Gale

Round, flat, white to faintly yellowish tablet, scored on one side, with an embossed "BC" in a regular hexagon on the other side.
Each tablet contains 50 mg cyproterone acetate.
Excipients/Inactive Ingredients: Cyproterone Acetate, Povidone (PVP K-30), Lactose Monohydrate, Corn Starch, Colloidal Silicon Dioxide, Magnesium Stearate, Isopropyl Alcohol.

ATC code: G03HA01.
Pharmacology: Pharmacodynamics: Prostatic carcinoma and its metastases are generally dependent on androgens. Cyproterone acetate is a progestational steroid with strong anti-androgen activities, and in addition cyproterone acetate exerts a negative feedback on the hypothalamic receptors; therefore suppressing gonadotrophin release, and hence secretion of testosterone (and other androgens) is reduced.
Meningioma: Based on results from a French epidemiological cohort study, a cumulative dose dependent association between cyproterone acetate and meningioma has been observed. This study was based on data from the French Health insurance (CNAM) and included a population of 253,777 women using 50-100 mg cyproterone tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose ≥3 g) and women who were slightly exposed to cyproterone acetate (cumulative dose <3 g). A cumulative dose-response relationship was demonstrated. (See table.)

Click on icon to see table/diagram/image

A cumulative dose of 12 g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.
Pharmacokinetics: Following oral administration of tablets, cyproterone acetate is quickly and completely absorbed over a wide dosage range. The absolute bioavailability of cyproterone acetate is almost complete. The maximal plasma levels after a single dose are achieved after about 3 hours. After oral administration of 100 mg daily the steady state plasma concentration is 260±50 ng/ml. The mean plasma half life is about 2 days.
Cyproterone acetate is metabolised by hydrolysis to free cyproterone, and then to 15 β-hydroxycyproterone. Excretion occurs via the bile (70%) and urine (30%). Only small amounts of unchanged drug are found in the bile, most is excreted in the form of metabolites.
Cyproterone acetate is almost exclusively bound to plasma albumin. About 3.5-4% of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.
Toxicology: Preclinical safety data: Systemic toxicity: Preclinical data revealed no specific risk for humans based on conventional studies of repeated dose toxicity beyond those discussed in other sections of the SPC.
Experimental investigations produced corticoid-like effects on the adrenal glands in rats and dogs following higher dosages, which could indicate similar effects in humans at the highest given dose (300 mg/day).
Genotoxicity and carcinogenicity: Recognised first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes, the DNA-adduct level in the dog liver cells was extremely low.
This DNA-adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. One in vivo consequence of cyproterone acetate treatment was the increased incidence of focal, possibly preneoplastic, liver lesions in which cellular enzymes were altered in female rats and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutation. The clinical relevance of these findings is presently uncertain. Clinical experience to date would not support an increased incidence of hepatic tumours in man.
In long-term carcinogenicity studies in rats cyproterone acetate increased the incidence of liver tumours including carcinomas at high doses which concomitantly caused liver toxicity and exceeded the maximum human dose. Further investigations into rodents at lower, non-hepatotoxic doses revealed benign liver proliferations similar to effects described for other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.

For use in men: For control of libido in severe hypersexuality and/or sexual deviation in the adult male. For reduction of drive in sexual deviations in men, cyproterone acetate 50 mg can be used when other interventions are considered inappropriate.
For the management of patients with prostatic cancer to suppress "flare" with initial LHRH analogue therapy, in long-term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or oral therapy is preferred, and in the treatment of hot flushes in patients under treatment with LHRH analogues or who have had an orchidectomy.
For use in women: Severe signs of androgenisation, e.g. very severe hirsutism, androgen-dependent severe loss of scalp hair eventually resulting in baldness (severe androgenic alopecia), often attended by severe forms of acne and/or seborrhoea.

For oral administration only.
Control of libido in severe hypersexuality and/or sexual deviation: Adults and the elderly: The usual dose is started with one Cyproterone Acetate 50 mg Tablet twice daily. The duration of cyproterone acetate treatment should be defined on an individual basis. When a satisfactory result has been achieved, the therapeutic effect should be maintained with the lowest possible dose. When changing the dose or when discontinuing cyproterone acetate, this should be done gradually.
The daily dose should be divided and taken after the morning and evening meals.
The management of patients with prostatic cancer: The maximum daily dose is 300 mg.
Adults and the elderly: To suppress "flare" with initial LHRH Analogue therapy: Initially 2 tablets of Cyproterone Acetate 50 mg Tablets twice daily (200 mg) alone for 5-7 days, followed by 2 tablets of Cyproterone Acetate 50 mg Tablets twice daily (200 mg) for 3-4 weeks together with the LHRH analogue therapy in the dosage recommended by the marketing authorization holder (see SmPC of LHRH analogue).
In long term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or when oral therapy is preferred: 200-300 mg/day.
For the previously mentioned two indications the dosage should be divided into 2-3 doses per day and taken after meals.
In the treatment of hot flushes in patients under treatment with LHRH analogues or who have had an orchidectomy: 50 mg starting dose with upward titration, if necessary, within the range 50-150 mg/day. For this indication, the dosage should be divided into 1-3 doses per day and taken after meals.
Additional information on special population (applies to all indications): Children and adolescents: Cyproterone acetate is not recommended for use in male children and adolescents below 18 years of age due to lack of data on safety and efficacy.
Cyproterone acetate must not be given before the conclusion of puberty since an unfavourable influence on longitudinal growth and still unstabilised axes of endocrine function cannot be ruled out.
Elderly patients: There are no data suggesting the need for a dosage adjustment in elderly patients.
Patients with hepatic impairment: The use of cyproterone acetate is contraindicated in patients with liver diseases (see Precautions and Adverse Reactions).
Patients with renal impairment: The use of cyproterone acetate in patients with renal impairment has not been investigated. There are no data suggesting the need for dosage adjustment in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).

There have been no reports of ill effects from overdosage, which is, therefore, generally unnecessary to treat. There are no special antidotes and treatment should be symptomatic. If overdosage is discovered within 2 to 3 hours and is so large that treatment seems desirable, gastric lavage can be safely used.

Cyproterone acetate must not be used in patients with: Use in patients known to be hypersensitive to cyproterone acetate or to any of the ingredients of the Cyproterone Acetate Tablets.
Cyproterone acetate must not be used in patients with meningioma or a history of meningioma.
Additional contraindications for patients being treated for hypersexuality/sexual deviation: Cyproterone acetate is contraindicated for use in patients with liver diseases (including Dubin-Johnson syndrome and Rotor syndrome); malignant tumours (other than prostatic cancer); wasting diseases (with the exception of inoperable carcinoma of the prostate) (because of transient catabolic action); a history of or existing thrombosis or embolism; severe diabetes with vascular changes; sickle-cell anaemia; severe chronic depression.
Cyproterone acetate should not be given to youths under the age of 18 or to those whose bone maturation and testicular maturation is incomplete.

Liver: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200-300 mg/day cyproterone acetate. 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 pre-treatment, regularly during treatment and whenever any symptoms or signs suggestive of hepatotoxicity occur. If hepatotoxicity is confirmed, cyproterone acetate should normally be withdrawn, unless the hepatotoxicity can be attributed to another cause, e.g. metastatic disease, in which case cyproterone acetate should be continued only if the perceived benefit outweighs the risk.
Very rarely liver tumours, leading in isolated cases to life-threatening intra-abdominal haemorrhage, have been observed after the use of sex steroids, to which class cyproterone acetate belongs. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, hepatic tumour should be considered in the differential diagnosis and, if necessary, cyproterone acetate should be withdrawn.
Thromboembolism: The occurrence of thromboembolic events has been reported in patients using cyproterone acetate, although a causal relationship has not been established. Patients with a history of arterial or venous thrombotic/thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, myocardial infraction), with a history of cerebrovascular accidents or with advanced malignancies are at increased risk of further thromboembolic events, and may be at risk of recurrence of the disease during cyproterone acetate therapy. In patients with a history of thromboembolic disorders or suffering from sickle-cell anaemia or severe diabetes with vascular changes, the risk benefit ratio must be considered carefully in each individual case before cyproterone acetate is prescribed.
In very rare cases, the occurrence of thromboembolic events has been reported in temporal association with the use of cyproterone acetate; a causal relationship seems however questionable.
Chronic depression: It has been found that some patients with severe chronic depression deteriorate during cyproterone acetate therapy. Such patients should be closely monitored for signs of deterioration and warned to contact their doctor immediately if their depression worsens.
Breathlessness: Shortness of breath may occur. Possibly due to the known stimulatory effect of progesterone and synthetic progestogens on breathing, which is accompanied by hypocapnia and compensatory alkalosis, but it is not considered that treatment is required.
Adrenocortical function: During treatment adrenocortical function should be monitored regularly, as preclinical data suggest a possible suppression due to the corticoid-like effect of Cyproterone Acetate.
Diabetes mellitus: Strict medical supervision is necessary if the patient suffers from diabetes as cyproterone acetate can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment because the requirement for oral antidiabetics or insulin can change.
Haemoglobin: Hypochromic anaemia has been found rarely during long term treatment, and blood counts before and at regular intervals during treatment are advisable.
Nitrogen balance: A negative nitrogen balance is usual at the start of treatment, but usually does not persist.
Spermatogenesis: A spermatogram should be recorded before starting treatment in patients of procreative age, as a guard against attribution of pre-existing infertility to cyproterone acetate at a later stage.
It should be noted that decline in spermatogenesis is slow and cyproterone acetate should not be regarded as a male contraceptive.
Medico-legal consideration: Doctors are advised to ensure that the fully informed consent of the patient to cyproterone acetate treatment is obtained, witnessed and can be verified.
Lactose: The tablets also contain lactose (see Description). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Patients who are on a lactose-free diet should take this amount into consideration.
Meningiomas: The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate primarily at doses of 25 mg and above. The risk of meningioma increases with increasing cumulative doses of cyproterone acetate (see Pharmacology: Pharmacodynamics under Actions). High cumulative doses can be reached with prolonged use (several years) or shorter duration with high daily doses. Patients should be monitored for meningiomas in accordance with clinical practice. If a patient treated Cyproterone Acetate is diagnosed with meningioma, treatment with Cyproterone Acetate and other cyproterone containing products must be permanently stopped (see 'Contraindications').
There is some evidence that the meningioma risk may decrease after treatment discontinuation of cyproterone.
Anaemia: Anaemia has been reported during long-term treatment. Therefore, the red blood count should be checked regularly during treatment.
Effects on ability to drive and use machines: Fatigue and lassitude are common in the first few weeks of therapy but usually become much less marked from the third month - patients should be warned about this and if affected should not drive or operate machinery.
The marked lassitude and asthenia necessitate special care when driving or operating machinery.

Fertility, pregnancy and lactation: Not applicable. Cyproterone acetate is not indicated for use in women.

The most frequently observed adverse drug reactions (ADRs) in patients receiving cyproterone acetate are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.
The most serious ADRs in patients receiving cyproterone acetate are hepatic toxicity, benign and malignant liver tumours which may lead to intra-abdominal haemorrhage and thromboembolic events.
The following approximate incidents were estimated from published reports of a number of small clinical trials and spontaneous ADR reports: very common: incidence ≥1:10; common: incidence <1:10 but ≥1:100; uncommon: incidence <1:100 but ≥1:1,000; rare: incidence <1:1,000 but ≥1:10,000; very rare: incidence <1:10,000; not known (cannot be estimated from available data).
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Very rare: Benign and malignant liver tumours which may lead to life threatening intra-abdominal haemorrhage (see Precautions).
Rare: The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate (see Precautions).
Blood and lymphatic system disorders: Not known: Anaemia during long-term treatment.
Immune system disorders: Rare: Hypersensitivity reactions.
Endocrine disorders: Not known: Suppression of adrenocortical function.
Metabolism and nutritional disorders: Common: Changes in bodyweight during long-term treatment (chiefly weight gains in association with fluid retention).
Psychiatric disorders: Common: Depressive moods and restlessness (temporary).
Vascular disorders: Not known: Thromboembolic events, although a causal relationship has not been established (see Precautions).
Respiratory, thoracic & mediastinal disorders: Common: Dyspnoea (see Precautions).
Hepatobiliary disorders: Common: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, have been reported in patients treated with 200-300 mg cyproterone acetate (usually at dosages of 100 mg and above) (see Precautions). Most reported fatal cases were in men with advanced carcinoma of the prostate.
Toxicity is dose related and develops, usually, several months after treatment has begun.
Skin & subcutaneous tissue disorders: Uncommon: Rash.
Not known: Reduction of sebum production leading to dryness of the skin and consequently improvement of existing acne vulgaris has been reported as well as; transient patchy loss and reduced growth of body hair, increased growth of scalp hair, lightening of hair colour and female type of pubic hair growth.
Musculoskeletal, connective tissue and bone disorders: Not known: Osteoporosis (due to long-term androgen deprivation).
Reproductive system disorders: Very common: Decreased libido, erectile dysfunction, reduced sexual drive and inhibition of gonadal function. These changes are reversible after discontinuation of therapy.
Inhibition of spermatogenesis: Very common: Sperm count and the volume of ejaculate is reduced.
Infertility is usual, and there may be azoospermia after eight weeks. There is usually slight atrophy of the seminiferous tubules. Follow up examinations have shown these changes to be reversible, spermatogenesis usually reverting to its previous state about three to five months after stopping treatment or in some users up to 20 months. That spermatogenesis can recover even after very long treatment is uncertain. There is evidence that abnormal sperms, which might give rise to malformed embryos, are produced during treatment.
Gynaecomastia: Common: Gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which usually regresses after withdrawal of the preparation.
Rare: Galactorrhoea and tender benign nodules.
Symptoms mostly subside after discontinuation of treatment or reduction of dosage.
General and administration site disorders: Common: Hot flushes, sweating, fatigue and lassitude.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Diabetes: The requirement for oral antidiabetic treatment or insulin can change. See also Precautions. At high therapeutic cyproterone acetate doses of three times 100 mg per day, cyproterone acetate may inhibit CYP2C8 (see as follows). Thiazolidinediones (i.e. the anti-diabetics pioglitazone and rosiglitazone) are substrates of CYP2C8 (increased blood levels of these anti-diabetics may require dose adjustment).
Cyproterone acetate can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment.
Chronic alcoholism: Alcohol appears to reduce the effect of cyproterone acetate, which is of no value in chronic alcoholics.
Other interactions: Clinical interaction studies have not been performed. However, since cyproterone acetate is metabolised by CYP3A4, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir and other strong inhibitors of CYP3A4 inhibits 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 cyproterone acetate doses of 100 mg three times per day. (This is three times the maximum total daily dose.)
The risk of statin-associated myopathy or rhabdomyolysis may be increased when those HMG-CoA inhibitors (statins) which are primarily metabolised by CYP3A4 are co-administered with high cyproterone acetate doses, since they share the same metabolic pathway.

Incompatibilities: None known.
Special precautions for disposal and other handling of the product: No special requirement for disposal.

Shelf life: 2 years.
Special precautions for storage: Do not store above 30°C.

Other Drugs Affecting Hormonal Regulation / Cancer Hormone Therapy

G03HA01 - cyproterone ; Belongs to the class of antiandrogen preparations.

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