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Cyproterone Acetate

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

Cyproterone AcetateSynonyms: Ciproteron-acetát; Ciproterona, acetato de; Ciproterono acetatas; Cyproteron-acetát; Cyproteronacetat; Cyproteroni Acetas; NSC-81430; SH-714; SH-881 (cyproterone); Syproteroniasetaatti
BAN: Cyproterone Acetate [BANM]
USAN: Cyproterone Acetate
INN: Cyproterone Acetate [rINNM (en)]
INN: Acetato de ciproterona [rINNM (es)]
INN: Cyprotérone, Acétate de [rINNM (fr)]
INN: Cyproteroni Acetas [rINNM (la)]
INN: Ципротерона Ацетат [rINNM (ru)]
Chemical name: 6-Chloro-1β,2β-dihydro-17α-hydroxy-3´H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione acetate
Molecular formula: C24H29ClO4 =416.9
CAS: 2098-66-0 (cyproterone); 427-51-0 (cyproterone acetate)
ATC code: G03HA01
Read code: y00Sq [Endocrine Use]; y0102 [Acne]; y02oV [Malignancy]

Note. Compounded preparations of cyproterone acetate may be represented by the following names:

Co-cyprindiol (BAN) — cyproterone acetate 2000 parts and ethinylestradiol 35 parts (w/w)

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Cyproterone Acetate). A white or almost white, crystalline powder. Practically insoluble in water sparingly soluble in dehydrated alcohol freely soluble in acetone very soluble in dichloromethane soluble in methyl alcohol. Protect from light.

Adverse Effects

When given to men cyproterone reduces libido, inhibits spermatogenesis, reduces the volume of ejaculate, and causes infertility. There may be azoospermia after 8 weeks and slight atrophy of the seminiferous tubules, but these changes are slowly reversible and spermatogenesis usually recovers to pre-treatment levels about 3 to 5 months after stopping cyproterone. Abnormal spermatozoa may be produced.

Gynaecomastia is common and permanent enlargement of the mammary glands may occur galactorrhoea and benign nodules have been reported rarely. Fatigue and weakness are common and depressive mood changes can occur occasionally. Patients may experience weight changes, alterations in hair pattern, dry skin, and rarely rashes or hyper sensitivity. Shortness of breath may occur, and anaemia and osteoporosis have been reported rarely. Liver function tests may be altered there have also been reports of hepatitis, jaundice, and hepatic failure,

sometimes fatal, developing usually after several months of high-dose cyproterone therapy, but an association with liver cancer is uncertain. When low-dose cyproterone is given with ethinylestradiol to women, adverse effects associated with combined oral contraceptives may occur.

Carcinogenicity

See Effects on the Liver, below.

Effects on the cardiovascular system

Combined oral contraceptives are associated with a small increased risk of cardiovascular disease. A case-control study suggested that the risk of venous thrombo embolism may be further increased for women taking combined contraceptives containing cyproterone compared with levonorgestrel. A review by the authorities in New Zealand considered the risk to be at least as great as with third-generation oral contraceptives, a conclusion further supported by a study in that country of the contraceptives used by women discharged from hospital with a diagnosis of deep-vein thrombosis or pulmonary embolism.

In 2002, the UK CSM warned that preparations containing cyproterone and ethinylestradiol should not be used solely for contraception, but for treatment of severe acne that had not responded to oral antibac-terials, or for moderately severe hirsutism, and that they should be withdrawn 3 or 4 cycles after the treated condition has completely resolved. However, others’ have questioned some study results, concluding that preparations containing cyproterone are not associated with a risk in excess of that associated with conventional combined oral contraceptives including those containing levonorgestrel.

Some have also called for the removal of the CSM recommendation to limit the duration of therapy, particularly as acne and hirsutism frequently recur after stopping cyproterone therapy. In 2008, the CHM (formerly the CSM) reconfirmed its 2002 advice on the use of cyproterone with ethinylestradiol. However, it added that for women with severe hyperandrogenism, in whom symptoms usually recur when treatment is stopped, therapy could be continued with regular specialist review until the symptoms were judged unlikely to recur. It was also recommended that, for all women, treatment can be restarted at any time if acne or hirsutism recurs after stopping therapy.

The study of any association may be confounded by the adverse cardiovascular risk associated with polycystic ovary disease, an underlying condition in many women given cyproterone with ethinylestradiol to manage acne and hirsutism.

Cyproterone AcetateEffects on the eyes

Bilateral optic atrophy in an elderly male patient was thought to be associated with cyproterone. The authors could find no other cases from the published literature or the manufacturers’ records. Central retinal vein occlusion occurred in a 28-year-old woman given cyproterone for the treatment of hair loss.

Effects on the liver

There have been numerous reports of hepatic reactions associated with cyproterone acetate. In February 1995, the UK CSM noted that it had received 96 reports of reactions including hepatitis, cholestatic jaundice, and hepatic failure, following cyproterone treatment 33 cases had led to fatalities. Nearly all cases (91 of 96) were in elderly men typically receiving high doses (300 mg daily) for prostatic cancer, and tox-icity usually developed after several months of treatment. In view of this it was recommended that the use of cyproterone acetate in prostatic cancer be restricted to short courses for the testosterone flare associated with the commencement of gonadorelin analogue therapy, or for hot flushes after surgical or chemical castration, or for patients unresponsive to, or intolerant of, other treatments.

A retrospective analysis of data from 105 patients with advanced prostate cancer, who had received cyproterone acetate 150 mg daily, found mild to moderate hepatotoxicity in 6 patients and severe toxicity in 4. There was a higher occurrence ofhepatotoxicity (19 cases out of 124 patients) in a similar group that had been given flutamide. Fourteen published case reports have also been briefly reviewed. Patients with chronic viral hepatitis might be at higher risk of developing hepatotoxicity from cyproterone therapy.

Although there is little doubt of the risk ofhepatotoxicity, suggestions of an association between cyproterone therapy and the development of liver cancer remain contentious. There are individual reports of hepatocellular carcinoma developing in patients receiving cyproterone, and some evidence in vitro of the formation of DNA adducts in exposed hepatocytes, but there does not seem to be clinical evidence to support any association between use of cyproterone acetate and the development of liver tumours.

Precautions

When used for hypersexuality, cyproterone is contra-indicated in men with liver diseases or malignant or wasting diseases. In addition, it should not be given to men with severe chronic depression, severe diabetes with vascular changes, sickle-cell anaemia, or to those with a history of thromboembolic disorders. It may delay bone maturation and testicular development and so should not be given to immature youths. When used for prostate cancer, there are no absolute contra-indications to the use of cyproterone, but the above conditions should prompt cautious consideration of the risks and benefits.

In men treated with cyproterone, liver function should be monitored before starting, and regularly during, treatment, and whenever any symptoms or signs suggestive ofhepatotoxicity occur. If cyproterone-induced hepatotoxicity occurs, treatment should be withdrawn. In men with prostate cancer, it may be advisable to limit the duration of treatment (see Effects on the Liver, above). Men with diabetes require careful monitoring of diabetic control. Since anaemia has been seen, regular blood counts are recommended before and during treatment. Adrenocortical suppression has been reported and function should be monitored regularly during treatment. Patients should be advised that fatigue and weakness are common and may interfere with driving and the operation of machinery. When cyproterone is given with ethmylestradiol to women the precautions for combined oral contraceptives should be observed.

Pregnancy

Use of cyproterone during pregnancy might carry a risk of feminisation of a male fetus. However, there are a few case reports of healthy male infants born to mothers who had inadvertently taken a combination of cyproterone acetate and ethmylestradiol during the early stages of pregnancy, and of a male fetus that was found to have no malformations after abortion was induced. For further information on oral contraceptive use in pregnancy.

Interactions

UK licensed product information states that alcohol may reduce the effectiveness of cyproterone acetate as it is ineffective in chronic alcoholics. Dosage requirements of oral antidiabetics and insulin may be altered because of cyproterone’s effects on carbohydrate metabolism.

When given with ethinylestradiol to women, interactions similar to those for combined oral contraceptives might be anticipated.

Pharmacokinetics

Cyproterone acetate is slowly absorbed from the gastrointestinal tract with peak plasma concentrations being achieved in about 3 hours. It is about 96% bound to plasma proteins, mainly albumin. The terminal elimination half-life is about 43 hours. Cyproterone is metabolised by various pathways including hydroxylation and conjugation about 35% of a dose is excreted in urine, the remainder being excreted in the bile. The principal metabolite, 15p-hydroxycyproterone, has anti-androgenic activity.

The elderly

In a study of healthy men, a decrease in hepatic clearance of cyproterone acetate was found in elderly men and thought to be due to an age-related reduction in liver volume.

Uses and Administration

Cyproterone acetate is a progestogen (see Progesterone) with anti-androgenic properties. It is used for the control of libido in severe hypersexuality or sexual deviation in men (see Disturbed Behaviour). The usual oral dose is 50 mg twice daily after meals.

It is also used for the palliative treatment of prostatic carcinoma, to control disease flare or hot flushes associated with gonadorelin analogue therapy, and to control hot flushes associated with orchidecto-my. In palliative treatment where gonadorelin analogues or surgery are contra-indicated, not tolerated, or where oral therapy is preferred, doses of 200 to 300 mg daily are given in 2 or 3 divided doses after meals. The usual initial dose for disease flare is 300 mg daily in 2 or 3 divided doses after meals, which may be reduced to 200 mg daily if the higher dose is not tolerated. For the treatment of hot flushes, a dose of 50 mg daily is used this may be increased up to 150 mg daily in 3 divided doses if necessary.

Cyproterone acetate may be used with ethinylestradiol in women for the control of acne and hirsutism (see below). The usual oral doses are 2 mg of cyproterone acetate with 35 micrograms of ethinylestradiol given daily for 21 days of each menstrual cycle the first treatment course is started on the first day of the menstrual cycle and each subsequent course is started after 7 tablet-free days have followed the preceding course. This regimen also provides contraception, and patients relying on this effect should be given the same advice regarding missed doses and reduced efficacy due to vomiting and diarrhoea as that given for combined oral contraceptives. Treatment should be withdrawn 3 or 4 cycles after the androgen-dependent condition has completely resolved, but repeat courses may be given if it recurs.

Cyproterone acetate has also been given by depot intramuscular injection. A dose of 300 mg given once every 10 to 14 days has been used to control libido once a satisfactory effect has been obtained, the dose may be reduced by gradually increasing the interval between injections until a stable maintenance dose is reached. In palliative therapy of prostatic carcinoma, 300 mg may be given once every 2 weeks after orchidectomy, or once weekly without orchidectomy. Dose-related hepatotoxicity has occurred with cyproterone, particularly in men treated for prostate cancer (see Effects on the Liver and Precautions, above).

Acne

Cyproterone acetate may be used in the management of acne, generally in women with signs of hyperandrogenism. An oral combination of cyproterone acetate 2 mg with ethinylestradiol 35 micrograms, which also provides contraception, is often used in women whose condition is moderately severe, and may be considered in women with mild acne who wish to use hormonal contraception. In more severe disease, higher doses of cyproterone may be added to this low-dose regimen examples include giving cyproterone acetate 50 mg daily for 10 or 21 days of each cycle.A systematic review considered that a combination of ethinylestradiol with low-dose cyproterone acetate was more effective in the treatment of acne than combined oral contraceptives containing levonorgestrel, but noted that this was based on limited evidence.

Alopecia

Cyproterone acetate has been tried in the treatment of female-pattern alopecia. In premenopausal women, oral doses of 50 or 100 mg daily have usually been given in sequential regimens with an oestrogen or combined oral contraceptive continuous treatment using 50 mg daily has been given to post-menopausal women. It has generally been considered that women with other signs of hyperandrogenism, such as acne and seborrhoea, as well as hair loss are most likely to benefit from cyproterone but results from small studies have been mixed.

Gender reassignment

Cyproterone acetate is used for its anti-androgenic effects in male-to-female transsexuals. An oral dose of 50 mg twice daily is usually given with an oestrogen (see Estradiol).

Hidradenitis suppurativa

Beneficial responses to cyproterone acetate with ethinylestradiol have been seen in women with hidradenitis suppurativa, an androgen-dependent disorder of the skin and hair in the pubic and axillary regions.

Hirsutism

Hirsutism is an abnormal growth in females of coarse pigmented terminal hair in an adult male pattern, and is one of the clinical expressions of hyperandrogenism. Most women with hirsutism have increased concentrations of circulating androgens from the ovaries associated with polycystic ovary syndrome. In rare cases, the adrenal gland is the primary source of increased androgens, for example, in congenital adrenal hyperplasia. In a few cases, severe hirsutism is associated with frank virilisation due to massively increased circulating androgen concentrations from an androgen-secreting tumour. Hirsutism is an adverse effect of androgenic progestogens, such as norgestrel, used in hormonal contraceptives and HRT. Androgens and anabolic steroids may also cause hirsutism in females.

Treatment for hirsutism uses topical cosmetic treatments such as bleaching, shaving, plucking, electrolysis, and laser hair removal, and in the mildest cases this may be all that is required. However, such mechanical means of treatment are more usually combined with drug therapy to prevent further conversion of vellus to terminal hair, and to slow the regrowth of terminal hair, which may become lighter and softer. Because the growth cycle of hair is long, a response to therapy may not be seen for 6 to 12 months.

Combined hormonal contraceptives containing non-androgenic progestogens are widely used for hirsutism but their effects are generally limited. The mainstay of oral drug therapy for hirsutism is an anti-androgen, the most commonly used being the steroidal anti-androgens cyproterone acetate and spironolactone. To increase efficacy (by suppressing ovarian androgen production) and minimise the chance of conception (because of the risk of feminisation of a male fetus), cyclical ethinylestradiol is commonly used with cyproterone acetate. Combined non-androgenic hormonal contraceptives are commonly used with spironolactone, which has no progestogenic activity.

Cyproterone acetate may be used in a low-dose combined preparation containing cyproterone acetate 2 mg with ethinylestradiol 35 micrograms. In more severe hirsutism, the two drugs may be prescribed separately in a ‘reversed sequential regimen’. High-dose regimens have used cyproterone acetate 100 mg daily given on days 5 to 14 of the menstrual cycle with ethinylestradiol 50 micrograms on days 5 to 24. However, lower doses are also effective, with fewer adverse effects such regimens include cyproterone acetate 50 mg (days 5 to 15) with ethinylestradiol 20 micrograms (days 5 to 25), or cyproterone acetate 12.5 mg (days 5 to 15) with ethinylestradiol 10 to 20 micrograms (days 5 to 25). Alternatively, cyproterone acetate 25 to 50 mg daily may be added to the first 10 days of any low-dose combined oral contraceptive. When a satisfactory response has been achieved, the cyproterone dosage is gradually reduced, and eventually the low-dose combination preparation may be sufficient.

In some countries spironolactone is the drug of choice for the treatment of hirsutism, particularly if there is associated obesity and hypertension doses of 100 to 200 mg daily are generally used. Despite its wide use, however, evidence of benefit is considered scanty. Flutamide.finasteride, and leuprorelin have also been shown to be effective, although some consider finas-teride to be less active. The condition has also been reported to respond to ketoconazole. Eflornithine is used topically for the reduction of facial hair. It is thought to slow hair growth by the inhibition of ornithine decarboxylase in hair follicles.

Corticosteroids can suppress adrenal androgen production, but results with dexamethasone have been disappointing and the addition of an anti-androgen is usually needed Corticosteroids may have a limited role in managing hirsutism associated with congenital adrenal hyperplasia.

Precocious puberty

Although cyproterone acetate has been used for the treatment of central precocious puberty, it has generally been superseded and is now given in a short course to prevent the initial stimulatory effect of gonadorelin analogue therapy. The use of an oral dose of cyproterone acetate 50 mg twice daily, given from 3 weeks before to 2 weeks after starting the gonadorelin analogue, has been reported. Menstrual-like bleeding may occur in girls after stopping cyproterone, depending on the degree of precocity. Gonadorelin analogue therapy does not control adrenal production of sex hormones, which, if overactive, can stimulate adrenarche and advancement of bone age cyproterone acetate in usual doses of 10 to 20 mg twice daily has been used to treat this.

Cyproterone acetate may sometimes be used to suppress sexual maturation in the management of peripheral forms of precocious puberty. Although it is not licensed for this, the BNFC includes an initial oral dose of 25 mg twice daily, adjusted according to response.

Preparations

British Pharmacopoeia 2008: Cyproterone Tablets.

Proprietary Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Androcur; Androstat; Asisdun; Asoteron; Ceprater; Ciclamil; Ciprofarma; Ciproplex; CPD; Kebirterona; Omnigeriat; Purfilx; Rubidox;
Australia: Androcur; Cyprohexal; Cyprone; Cyprostat¤; Procur;
Austria: Andro-Diane; Androcur; Curandron;
Belgium: Androcur;
Brazil: Androcur; Androneo; Androsteron; Bioterona; Cetoteron;
Canada: Alti-CPA¤; Androcur;
Chile: Ciproviron¤;
Czech Republic: Androcur; Cyproplex;
Denmark: Androcur; Finland: Androcur;
France: Androcur; Germany: Androcur; Virilit;
Greece: Androcur; Hong Kong: Androcur;
Hungary: Androcur; Ireland: Androcur;
Israel: Androcur; Armocur¤; Cypron;
Italy: Androcur;
Malaysia: Androcur;
Mexico: Androcur; Neoproxil;
Netherlands: Androcur;
Norway: Androcur;
New Zealand: Androcur; Procur; Siterone;
Portugal: Androcur;
Russia: Androcur (Андрокур);
South Africa: Androcur;
Singapore: Androcur;
Spain: Androcur;
Sweden: Androcur; Diane;
Switzerland: Androcur;
Thailand: Androcur;
United Kingdom: Androcur; Cyprostat;
Venezuela: Androcur

Multi-ingredient Preparations

Argentina: Climene; Diane; Mileva;
Australia: Brenda-35 ED; Climen; Diane; Estelle; Juliet¤;
Austria: Climen; Diane; Minerva; Sterigynon;
Belgium: Climen; Diane;
Brazil: Climene; Diane; Elamax; Ferane 35; Selene;
Canada: Diane;
Chile: Anuar; Climene; Diane; Dixi-35; Drina; Evilin; Lady-Ten 35;
Czech Republic: Climen; Diane;
Denmark: Climen; Diane; Feminil;
Finland: Diane; Femilar;
France: Climene; Diane; Evepar; Holgyeme; Lumalia; Minerva;
Germany: Climen; Diane;
Greece: Gynofen 35;
Hong Kong: Climen 28; Diane;
Hungary: Climen; Diane;
India: Ginette;
Ireland: Dianette;
Israel: Diane;
Italy: Climen; Diane; Pausene;
Malaysia: Climen; Diane;
Mexico: Climene; Diane;
Netherlands: Climene; Diane;
Norway: Climen; Diane;
New Zealand: Diane; Estelle;
Portugal: Climen; Diane;
Russia: Climen (Климен); Diane (Диане);
South Africa: Climen; Diane; Ginette; Minerva;
Singapore: Climen; Diane; Estelle;
Spain: Climen; Clisin; Diane;
Switzerland: Climen; Diane; Feminac; Minerva;
Thailand: Climen; Diane; Helen; Lady-35; Manoane; Preme; Sucee; Tina¤;
United Kingdom: Acnocin; Cicafem; Dianette; Diva;
Venezuela: Climene; Diane

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