with hepatic impairment or liver disease. Discontinue if hepatotoxicity develops during treatment.
Meningioma: Permanently discontinue cyproterone.
Prostate specific antigen progression: Discontinue cyproterone immediately; monitor for 6 to 8 weeks for withdrawal response.
Thrombophlebitis/thromboembolism: Discontinue cyproterone.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined.
Cardiovascular: Acute myocardial infarction, cardiac failure, cerebrovascular accident, edema, hypotension, phlebitis, pulmonary embolism (including oil microembolism), retinal thrombosis, retinal vascular disease, shock, syncope, tachycardia, thrombosis (deep vein thrombosis, embolism, superficial venous thrombosis), vasodepressor syncope
Dermatologic: Diaphoresis, eczema, erythema nodosum, exfoliative dermatitis, loss of body hair (patchy), maculopapular rash, pruritus, skin discoloration, skin photosensitivity, skin rash, urticaria, xeroderma (sebum reduction)
Endocrine & metabolic: Adrenal suppression (dose-related), decreased cortisol, decreased libido, diabetes mellitus, galactorrhea not associated with childbirth, gynecomastia, hirsutism, hot flash, hypercalcemia, hyperglycemia, hypernatremia, negative nitrogen balance, secondary adrenocortical insufficiency, weight gain, weight loss
Gastrointestinal: Anorexia, constipation, diarrhea, dyspepsia, glossitis, nausea, pancreatitis, vomiting
Genitourinary: Benign breast nodule, breast hypertrophy, breast tenderness, crystalluria, hematuria, impotence, inhibition of spermatogenesis, urinary frequency, uterine hemorrhage
Hematologic & oncologic: Anemia, bladder carcinoma, decreased prothrombin time, hemolytic anemia, hemorrhage, hepatic carcinoma, hypochromic anemia, increased serum fibrinogen, leukocytosis, leukopenia, normocytic anemia, thrombocytopenia, uterine fibroid enlargement
Hepatic: Ascites, cholestatic jaundice, hepatic cirrhosis, hepatic coma, hepatic failure, hepatic insufficiency (dose-related), hepatic necrosis, hepatic neoplasm, hepatitis, hepatomegaly, increased serum alanine aminotransferase, increased serum aspartate aminotransferase
Hypersensitivity: Hypersensitivity reaction
Local: Injection site reaction
Nervous system: Abnormal gait, aphasia, chills, coma, depression, dizziness, encephalopathy, fatigue, headache, hemiplegia, lassitude, malaise, myasthenia, personality disorder, psychotic depression, restlessness, vascular headache
Neuromuscular and skeletal: Asthenia, osteoporosis, systemic sclerosis
Ophthalmic: Accommodation disturbance, blindness, optic atrophy, optic neuritis, visual disturbance
Renal: Increased serum creatinine, renal failure syndrome
Respiratory: Asthma, cough, dyspnea, dyspnea on exertion, hyperventilation, pulmonary fibrosis
Miscellaneous: Fever
Postmarketing: Hematologic & oncologic: Meningioma (rare: <1%; with increasing cumulative doses) (EMA 2020)
Hypersensitivity to cyproterone or any component of the formulation; liver disease or hepatic dysfunction; Dubin-Johnson syndrome; Rotor syndrome; previous or existing liver tumors (if not due to metastases from prostate cancer); presence or history of meningioma; wasting diseases (except inoperable prostate cancer); severe chronic depression; existing thromboembolic processes
Concerns related to adverse effects:
• Adrenalcortical function suppression: Suppression of the adrenal gland and adrenal function tests have been reported with cyproterone.
• Anemia: Hypochromic anemia has been observed (rarely).
• Antiandrogen withdrawal syndrome: Antiandrogens may promote prostate cancer growth in some patients with metastatic prostate cancer; may present as prostate-specific antigen (PSA) progression. Decreased PSA levels and/or clinical improvement have been reported following therapy discontinuation.
• Carcinogenesis: Benign and malignant hepatic tumors have been observed (rarely) after use; rule out the presence of tumor in patients presenting with severe upper abdominal discomfort, hepatic enlargement or signs of intra-abdominal hemorrhage. Meningioma formation has been reported with chronic therapy (years) at doses ≥25 mg/day.
• CNS depression: Lassitude, weakness, and fatigue are common during first few weeks of treatment; symptoms usually lessen from the third month after initiation. Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Dermatologic effects: Dry skin and/or transient alopecia may occur.
• Gynecomastia: Benign hyperplasia of the breast has been reported; subsides usually within 1 to 3 months after therapy discontinuation and/or dose reduction. Risk of treatment failure should be considered prior to discontinuation or dose reduction.
• Hepatotoxicity: [Canadian Boxed Warning]: Cyproterone is associated with hepatotoxicity. Dose-dependent hepatotoxicity (jaundice, hepatitis, acute hepatic failure) has been observed, including fatal case reports with doses ≥100 mg/day. Most reported fatalities were in males treated for prostate cancer. Hepatotoxicity typically develops a few weeks to several months after treatment initiation. Use caution with concurrent use of other hepatotoxic drugs.
• Metabolic effects: Changes in lipid profile, hypercalcemia, and/or fluid retention may occur; a negative nitrogen balance is usual at therapy initiation but typically corrects itself within 3 months of ongoing therapy.
• Respiratory effects: Shortness of breath was commonly observed in patients receiving cyproterone doses of 300 mg/day; patients with existing pulmonary dysfunction may be more susceptible to respiratory effects.
• Thromboembolism: Cyproterone may increase the risk of thromboembolism (particularly when used in combination with ethinyl estradiol). Use with caution in patients with an inoperable prostate tumor, history of thromboembolic processes, sickle cell anemia or severe diabetes with vascular changes.
Disease-related concerns:
• Depression: Carefully observe patients with a tendency toward depression; cyproterone has been associated with an increased incidence of depressive mood changes, particularly early in the course of therapy (initial 6 to 8 weeks).
• Diabetes: Cyproterone may impair carbohydrate metabolism. Patients with diabetes may require adjustments in diabetes medications during cyproterone treatment.
Dosage form specific issues:
• Injection: Solution is oil based and must be injected by slow intramuscular injection only; avoid intravascular injection. Pulmonary microembolism of oily solutions can occur and lead to cough, dyspnea, angina and vasovagal reactions (eg, syncope, malaise, dizziness, hyperhidrosis, paresthesia). Reactions can occur during or immediately after the injection and are reversible; may usually be managed with supportive care (eg, oxygen).
Other warnings/precautions:
• Ethanol consumption: Although the relevance to the treatment of prostate cancer is unknown, the antiandrogen effects in hypersexuality may be reduced with ethanol. Ethanol should be avoided during treatment.
• Combination therapy: Retrospective meta-analysis data suggest that 5-year survival rates may be lower when used concomitantly with a GnRH agonist or orchiectomy versus patients treated with castration alone.
Not available in the US
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Oil, Intramuscular:
Androcur Depot: 100 mg/mL (3 mL)
Tablet, Oral:
Androcur: 50 mg
Generic: 50 mg
IM: Administer IM injections slowly and avoid intravascular injection, which can lead to pulmonary microembolism.
Oral: Administer tablets at the same time each day, after meals and with liquids.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Cyproterone may cause carcinogenicity, teratogenicity, reproductive toxicity, genotoxicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Note: Not approved in the United States.
Prostate cancer, advanced: Palliative treatment of advanced prostate cancer.
Hormone therapy for transgender females (assigned male at birth); Paraphilia
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May diminish the therapeutic effect of Cyproterone. More specifically, alcohol may interfere with antiandrogenic effects of Cyproterone. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Cyproterone. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cyproterone. Risk C: Monitor therapy
Flotufolastat F18: Antiandrogens may diminish the diagnostic effect of Flotufolastat F18. Management: Therapies targeting the androgen pathway may result in changes in the uptake of flotufolastat F18 in prostate cancer. The impact of these therapies on the performance of flotufolastat F18 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Gallium Ga 68 PSMA-11: Antiandrogens may diminish the therapeutic effect of Gallium Ga 68 PSMA-11. Management: Therapies targeting the androgen pathway may result in changes in the uptake of gallium Ga 68 PSMA-11 (gozetotide) in prostate cancer. The impact on the performance of gallium Ga 68 PSMA-11 (gozetotide) is unknown; consider use of alternative agents. Risk D: Consider therapy modification
HMG-CoA Reductase Inhibitors (Statins): Cyproterone may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Piflufolastat F18: Antiandrogens may diminish the diagnostic effect of Piflufolastat F18. Management: Therapies targeting the androgen pathway may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of these therapies on the performance of piflufolastat F18 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
St John's Wort: May decrease the serum concentration of Cyproterone. Risk C: Monitor therapy
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Ethanol may reduce the effect of cyproterone (not established in the treatment of prostatic carcinoma). Management: Avoid concurrent use.
When used for the treatment of advanced prostate cancer, sperm count and volume of ejaculate will be reduced at oral doses of 50 to 300 mg/day. After ~2 months of treatment, infertility may be noted. Changes are reversible upon discontinuation of therapy, usually within 3 to 5 months although in some patients may take up to 20 months. Production of abnormal spermatozoa has been observed although the effect on fertilization or embryo formation is unknown.
Cyproterone is used off-label in combination with estrogen to block androgens in transgender females. Complete suppression of spermatogenesis may not occur; therefore, contraception is recommended to prevent unintended pregnancies. Patients should consider options for fertility preservation prior to gender-affirming hormone therapy (Vereecke 2021).
Not indicated for use in patients who can become pregnant.
Cyproterone is present in breast milk.
A single oral dose of cyproterone 50 mg was administered to 6 women 8 days postpartum. Cyproterone concentrations 3 hours after the maternal dose were 65 to 449 ng/mL (plasma) and 16 to 260 ng/mL (breast milk). Nine hours after the maternal dose, cyproterone concentrations were 76 to 267 ng/mL (plasma) and 55 to 130 ng/mL (breast milk) (Stoppelli 1980).
LFTs (at baseline and periodically thereafter, or as clinically indicated with signs or symptoms suggestive of hepatotoxicity), CBC (regularly), adrenal function tests (via serum cortical assay [periodically]), electrolytes (regularly), fasting blood glucose and glucose tolerance (at baseline and regularly during treatment in patients with diabetes). In patients with prostate-specific antigen (PSA) progression, monitor for withdrawal response syndrome (eg, decrease in PSA levels) for 6 to 8 weeks following cyproterone discontinuation. Monitor for signs/symptoms of depression.
Transgender hormone therapy: Serum testosterone levels (goal: <50 ng/dL) every 3 months during the first year and then annually or biannually; routine cancer and laboratory screening as in non-transgender individuals for all tissues present (ES [Hembree 2017]).
Paraphilia (Guay 2009; Reilly, 2000): ECG; hepatic function test (baseline and during treatment if suspected hepatotoxicity); CBC (baseline); serum testosterone (baseline then monthly for 4 months then every 6 months); serum luteinizing hormone and prolactin (baseline and every 6 months); follicle-stimulating hormone (baseline); glucose; bone scan (baseline then annually) if serum testosterone significantly suppressed; blood pressure; weight gain.
Cardiovascular monitoring for patients with prostate cancer: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking; baseline and serial ECGs are recommended in patients at risk of QTc prolongation during androgen deprivation therapy (ADT); estimate 10-year cardiovascular disease risk in patients without cardiovascular disease at baseline; assess cardiovascular risk annually during ADT (ASCO [Armenian 2017]; ESC [Lyon 2022]).
Cyproterone is a steroid with antiandrogenic, antigonadotropic, and progestin-like activity. Blocks binding of dihydrotestosterone (DHT) to prostatic cancer cells and exerts negative feedback on hypothalamic-pituitary axis by inhibiting luteinizing hormone (LH) secretion leading to decreased testosterone production.
Absorption: Oral: Complete
Protein binding: 96% (Guay 2009)
Metabolism: Hepatic; primary metabolite is 15beta-hydroxy-cyproterone acetate
Distribution: Vd: IM: 20.6 L/kg (Guay 2009)
Bioavailability: Oral: 88% (Guay 2009)
Half-life elimination: Oral: 38 ± 5 hours; Depot injection: 4 days
Time to peak, plasma: Oral: 3 to 4 hours; Depot injection: 3.4 days
Excretion: Feces (60%); urine (33%; mainly as unconjugated metabolites)
Elderly: Oral: Clearance decreased 25%, volume of distribution increased 55%, and half-life increased 2-fold (Guay 2009).
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