Cyproterone

Cyproterone acetate is an antiandrogen: it competitively inhibits the effect of androgens, which the female body also produces in small amounts. It additionally has progestogenic and antigonadotropic activity. In men these actions reduce sexual drive and potency, inhibit gonadal function and protect the prostate from androgens of testicular and adrenal origin. The changes are reversible when treatment stops.

Mechanism of Action

• Androgen-receptor blockade: cyproterone acetate prevents androgens from acting on androgen-dependent target organs. In prostate cancer it blocks the binding of dihydrotestosterone to the receptors of the tumour cell.
• Central antigonadotropic effect: it inhibits the secretion of luteinising hormone, which lowers testosterone synthesis in the testes and so serum testosterone. This also happens when it is combined with GnRH agonists, and it reduces the initial rise in testosterone those medicines cause.
• Progestogenic action: it also acts like a progestogen. At the highest doses a tendency to a moderate rise in prolactin has been seen.
• In women: hirsutism decreases, as do androgenetic alopecia and overactivity of the sebaceous glands. Ovulation is inhibited during treatment.
• In men: the described effects are reduced sexual drive and potency, inhibited gonadal function, reduced activity of the sebaceous glands and an influence on hair growth.
• Active metabolite: the 15β-hydroxy derivative is the main plasma metabolite; DrugBank describes it as keeping the antiandrogenic activity with less progestogenic activity.

Pharmacokinetics

• Absorption: complete after oral dosing over a wide dose range; absolute bioavailability is practically complete (88% of the dose). After 50 mg the peak serum level is about 140 ng/mL, reached after about 3 hours.
• Distribution: bound almost entirely to plasma albumin; the unbound fraction is about 3.5–4%. Because the binding is non-specific, changes in sex hormone-binding globulin (SHBG) do not alter its kinetics. With the long terminal half-life and daily dosing, serum levels accumulate about threefold.
• Metabolism: through hydroxylations and conjugations; the main plasma metabolite is the 15β-hydroxy derivative. Phase I metabolism is mainly by CYP3A4.
• Elimination: serum levels fall over roughly 24–120 hours, with an elimination half-life of 43.9 ± 12.8 hours and a total serum clearance of 3.5 ± 1.5 mL/min/kg. Part of the dose is excreted unchanged in bile; most is excreted as metabolites, with a urine-to-bile ratio of 3:7. Renal and biliary excretion corresponds to a half-life of 1.9 days, and plasma elimination of the metabolites to 1.7 days.
• Breast milk: about 0.2% of the dose passes into milk, roughly 1 microgram/kg.
• Special populations: the SmPC gives no pharmacokinetic data for special groups; see Administration and Dosage for the elderly and for renal and hepatic impairment.

Cyproterone acetate is authorised nationally, not through a central EU procedure. The indications below are taken from the Spanish SmPC for Androcur 50 mg tablets, which lists one further use in men; product information in other countries may differ.

In men

• Advanced hormone-dependent prostate cancer: treatment of advanced hormone-dependent prostate carcinoma.
• Start of GnRH-analogue treatment: reduction of androgen levels at the start of treatment with GnRH analogues.
• Hot flushes: treatment of hot flushes caused by reduced androgen levels.

In women

• Severe androgenisation: severe manifestations of androgenisation, for example very pronounced hirsutism or severe androgenetic alopecia, often with severe acne and/or seborrhoea. Cyproterone acetate 50 mg is indicated when satisfactory results have not been achieved with products containing lower doses of cyproterone acetate or with other treatment options.

The contraindications depend on the indication and on the sex of the patient.

• All patients: hypersensitivity to cyproterone acetate or any excipient; liver disease; Dubin-Johnson syndrome or Rotor syndrome; a meningioma or a history of meningioma; severe chronic depression.
• Women: current or past liver tumours; wasting diseases; current or past thromboembolic processes; severe diabetes with vascular changes; sickle-cell anaemia.
• Men treated for advanced hormone-dependent prostate cancer: the same list applies with these differences. Liver tumours contraindicate treatment only if they are not due to metastases; wasting diseases are excepted in advanced hormone-dependent prostate cancer; only a current thromboembolic process is listed, not a past one; severe diabetes with vascular changes and sickle-cell anaemia are not listed for this indication (see Thromboembolic Events under Special Instructions).
• Women, in addition: pregnancy; breastfeeding; a history of jaundice or persistent itching in a pregnancy; a history of herpes gestationis. When a combined oral contraceptive is used alongside, its own contraindications also apply.

The most serious reactions linked to Androcur are liver toxicity, benign and malignant liver tumours that can cause life-threatening intra-abdominal bleeding, and thromboembolic events. Meningiomas (single or multiple) have also been reported. The SmPC lists the reactions separately for men and women.

In Men

The most frequent reactions are decreased libido, erectile dysfunction and reversible inhibition of sperm production.

Very common (≥1/10): psychiatric — decreased libido, erectile dysfunction; reproductive system — reversible inhibition of spermatogenesis.

Common (≥1/100 to <1/10): weight increase or decrease; depressed mood and temporary restlessness; dyspnoea; liver toxicity, including jaundice, hepatitis and hepatic failure; gynaecomastia; fatigue, hot flushes and sweating.

Uncommon (≥1/1,000 to <1/100): rash.

Rare (≥1/10,000 to <1/1,000): meningioma; hypersensitivity reaction.

Very rare (<1/10,000): benign and malignant liver tumours.

Not known: anaemia; thromboembolic events (a causal link has not been established); intra-abdominal haemorrhage; osteoporosis.

Gynaecomastia, sometimes with tender nipples, usually goes away when the medicine is stopped. Sperm production is inhibited within a few weeks and recovers gradually some months after stopping; the fall in sexual drive and potency is also reversible. Prolonged androgen deprivation in men can lead to osteoporosis.

In Women

The most frequently reported reactions are bleeding or spotting, weight gain and depressed mood. The SmPC list is based on post-marketing experience, so frequencies could not be estimated for most reactions.

Rare (≥1/10,000 to <1/1,000): meningioma.

Not known: benign and malignant liver tumours with intra-abdominal haemorrhage; hypersensitivity reactions; weight increase or decrease; depressed mood, temporary restlessness, increased or decreased libido; thromboembolic events (a causal link has not been established); dyspnoea; liver toxicity, jaundice, hepatitis, hepatic failure; rash; inhibition of ovulation, breast pain, bleeding; fatigue.

Ovulation is inhibited under the combined treatment, so the woman is infertile while taking it.

Cyproterone acetate is metabolised by CYP3A4. No clinical interaction studies have been done, so the CYP3A4 interactions below are expected from its metabolism rather than measured.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clotrimazole, ritonavir and others): expected to inhibit the metabolism of cyproterone acetate.
• CYP3A4 inducers (rifampicin, phenytoin, products containing St John’s wort): may lower cyproterone acetate concentrations.
• High-dose enzyme inhibition: in vitro studies indicate that inhibition of CYP2C8, 2C9, 2C19, 3A4 and 2D6 is possible at high therapeutic doses (100 mg three times a day).
• Statins: the risk of myopathy or rhabdomyolysis with HMG-CoA reductase inhibitors that are metabolised mainly by CYP3A4 may rise when they are given with high therapeutic doses of cyproterone acetate, as they share the pathway.
• Antidiabetic medicines: in diabetes the need for oral antidiabetic medicines or insulin may change during treatment, so strict medical supervision is needed.
• Alcohol: DrugBank advises avoiding alcohol.
• Combined oral contraceptive: in women of childbearing potential Androcur is given with a combined oral contraceptive (preferably cyproterone–ethinylestradiol); that product’s own SmPC applies, including its contraindications and its advice on missed tablets.
• Food: the tablets are swallowed with some liquid after a meal.

Androcur tablets are taken by mouth with some liquid after a meal. The dose depends on the indication and on the sex of the patient; in men the maximum daily dose is 300 mg. The duration of treatment is defined individually, and dose changes and stopping are made gradually.

Doses in Men

• Advanced hormone-dependent prostate cancer: 200–300 mg a day (2 tablets two or three times daily). Treatment must not be interrupted or the dose reduced after improvement or remission.
• Start of GnRH-agonist treatment: 200 mg a day (2 tablets twice daily) alone for 5–7 days, then 200 mg a day for 3–4 weeks together with a GnRH agonist at its recommended dose.
• Hot flushes during GnRH-analogue treatment or after bilateral orchidectomy: 50–150 mg a day (1–3 tablets), raised to 300 mg a day (2 tablets three times daily) if needed.

Doses in Women

• Women of childbearing potential: pregnancy must be excluded before treatment. Treatment starts on day 1 of the cycle (the first day of bleeding); only in amenorrhoea may it begin at once, counting that day as day 1. On days 1–10 of the cycle, 2 tablets (100 mg) are taken once daily after a meal. In addition, a combined oral contraceptive (preferably cyproterone–ethinylestradiol) is taken on days 1–21, at the same time every day, for contraceptive protection and cycle stabilisation. A 7-day break follows, with withdrawal bleeding. The next cycle starts exactly four weeks after the first, on the same weekday, whether or not the bleeding has stopped.
• After clinical improvement: the Androcur dose may be lowered to 1 or half a tablet (50 or 25 mg a day) during the 10 days alongside the contraceptive; the contraceptive alone may then be enough.
• Postmenopausal or hysterectomised women: Androcur can be given alone, without a contraceptive. Depending on severity, the average dose is 1 or half a tablet (50 or 25 mg) once daily for 21 days, followed by 7 days without medicine.
• Duration: benefit and risk are re-evaluated at the start of the menopause, and prolonged use over years should be avoided (see Meningioma).
• No withdrawal bleeding: if no bleeding occurs during the break, treatment is stopped until pregnancy is excluded.

Missed Tablets (Women)

• If the combined contraceptive is taken more than 12 hours late, contraceptive protection may be reduced in that cycle; follow that product’s SmPC.
• Missing Androcur can reduce its effect and cause bleeding between periods. Treatment continues as scheduled, the missed tablets are discarded, and two tablets are never taken to make up for a missed one. An additional non-hormonal contraceptive method (not the rhythm or temperature methods) is used in that cycle. If no bleeding follows that cycle, pregnancy is excluded before restarting.

Special Populations

• Children and adolescents: not indicated in boys, adolescent males or anyone under 18 years, for lack of efficacy and safety data. In women it is indicated only after puberty has ended; it must not be given earlier, because an unfavourable effect on longitudinal growth and on the not yet stable endocrine axis cannot be excluded.
• Elderly: no data suggest a dose adjustment.
• Hepatic impairment: contraindicated in liver disease (that is, until liver function values have returned to normal).
• Renal impairment: no data suggest a dose adjustment.

Meningioma

• Meningiomas (single and multiple) have been reported with cyproterone acetate, mainly at doses of 25 mg and above. The risk rises as the cumulative dose rises, and high cumulative doses can be reached through use over several years or through shorter treatment at high daily doses. A French cohort study found this cumulative, dose-dependent association (SmPC section 5.1).
• In line with clinical practice, patients should be monitored for meningioma. If a patient treated with Androcur is diagnosed with a meningioma, Androcur and any other product containing cyproterone must be stopped permanently.
• Cyproterone is contraindicated in anyone with a meningioma or a history of meningioma. Some data suggest that the risk may fall after cyproterone is stopped.
• The 50 mg strength is restricted: for severe androgenisation in women only when lower-dose cyproterone products or other options have not worked. Once a satisfactory result is reached, the lowest effective dose is kept.
• In women, prolonged use over years should be avoided, and benefit and risk are re-evaluated at the start of the menopause.
• These restrictions follow a 2020 EU review of the meningioma risk.

Liver Toxicity and Liver Tumours

• Direct liver toxicity (jaundice, hepatitis, hepatic failure) has been seen. At doses of 100 mg and above fatal cases have been reported, most of them in men with advanced prostate cancer. The toxicity is dose-related and usually appears several months after starting.
• Liver function is tested before treatment, at regular intervals during it, and whenever any symptom or sign suggests liver toxicity. If toxicity is confirmed, Androcur must be stopped.
• Benign and malignant liver tumours have caused life-threatening intra-abdominal bleeding, occasionally in women (frequency not known) and very rarely in men. Severe upper abdominal pain, an enlarged liver or signs of intra-abdominal bleeding should prompt consideration of a liver tumour.
• Stopping treatment should be considered for jaundice or raised transaminases, eye disorders (loss of vision, double vision, retinal vascular lesions) and severe headaches.

Thromboembolic Events

• Thromboembolic events have been reported, although a causal link has not been established. The risk is higher in patients with previous thrombotic or thromboembolic events (such as deep vein thrombosis, pulmonary embolism or myocardial infarction), previous stroke or advanced malignancy.
• In men with inoperable prostate cancer, previous thromboembolic processes, sickle-cell anaemia or severe diabetes with vascular changes, the balance of risk and benefit must be weighed carefully in each case before prescribing.

Other Monitoring

• Adrenal function: checked regularly, as non-clinical data suggest possible suppression from the corticoid-like effect of high doses.
• Diabetes: strict medical supervision, because antidiabetic needs may change.
• Dyspnoea: breathlessness can occur at high doses; the differential diagnosis should include the respiratory-stimulating effect known for progesterone and synthetic progestogens (low carbon dioxide with compensated respiratory alkalosis), which needs no treatment.
• Anaemia (men): has been reported; red blood cell counts are checked during treatment.

Checks Before and During Treatment in Women

• A thorough gynaecological examination, including the breasts and a cervical smear, is done before treatment, and pregnancy must be excluded.
• During combined treatment, light bleeding or spotting within the 3 weeks of contraceptive does not require stopping. Persistent bleeding, or bleeding that recurs at regular intervals, calls for a gynaecological examination to exclude organic disease.
• All the information in the combined contraceptive’s own SmPC must be observed.

Pregnancy, Breastfeeding and Fertility

• Pregnancy and breastfeeding: contraindicated. Pregnancy must be excluded before treatment in women of childbearing potential. About 0.2% of the dose is excreted in breast milk, roughly 1 microgram/kg.
• Fertility in women: ovulation is inhibited under the combined treatment, so the woman is infertile while taking it.
• Fertility in men: sperm production is inhibited over several weeks and recovers gradually some months after stopping; sexual drive and potency fall reversibly.

Lactose

Each tablet contains 103.31 mg of lactose. Patients with hereditary galactose intolerance, total lactase deficiency or problems absorbing glucose or galactose should not take it.

Effect on Driving

Androcur can cause lassitude and reduced vitality and can impair concentration. Patients whose work needs a high level of concentration, such as drivers and machine operators, should be warned.

Androcur tablets need no special storage conditions. They are supplied in PVC/aluminium blister packs; a pack holds 50 tablets (5 blisters of 10).

5 years.

Prescription only (Rx). Androcur is a tablet taken by the patient, so it is supplied to the patient or to the treating clinic on prescription. In women of childbearing potential, pregnancy must be excluded before treatment starts, and the SmPC calls for monitoring for meningioma, regular liver function tests and regular checks of adrenal function during treatment.