(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Bicalutamide). A fine, white to off-white powder. Sparingly to slightly soluble in alcohol; freely soluble in acetone and in tetrahydrofuran; soluble in acetonitrile. Store in airtight containers.

Adverse Effects and Precautions

As for Flutamide. Pruritus, asthenia, alopecia, hair regrowth, and dry skin occur commonly with bicalutamide. Hyper sensitivity reactions, including an-gioedema and urticaria, have been reported infrequentiyCardiovascular effects including angina, heart failure, arrhythmias, and ECG changes have been reported rarely. Interstitial pneumonitis and pulmonary fibrosis have also been reported rarely.

Effects on the gastrointestinal tract. There is some evidence that bicalutamide is associated with a lower incidence of diarrhoea than flutamide.

Effects on the lungs. For a review of cases of pneumonitis associated with anti-androgens including bicalutamide, see under Flutamide.

Gynaecomastia. For a discussion of gynaecomastia, a frequent adverse effect of anti-androgen therapy, and its management, see under Flutamide.

Interactions

Bicalutamide inhibits various cytochrome P450 isoenzymes, particularly CYP3A4, in vitro, and licensed product information recommends that terfenadine, astemizole, and cisapride should not be given with bicalutamide, and that other drugs with a narrow therapeutic index that are metabolised by cytochrome P450 isoenzymes should be used with caution. In vitro studies have shown that bicalutamide can displace warfarin from its protein binding sites (see also Antineoplastics).

Pharmacokinetics

Bicalutamide is well absorbed after oral doses. It undergoes extensive metabolism in the liver, the active R-enantiomer mainly by oxidation, the inactive S-enanti-omer mainly by glucuronidation. It is excreted as metabolites in urine and faeces. The half-life of the R-enantiomer is about 6 to 7 days, and may be prolonged still further in severe hepatic impairment. The S-enantiomer is cleared more rapidly. Bicalutamide is about 96% bound to plasma proteins.

Uses and Administration

Bicalutamide is a nonsteroidal anti-androgen with actions and uses similar to those of flutamide. It is used orally in the treatment of prostatic cancer. When used with a gonadorelin analogue in the palliative treatment of advanced prostatic cancer the usual dose is 50 mg daily. In the UK treatment is started at least 3 days before starting the gonadorelin analogue to suppress any flare reaction, but in the United States of America treatment is started at the same time. A similar dose is used with surgical castration, starting on the same day as surgery.

Bicalutamide in a dose of 150 mg daily may be given as monotherapy or adjuvant therapy to surgery or radiotherapy in men with locally advanced disease at high risk for disease progression. It has been used as mono-therapy in localised disease, but there is some evidence to suggest that in men without high risk of disease progression, who would otherwise be managed with watchful waiting, the immediate use of bicalutamide may increase the risk of death.

Preparations

Proprietary Preparations

Argentina: Androxinon †; Bicaprost; Bidrostat; Biolutam; Bitakebir; Bosconar; Casodex; Codebup; Dimalan; Finaband; Gepeprostin; Imda †; Liberprost; Raffolutil;

Australia: Cosudex;

Austria; Casodex;

Belgium: Casodex;

Brazil: Casodex; Gepeprostin; Lutamidal;

Canada: Casodex;

Chile: Casodex; Lutamidal;

Czech Republic: Bicaluplex; Calumid; Casodex; Lanbica;

Denmark: Casodex;

Finland: Casodex;

France: Casodex;

Germany; Casodex;

Greece: Bicalut; Bicamide; Casodex; Verodex;

Hong Kong; Casodex;

Hungary: Bicatlon; Bilutamid; Calumid; Casodex;

India: Caluran; Calutide;

Indonesia: Casodex;

Ireland: Casodex;

Israel: Casodex;

Italy: Casodex;

Malaysia: Casodex;

Mexico: Casodex;

The Netherlands: Casodex;

Norway: Casodex;

New Zealand: Cosudex;

Philippines: Casodex;

Poland: Casodex;

Portugal: Casodex;

Russia: Bilumid; Calumid; Casodex;

South Africa; Casodex;

Singapore: Casodex;

Spain: Casodex;

Sweden: Casodex;

Switzerland: Casodex;

Thailand: Casodex;

Turkey: Casodex;

United Kingdom (UK): Casodex;

United States of America (US and USA): Casodex;

Venezuela: Calutol; Casodex.

Multi-ingredient

Australia: Zolacos GR

Drug Approvals

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

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe and Japan.

European Pharmacopoeia, 6th ed. (Tamsulosin Hydrochloride). A white or almost white powder. Slightly soluble in water and anhydrous alcohol freely soluble in formic acid.

Adverse Effects, Treatment, and Precautions

As for Prazosin Hydrochloride. Because tamsulosin is selective for a₁ receptors in the prostate the vasodilator effects may be less frequent. Tamsulosin may cause ejaculation abnormalities. It should be avoided in severe hepatic impairment.

Incidence of adverse effects. A study using prescription event monitoring data for more than 12 000 patients treated with tamsulosin found that dizziness, headache, malaise, and hypotension were the adverse effects most commonly reported.

Surgical procedures. In 2005 the manufacturers of tamsulosin warned that a syndrome of flaccidity of the iris, progressive miosis, and potential prolapse (intraoperative floppy iris syndrome IFIS) had been reported in some patients undergoing cataract surgery who were receiving, or had received, alpha Mockers. One group of workers had reported that in one series of 741 patients undergoing cataract surgery, 15 of the 16 who developed IFIS had received tamsulosin. An earlier retrospective study of 511 similar patients by the same workers had found IFIS in 10 of the 16 patients with a history of tamsulosin treatment but no cases in any of the other patients, including in 11 patients who had received other alpha blockers. The US manufacturer stated that although most cases had occurred in patients who had been taking alpha blockers concurrently or up to 2 weeks before surgery the benefit of stopping such therapy before cataract surgery has not been established as a few cases had included patients who discontinued alpha blockers up to 9 months before surgery. The manufacturers of tamsulosin recommend that patients being considered for cataract surgery should be questioned to ascertain whether they are taking the drug. A literature review found that other alpha blockers, including alfuzosin, doxazosin, and terazosin, have also been associated with IFIS in this patient group however, IFIS has been most strongly associated with the use of tamsulosin. In the UK, the MHRA has required the inclusion of a warning in the labelling of all alpha blockers advising patients to inform their cataract surgeon about past and current use of these drugs.

Interactions

As for Prazosin Hydrochloride.

Pharmacokinetics

Tamsulosin is absorbed from the gastrointestinal tract and is almost completely bioavailable. The extent and rate of absorption are reduced by food. After oral doses of an immediate-release preparation, peak plasma concentrations occur after about 1 hour. Tamsulosin is about 99% bound to plasma proteins. It is metabolised slowly in the liver primarily by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4 it is excreted mainly in the urine as metabolites and some unchanged drug. The plasma elimination half-life has been reported to be between 4 and 5.5 hours. Some of the pharmacokinetic values cited above may be altered when tamsulosin is given as a modified-release preparation, the form in which it is usually used for instance, peak plasma concentrations occur about 6 hours after a dose and the apparent elimination half-life may be 10 to 15 hours.

Renal impairment. Plasma-tamsulosin concentrations were reported to be increased in patients with renal impairment when compared with subjects with normal renal function. However, plasma concentrations of unbound, pharmacologically active drug were similar in both groups and it was suggested that the raised total plasma concentrations were due to an increase in plasma protein binding.

Uses and Administration

Tamsulosin is an alpha1-adrenoceptor blocker with actions similar to those of prazosin it is reported to be more selective for the alpha_1A-adrenoceptor subtype, which accounts for about 70% of the a₁ adrenoceptors in the prostate. It is used in benign prostatic hyperplasia to relieve symptoms of urinary obstruction.

In benign prostatic hyperplasia, tamsulosin hydrochloride is given orally in a modified-release formulation, in a dose of 400 micrograms once daily. Licensed US product information states that the dose may be increased after 2 to 4 weeks, if necessary, to 800 micrograms once daily.

Antidepressant-induced genito-urinary disorders. Tamsulosin was used successfully to treat urinary hesitancy observed in 6 male patients receiving reboxetine. Painful ejaculation associated with reboxetine was also treated successfully in 2 men.

Prostatitis. Alpha₁-adrenoceptor blockers are one of a number of classes of drugs that have been tried for symptomatic relief in men with chronic prostatitis. In a 6-week multicentre, double-blind placebo-controlled study involving 58 men with moderate to severe chronic prostatitis/chronic pelvic pain syndrome, tamsulosin 400 micrograms daily produced greater symptomatic relief than placebo the effect was considered clinically significant for men with severe prostatitis. The benefit appeared to take several weeks to develop, and it was considered possible that longer exposure would produce additional benefit.

Renal calculi. In the conservative management of renal calculi there is increasing interest in the possible use of drug treatment to ease the spontaneous passage of the stone down the ureter. Alpha₁-adrenoceptor blockers can decrease smooth muscle spasm in the ureter, reducing obstruction and improving urine flow. In studies of patients with uncomplicated lower ureteral stones, tamsulosin has been reported to improve the rate of stone expulsion and expulsion time, and to reduce analgesic requirements. Tamsulosin was generally given orally in a dose of 400 micrograms daily for up to 4 weeks. Comparison groups were treated with various other antispasmodics including benzodiazepines, phloroglucinol, and nifedipine in most studies patients were also treated with antibacterial prophylaxis, deflazacort, and NSATDs.

A review found evidence suggesting that adjunctive tamsulosin is safe and effective in enhancing the clearance of renal stones with a larger diameter when used with extracorporeal shock wave lithotripsy. Although evidence regarding ureteral stone clearance is inconclusive, adjunctive tamsulosin has been reported to reduce painful episodes.

Preparations

Proprietary Preparations

Argentina: Aclosan Controlpros Espontal Lostam Omnic Reduprost Secotex Tamsuna Tansiloprost

Australia: Flomax Flomaxtra

Austria: Alna

Belgium: Omic

Brazil: Contiflo Omnic Secotex Tamsulon

Canada: Flomax

Chile: Eupen Gotely Omnic Prostall Secotex Sulix Vi-Uril

Czech Republic: Apo-Tamis Damurgin Fokusin Lannatam Omnic Solesmin Taflosin Tamipro Tamsec Tamurox Tanyz Urostad

Denmark: Omnic

Finland: Expros Omnic Tamictor Tamsumin

France: Josir Omix

Germany: Alna Omnic

Greece: Omnic Pradif

Hong Kong: Harnal

Hungary: Fokusin Omnic Provosal Tamsol Tamsudil Tamsugen Tanyz Totalprost Urostad

India: Urimax

Indonesia: Harnal

Ireland: Omnexel Omnic Omsil Tamsu

Israel: Omnic

Italy: Omnic Pradif

Japan: Harnal

Mexico: Asoflon Secotex

The Netherlands: Mapelor Omnic

Norway: Omnic

New Zealand: Flomax Flomaxtra

Philippines: Harnal

Poland: Bazetham Fokusin Omnic Omsal Prostamnic Tamsudil TamsuLek Tanyz Uprox Urostad

Portugal: Omnic Pradif

Russia: Fokusin Hyperprost Omnic

South Africa: Flomax

Spain: Omnic Urolosin

Switzerland: Omix Pradif

Thailand: Harnal

Turkey: Flomax

United Kingdom: Bazetham Contiflo Flomaxf Flomaxtra Stronazon Tabphyn

USA: Flomax

Venezuela: Secotex Tamsulon

Multi-ingredient

India: Urimax  †

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Adverse Effects and Precautions

As for Finasteride.

Pharmacokinetics

Dutasteride is absorbed from the gastrointestinal tract, reaching a peak serum concentration in 1 to 3 hours, with a bioavailability of about 60%. It is highly bound to plasma proteins. Dutasteride is metabolised by the cytochrome P450 isoenzymes CYP3A4 and CYP3A5, and most of a dose is excreted as metabolites in the faeces. At steady state the elimination half-life is about 3 to 5 weeks.

Uses and Administration

Dutasteride, like finasteride, is an inhibitor of 5α-reductase. Unlike finasteride, it is claimed to inhibit both the type-1 and type-2 isoforms of the enzyme. Dutasteride is used in the treatment of benign prostatic hyperplasia it may reduce the incidence of acute urinary retention and the need for surgery. Dutasteride is given in doses of 500 micrograms daily by mouth. Response may be delayed and treatment for 6 months may be required to assess whether benefit has been achieved. Dutasteride is under investigation for the prevention of prostate cancer, and has been investigated in the treatment of alopecia.

Proprietary Preparations

Argentina: Avodart

Austria: Avodart Avolve Zyfetor

Belgium: Avodart

Canada: Avodart

Chile: Avodart

Czech Republic: Avodart

Denmark: Avodart

Finland: Avodart

France: Avodart

Germany: Avodart

Greece: Avodart Duagen

India: Duprost

Indonesia: Avodart

Ireland: Avodart

Israel: Avodart

Italy: Avodart

Malaysia: Avodart

Mexico: Avodart

The Netherlands: Avodart Duagen

Norway: Avodart

Philippines: Avodart

Poland: Avodart

Portugal: Avodart Avolve Duagen

Russia: Avodart

South Africa: Avodart

Singapure: Avodart

Spain: Avidart Duagen

Sweden: Avodart

Switzerland: Avodart

Turkey: Avodart

UK: Avodart

USA: Avodart

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Profile

Medrogestone is a progestogen structurally related to progesterone that is used in the treatment of menstrual disorders, and as the progestogen in menopausal HRT. It is usually given orally in daily doses of 5 to 10 mg, generally in a cyclical regimen. Higher doses were used in the treatment of endometrial carcinoma, prostatic hyperplasia, and breast disorders including carcinoma. It has also been used for threatened or recurrent miscarriage, but such use is not recommended unless there is proven progesterone deficiency.

Preparations

Proprietary Preparations

Austria: Colpron

Belgium: Colpro †

France: Colprone

Germany: Prothil

Hong Kong: Colprone †

Italy: Colprone †

South Africa: Colpro †

Spain: Colpro

Switzerland: Colpro

Multi-ingredient

Austria: Premarin compositum † Premarin Plus

Belgium: Premplus

Czech Republic: Presomen Compositum †

Germany: Presomen Compositum

Hong Kong: Prempak

Italy: Prempak †

Malaysia: Prempak

The Netherlands: Premarin Plus

Portugal: Premarin Plus

South Africa: Prempak

Switzerland: Premarin Plus

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Testolactone). A white to off-white, practically odourless, crystalline powder. Soluble 1 in 4050 of water; soluble in alcohol and in chloroform; slightly soluble in benzyl alcohol; insoluble in ether and in petroleum spirit. Store in airtight containers.

Profile

Testolactone is a derivative of testosterone. It is reported to be an aromatase inhibitor that reduces peripheral oestrogen synthesis but has no significant androgenic activity. It has been used in the palliative treatment of advanced breast cancer in postmenopausal women. The usual oral dose is 250 mg four times daily. It should not be given to men with breast cancer. Peripheral neuropathies have occurred in patients given testolactone; gastrointestinal disturbances, pain or oedema of the extremities, hypertension, malaise, maculopapular erythema, and glossitis have also been reported.

Congenital adrenal hyperplasia. For mention of the use of testolactone with flutamide to block androgenic effects in congenital adrenal hyperplasia.

Precocious puberty. Encouraging results have been reported using testolactone in the treatment of 5 girls with precocious puberty due to the McCune-Albright syndrome. Testolactone is an aromatase inhibitor and blocks the synthesis of oestrogens from androgens. Long-term therapy (for up to 5 years) was associated with continued benefit in many patients; however, signs of puberty were not always completely suppressed, in some cases perhaps because of difficulties in maintaining the dosage regimen. Encouraging results were also obtained using testolactone with spironolactone in the treatment of familial precocious puberty in boys, although neither agent was successful when used alone. Again, signs of a reduced response to longer-term therapy have occurred; in this case control was restored by addition of a gonadorelin analogue Another study in 10 boys who were treated for at least 6 years with spironolactone and testolactone, with deslorelin added at the onset of secondary central precocious puberty, found normalisation in growth rate and bone maturation, and improvements in predicted adult height.

Preparations

The United States Pharmacopeia 31, 2008: Testolactone Tablets.

Single-ingredient Preparations

Belgium: Teslac; Chile: Teslac; Germany: Fludestrin; United States: Teslac

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

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, International, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Tamoxifen Citrate). A white or almost white, polymorphic, crystalline powder. Slightly soluble in water and in acetone; soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Tamoxifen Citrate). A white, fine, crystalline powder. Very slightly soluble in water, in alcohol, in acetone, and in chloroform; soluble in methyl alcohol. Protect from light.

Adverse Effects

The most frequent adverse effects of tamoxifen are hot flushes. Other adverse effects include fluid retention, nausea, gastrointestinal intolerance, vaginal bleeding or discharge, pruritus vulvae, rashes, dry skin, and alopecia. There have also been reports of dizziness, headache, depression, confusion, fatigue, and muscle cramps. There may be an increased tendency to thromboembolism, and pulmonary embolism has occurred. Tumour pain and flare may be a sign of response, but hypercalcaemia, sometimes severe, has developed in patients with bony metastases. Transient thrombocyto-penia and leucopenia have been reported. Blurred vision and loss of visual acuity, corneal opacities, retinopathies, and cataracts have occurred rarely. Tamoxifen has been associated with increased liver enzymes, and rarely with cholestasis and hepatitis. Hypertriglyceridaemia has occurred. Uterine fibroids and endometrial changes including hyperplasia and polyps may occur, and an increased incidence of endometrial carcinoma, and rarely uterine sarcoma, has been reported. Suppression of menstruation may occur in premenopausal women and cystic ovarian swellings have occasionally occurred. Very rare cases of interstitial pneumonitis have been reported.

Carcinogenicity. Tamoxifen has a stimulant effect on the endometrium (probably by acting as a partial oestrogen agonist) and its use has been associated with the development of endometrial polyps and endometriosis, and an increased risk of endometrial cancer. The risk, which increases with duration of therapy, is generally agreed to be modest, and the clinical benefit in women with breast cancer outweighs any increased risk of endometrial neoplasm. Women taking tamoxifen to prevent breast cancer have been estimated to have a 2.53-fold greater risk of developing endometrial carcinoma than untreated women. The risk may increase with more prolonged use and a case-control study has reported that long-term (over 2 years) users may have a worse prognosis if endometrial cancer develops, due to less favourable history and stage. Another case-control study showed that the relative risk of endometrial cancer increased with duration of tamoxifen treatment, up to at least 10 years. Risk was not associated with the daily dose of tamoxifen, and was comparable in pre- and postmenopausal women.

It has been recommended that women with breast cancer taking tamoxifen should have annual gynaecological examinations, and any unusual symptoms, including abnormal bleeding or spotting should be investigated promptly. Women taking tamoxifen for prophylaxis of breast cancer should be monitored carefully for endometrial hyperplasia. If atypical hyperplasia develops, tamoxifen should be stopped while the condition is treated and a hysterectomy should be considered before tamoxifen is re-started. However, up to 39% of postmenopausal women taking tamoxifen show endometrial changes and as these seldom progress to cancer, the value of routine endometrial biopsies has been questioned. Transvaginal ultrasonography has been used as a noninvasive method of endometrial screening, but has a high rate of false-positive results. It has been suggested that colour doppler ultrasonography, which distinguishes vascular-ised lesions such as polyps and carcinomas from avascular atrophic lesions, may be a useful alternative. There is some evidence that a levonorgestrel-releasing intra-uterine device can protect against the uterine changes induced by tamoxifen.

Although rare, there is an increase in the risk of uterine sarcoma in women receiving tamoxifen. Between 1978, when tamoxifen was first marketed in the USA, and April 2001, the FDA was aware of 43 cases in women who had been receiving tamoxifen; there had also been reports in 116 women in other countries. Although less than the expected rate in this population, this was considered to be due to underreporting. An evaluation of data from 39 451 breast cancer patients initially treated with tamoxifen found that the overall risk of uterine corpus cancer was more than doubled with the use of tamoxifen; the risk of rare but aggressive forms of uterine tumours, notably malignant mixed mullerian tumours, was increased more than fourfold.

Tamoxifen has been shown to form DNA adducts in rat livers, and there has been speculation that it may cause liver cancer in humans. However, there is considerable interspecies variation in the metabolism of tamoxifen and several large-scale clinical trials did not find an increase in liver carcinogenicity in humans. There is also little evidence of an increased relative risk of other secondary malignancies such as gastrointestinal or ovarian cancers.

Effects on the blood. Pancytopenia developed shortly after beginning tamoxifen therapy in an elderly woman, and persisted for some years; the patient eventually developed very severe leucopenia and died of infection. Thrombocytopenia has also been reported.

Effects on blood lipids. Tamoxifen has been reported to have a generally favourable effect on serum lipid profiles. Patients with breast cancer and subsequent chemotherapy-induced ovarian failure developed marked increases in total cholesterol and low-density lipoprotein levels; adjuvant tamoxifen was found to decrease these serum lipid concentrations to below baseline concentrations. No significant changes in high-density lipoprotein or serum triglyceride concentrations were observed. However, some cases of increased serum triglycerides in women with preexisting hypertriglyceridaemia have been reported. Pancreatitis has also resulted. It has been suggested that tamoxifen should be used with caution in patients with hypertriglyceridaemia.

Effects on the cardiovascular system. ISCHAEMIC HEART DISEASE. For discussion of whether the effects of tamoxifen on lipid profiles can alter the incidence of ischaemic heart disease, see Cardiovascular Disorders under Uses and Administration, below.

STROKE. An excess risk of stroke was seen in tamoxifen compared with placebo recipients (5 cases versus 1) in a study of adjuvant tamoxifen. A statistically non-significant increase in stroke was also seen in a study on the use of tamoxifen for breast cancer prevention (0.5 excess cases per 1000 women per year). A meta-analysis of 9 trials for prevention or treatment of breast cancer, involved data from 39 601 women, of whom 19 954 received tamoxifen. It concluded that use of tamoxifen increased the risk of ischaemic stroke by 82%, and the risk of any stroke by 29%; however, the absolute increase in risk was small.

In contrast, a case-control study of 11 045 women with breast cancer, found that tamoxifen use was not associated with an increased risk of first stroke.

THROMBOEMBOLISM. A case control study, involving 25 cases of deep-vein thrombosis or pulmonary embolism among more than 10 000 women with breast cancer, suggested that current use of tamoxifen was associated with an estimated relative risk of developing idiopathic venous thromboembolism of 7.1 (95% confidence interval 1.5 to 33). Past use of tamoxifen was not associated with a materially increased risk. In a randomised placebo-controlled study, there was an increase in pulmonary emboli in women receiving tamoxifen for cancer prevention (excess of 0.46 cases per 1000 women per year). The fatality rate from pulmonary emboli in tamoxifen recipients was about 17%. In this study, there was also a trend towards more deep-vein thrombosis in tamoxifen recipients. In another controlled study of breast cancer prevention, tamoxifen approximately doubled the risk of developing a major thromboembolic event such as pulmonary embolism, deep-vein thrombosis, or retinal thrombosis. Cerebral sinus thrombosis has also been reported. An analysis of 4 tamoxifen prevention studies also found that venous thromboembolic events were increased in all studies, with a relative risk of 1.9 for those taking tamoxifen compared with placebo. However, another randomised study found only a borderline significantly higher risk of developing venous thromboem-bolic events in those women allocated to tamoxifen; most of these events were superficial thrombophlebitis. Furthermore, women already at risk for atherosclerosis had a higher risk of venous thrombo embolism. While the authors could not exclude a selection bias for healthier subjects in the study, they commented that the prothrombotic effect of tamoxifen may depend on the patient’s existing endocrine status, and may be attenuated in those women taking HRT, especially when it is used transdermally.

Effects on the eyes. Tamoxifen has been reported to be associated with decreased visual acuity, corneal opacities and cataract, and retinopafhy. The latter is sometimes progressive although in most cases it has shown improvement once the drug was stopped. A prospective study in 63 patients taking tamoxifen 20 mg daily found evidence of decreased visual acuity, macular oedema, and retinal opacities in 4, occurring after 10 to 35 months of therapy. A small excess risk of developing cataracts (3.1 extra per year per 1000 women) and of requiring cataract surgery (1.7 per year per 1000 women) was found in women taking tamoxifen for up to 5 years to reduce the risk of breast cancer. Studies in vitro have suggested that cataract formation may be due to inhibition of chloride channels in the lens by tamoxifen or its hydroxy metabolite. Retinopafhy after high-dose tamoxifen treatment may be associated with crystalline deposition of the drug in the retina.

Effects on the genito-urinary system. Persistent nocturnal priapism was reported in a man receiving tamoxifen 20 mg daily. Symptoms abated within 24 hours of withdrawing the drug. Impotence has been reported in men receiving tamoxifen, and has been attributed to a paradoxical oestrogenic effect.

Effects on the liver. Cholestasis and increased liver enzyme values have been reported on use of tamoxifen in a 75-year-old patient. Enzyme activity rose again on rechallenge with tamoxifen. Fatal hepatocellular necrosis and agranulocytosis, possibly exacerbated by continuing to take the drug once jaundice developed, has also been reported; the authors noted that 4 cases of hepatic failure (3 fatal) and 5 cases of hepatitis (1 fatal) had been reported to the UK CSM. Patients taking tamoxifen may also develop steatohepatitis, which must be distinguished from alcohol-induced liver disease. Steatohepatitis is reversible on withdrawal of tamoxifen. A study in healthy women who had had hysterectomies found the risk of steatohepatitis to be particularly high among obese women, moderately high among overweight women, and similar to that with placebo in women of normal weight. Bezafibrate has been tried to prevent progression of steatohepatitis and permit continued use of tamoxifen. For a report of peliosis hepatis and liver haemorrhage in a patient receiving tamoxifen and warfarin, see under Interactions, below.

For reference to studies in animals suggesting that tamoxifen has the potential to cause liver cancer, see Carcinogenicity, above.

Effects on the ovaries. Ovarian cysts are relatively common as an adverse effect in women receiving adjuvant tamoxifen: a study in 95 such women reported the development of ovarian cysts in 6 of 16 (37.5%) who were premenopausal and in 5 of 79 postmenopausal women (6.3%). In 2 of the premenopausal women the cysts were complex. Two women underwent laparot-omy for persistent cysts that were found to be benign, and 1 for leiomyoma; the cysts in the other 8 women resolved after withdrawal of tamoxifen. A study of 142 breast cancer patients receiving tamoxifen found ovarian cysts in 24 patients after treatment. Cyst development was more common in pre-menopausal women, patients with high oestrogen levels, and patients who did not receive high-dose chemotherapy. There is little evidence that tamoxifen increases the risk of ovarian cancer (see Carcinogenicity, above).

Effects on the skin and hair. Vasculitis has been reported in patients given tamoxifen.,t Withdrawal of the drug resulted in complete clearance of the lesions; in one case, on re-introduction, purpura developed again within a few days. The results suggest that tamoxifen can produce immune-mediated vascular damage.

In another report a patient with white hair developed darkening and repigmentation of the hair after about 2 / years of tamoxifen therapy. Alopecia has also been reported in women given tamoxifen, and in older patients the follicle may not recover.

Precautions

All patients being considered for treatment with tamoxifen should be assessed for any increased risk of thromboembolism. Tamoxifen should not be used for treatment of infertility or the prophylaxis of breast cancer in women with a history of thromboembolic events. When used to treat breast cancer in such women, the risks and benefits should be considered; in some patients, especially those given cytotoxic drugs, prophylactic anticoagulation may be justified. Care is also needed during or immediately after major surgery or prolonged immobility; all patients should be given prophylaxis against thrombosis. In patients being treated for infertility, tamoxifen should be stopped at least 6 weeks before surgery or long-term immobility and only restarted when the patient is fully mobile. Patients should be made aware of the symptoms of thromboembolism and advised to report sudden breathlessness or any pain in the calf of one leg. Tamoxifen should be withdrawn immediately in any patient developing thromboembolism and appropriate treatment given. Treatment should not usually be restarted for infertility therapy but resumption of tamoxifen with prophylactic anticoagulation may be justified in selected patients with breast cancer.

Women treated with tamoxifen should have routine gynaecological monitoring, and any abnormal symptoms such as menstrual irregularities, abnormal vaginal bleeding or discharge, or pelvic pain should be investigated (see also under Carcinogenicity, above). Periodic complete blood counts and liver function tests have been suggested.

Abuse. Although the supervised use of tamoxifen for the treatment of gynaecomastia resulting from the abuse of anabolic steroids has been reported it also appears to be widely used without medical supervision. Tamoxifen can be used to treat idiopathic gynaecomastia and gynaecomastia resulting as an adverse effect of nonsteroidal anti-androgens used to treat prostate cancer (see under Breast Disorders, Non-malignant, below).

Breast feeding. Tamoxifen was shown to inhibit lactation in 60 puerperal women. Licensed product information recommends that it should not be given to lactating women.

Porphyria. Tamoxifen has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Pregnancy. Tamoxifen is contra-indicated in pregnancy. Ambiguous genitalia have been reported in an infant exposed to tamoxifen in utero, although no causal link was demonstrated. Another infant was born with Goldenhar’s syndrome (oculoau-riculovertebral dysplasia) after exposure to tamoxifen throughout a 26-week pregnancy. The mother had also taken cocaine and marijuana during the first 6 weeks of pregnancy, and a bone scan using technetium Tc99m medronate had been performed. The US manufacturer of tamoxifen (Zeneca, USA) was aware of 50 pregnancies in patients taking tamoxifen, resulting in 19 normal births, 8 terminations, 13 unknown outcomes and 10 infants with fetal or neonatal abnormalities.

Tamoxifen has also been used to stimulate ovulation in women with luteal phase dysfunction. In one study tamoxifen was given to 40 women, resulting in 14 pregnancies. Although 9 infants were born with no congenital abnormalities, there were 5 spontaneous abortions, which the authors felt was unacceptably high. Another study, using lower doses of tamoxifen (in some cases sequentially with clomifene), reported 32 pregnancies and only 3 spontaneous abortions in 65 treated patients.

Radiotherapy. There are reports of radiation recall, with erythema at the site of previous radiotherapy, in patients receiving tamoxifen.

Interactions

There is a risk of increased anticoagulant effect if tamoxifen is given with coumarin anticoagulants. Conversely, use with cytotoxic drugs may increase the risk of thromboembolic events; prophylactic anticoagulation should be considered. Tamoxifen increases the dopaminergic effect of bromocriptine. Use with inhibitors of cytochrome P450 isoenzyme CYP2D6 has been shown to reduce plasma concentrations of en-doxifen, a tamoxifen metabolite (see Pharmacokinetics, below); the clinical relevance is unclear.

Allopurinol. For reference to exacerbation of hepatotoxicity when tamoxifen was given with allopurinol.

Antibacterials. Rifampicin was found to decrease plasma concentrations of tamoxifen in 10 healthy subjects. This was thought to be due to induction of cytochrome P450 isoenzyme CYP3A4 by rifampicin.

Anticoagulants. Cases of a potentially life-threatening interaction between tamoxifen and warfarin, with marked prolongation of prothrombin times, haematuria, and haematoma, have been reported. It has been suggested that in addition to enhancement of the effects of warfarin, competition for the same metabolic enzyme systems might reduce the activity of tamoxifen against tumours, but this remains speculative.

Peliosis hepatis and fatal liver haemorrhage have been reported in a patient who was receiving tamoxifen with warfarin and a liothyronine-levothyroxine preparation.

Antidepressants. The metabolism of tamoxifen to an active metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen), may be inhibited by paroxetine, a potent inhibitor of the cytochrome P450 isoenzyme CYP2D6. However, the clinical consequences of this are, as yet, unclear. In addition, a case-control study found that patients taking tamoxifen with known inhibitors of CYP isoenzymes, including CYP2D6, were no more likely to relapse than those not receiving a CYP inhibitor.

Antineoplastics. Aminoglutethimide reduces serum tamoxifen concentrations, possibly by increasing its metabolism. For mention of an increased risk of haemolytic-uraemic syndrome in patients who received therapy with tamoxifen and mitomycin see Effects on the Kidneys, under Mitomycin. Tamoxifen is reported to reduce plasma concentrations of letrozole.

Immunosuppressants. For the results of a study in vitro suggesting that tamoxifen might inhibit the metabolism of tacrolimus by inhibiting the cytochrome P450 isoenzyme system, see under Interactions of Tacrolimus.

Neuromuscular blockers. For reference to prolonged neuromuscular blockade in a patient given atracurium while receiving tamoxifen.

Pharmacokinetics

Peak plasma concentrations of tamoxifen occur 4 to 7 hours after an oral dose. It is extensively protein bound. Plasma clearance is reported to be biphasic and the terminal half-life may be up to 7 days. It is extensively metabolised by the cytochrome P450 isoenzymes CYP3A4, CYP2C9, and CYP2D6. The major serum metabolite, N-desmethyltamoxifen, has a half-life at steady state of about 14 days. 4-Hydroxytamoxifen is a minor metabolite. In-vitro studies suggest that both these metabolites are further metabolised to 4-hydroxy-N-desmethyltamoxifen (endoxifen). Several of the metabolites are stated to have similar pharmacological activity to the parent compound. Tamoxifen is excreted slowly in the faeces, mainly as conjugates. Small amounts are excreted in urine. Tamoxifen appears to undergo enterohepatic circulation.

Genetic factors. Tamoxifen is metabolised by the cytochrome P450 isoenzymes, and its metabolites may play a role in its anti-neoplastic effect. Studies have suggested that patients with low or absent CYP2D6 activity or who are being treated with CYP2D6 inhibitors have lower concentrations of endoxifen. Patients with CYP2D6*3, *4, *5, and *6 alleles are designated as poor metabolisers, those with *9, *10, *17, *29, and *41 as intermediate metabolisers, and those with *1, *2, and *35 as extensive metabolisers. Genetic polymorphism in the enzymes responsible for tamoxifen biotransformation has the potential to affect clinical outcomes. While a small study showed a decreased risk of breast cancer recurrence in patients with the CYP2D6*4 allele when treated with tamoxifen, another found that this allele was an independent predictor of a higher risk of disease relapse and a lower incidence of hot flashes in postmenopausal women with breast cancer. A further study found that carriers of CYP2D6 alleles *4 or *5 showed a greater risk for breast cancer relapse. Furthermore, carriers of the CYP2C19*17 genotype had a more favourable clinical outcome. These results prompted the Clinical Pharmacology Subcommittee of the US FDA Advisory Committee for Pharmaceutical Science to advise that availability of genotypic testing be included in licensed product information for tamoxifen. Some have commented that it would seem reasonable to confine CYP2D6 testing to situations where it might guide the choice between tamoxifen and an alternative.

Metabolism. Tamoxifen is extensively metabolised by cytochrome P450 isoenzymes, to active metabolites that include N-desmethyltamoxifen, 4-hydroxytamoxifen, and 4-hydroxy-N-desmethyltamoxifen (endoxifen). In-vitro studies suggest that both N-desmethyltamoxifen and 4-hydroxytamoxifen are further metabolised to endoxifen. However, the biotransformation of tamoxifen has not been fully elucidated, and there is growing interest in how genetic polymorphism might influence the efficacy and toxicity of tamoxifen and its metabolites (see Genetic Factors, above).

Uses and Administration

Tamoxifen is an oestrogen antagonist with actions similar to those of clomifene citrate. It may also inhibit the production or release of cellular growth factors and induce apoptosis. It is used in the adjuvant endocrine therapy of node-positive breast cancer, in the treatment of metastatic disease, and for prophylaxis in women at increased risk including those with ductal carcinoma in situ. It has been tried in some other malignancies including tumours of the ovary and in malignant melanoma. Tamoxifen is also used to stimulate ovulation in women with anovulatory infertility. See also the cross-references below. Tamoxifen is given orally as the citrate but doses are calculated in terms of the base; tamoxifen citrate 15.2 mg is equivalent to about 10 mg of tamoxifen. In the treatment of breast cancer, usual doses are tamoxifen 20 mg daily, in 2 divided doses or as a single daily dose. Doses of up to 40 mg daily may be given butno additional benefit has been demonstrated. Adjuvant therapy is normally continued for up to 5 years, although the optimum duration is still uncertain. To reduce breast cancer incidence in women at high risk of the disease, the licensed dose of tamoxifen is 20 mg daily for 5 years.

In the treatment of anovulatory infertility the usual dose is tamoxifen 20 mg daily on days 2 to 5 of the menstrual cycle, increased if necessary in subsequent cycles up to 80 mg daily. In women with irregular menstruation the initial course may be begun on any day, and a second course begun at a higher dose after 45 days if there has been no response. If the patient responds with menstruation, subsequent courses may begin on day 2 of the cycle.

A topical formulation of 4-hydroxytamoxifen, a metabolite of tamoxifen, is under investigation for the treatment of cyclic mastalgia.

Breast disorders, non-malignant. GYNAECOMASTIA. Tamoxifen, usually in doses of 10 mg twice daily, has been reported to be effective in reducing pain, swelling, and breast size in men or pubertal boys with gynaecomastia. Tamoxifen has been recommended as a drug of choice in patients requiring drug therapy, given for 3 months to see if a response occurs. It has also been reported to be effective for the prevention and treatment of gynaecomastia and breast pain caused by the nonsteroidal anti-androgen bicalutamide, which is used in the treatment of prostate cancer (see Gynaecomastia under Adverse Effects and Precautions of Flutamide).

MASTALGIA. Tamoxifen 20 mg daily has been shown to be effective in patients with both cyclic and non-cyclic mastalgia, and improvement has also been reported at a lower dose of 10 mg daily. However, there is concern about the use of tamoxifen in otherwise healthy premenopausal women, particularly since many patients relapse on withdrawal, and it has been recommended that tamoxifen be reserved for patients who fail to respond to other drugs. A topical formulation of 4-hydroxytamoxifen, a metabolite of tamoxifen, is under investigation in the treatment of cyclic mastalgia.

Cardiovascular disorders. Tamoxifen has been reported to have a generally favourable effect on lipid profiles (see Effects on Blood Lipids, under Adverse Effects, above) suggesting it may have cardiovascular benefits. A cohort study of adjuvant tamoxifen found that the drug reduced the incidence of myocardial infarction, and a randomised study of the same therapy also showed a trend towards a decrease in mortality from coronary heart disease. However, in a much larger breast cancer prevention trial, tamoxifen did not reduce the risk of, and mortality from, ischaemic heart disease, neither of which differed between placebo and tamoxifen recipients. This lack of difference was independent of pre-existing cardiovascular disease. A review noted that while the available data suggested an overall benefit, most of them came from studies in women at low absolute risk of myocardial infarction; studies in men at high absolute risk would be needed to determine whether tamoxifen and related drugs were suitable as cardioprotectants.

Disorders related to the menstrual cycle. Apart from cyclic mastalgia (see above) tamoxifen has been used in a number of cases in which disorders were linked to the hormonal changes of the menstrual cycle, including menorrhagia due to myometrial hypertrophy, an auto-immune dermatitis due to post-ovulatory rises in serum progesterone (see Effects on the Skin under Progesterone, p.2125), and premenstrual migraine. However, tamoxifen was thought to be a cause of recurrent migraines in another patient, because of its action at oestrogen receptors.

Infertility. Tamoxifen is reported to be as effective as clomifene in the treatment of anovulatory infertility in women, and may be useful in women in whom abnormal cervical mucus acts as a barrier to spermatozoa. In infertile men, however, results are reportedly contradictory, with some studies reporting increase in sperm density and improved pregnancy rates while others failed to demonstrate any effect The addition of testosterone may improve outcomes, however, and a later study of men with idiopathic oligozoospermia reported that tamoxifen with testosterone improved sperm variables and pregnancy rates compared with a placebo group (there was no comparison with tamoxifen alone).

Malignant neoplasms. For reference to the use of tamoxifen in malignant neoplasms of breast, ovary, and in cutaneous melanoma. The most common use of tamoxifen is for the endocrine therapy of oestrogen-receptor positive early or advanced breast cancer, where there seems to be a clear benefit. How long such therapy should be continued remains uncertain although continuing therapy beyond 5 years may not increase the overall benefit. However, extending therapy by following 5 years of tamoxifen therapy with several years of an aromatase inhibitor such as letrozole does seem to provide additional benefit.

Extension of tamoxifen use to the attempted prophylaxis of breast cancer has proved controversial. Nonetheless, evidence that tamoxifen can reduce short-term incidence of breast cancer in some women at increased risk has been seen, and tamoxifen has been approved for such use in the USA. Despite some positive data, tamoxifen does not appear to be effective in the treatment of hepatocellular carcinoma.

Osteoporosis. Tamoxifen has been reported to have favourable effects on bone mass, but any general role in the prevention of osteoporosis seems unlikely given concerns about the carcinogenic ity of tamoxifen. The effects are reported to be comparable in magnitude to those of calcium supplementation, and less than those of oestrogens or bisphosphonates. It has been suggested that such an effect on bone would provide an additional benefit in women receiving tamoxifen for the prophylaxis of breast cancer, although others dispute the benefits.

Precocious puberty. Tamoxifen has been reported to be beneficial in the treatment of precocious puberty.

Preparations

British Pharmacopoeia 2008: Tamoxifen Tablets

The United States Pharmacopeia 31, 2008: Tamoxifen Citrate Tablets

Single-ingredient Preparations

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

Argentina: Crisafeno; Diemon; Farmifeno¤; Ginarsan; Nolvadex; Rolap; Tamofen¤; Tamoxis; Taxfeno; Trimetrox; Australia: Estroxyn¤; Genox; Kessar¤; Nolvadex; Noxitem¤; Tamosin; Tamoxen; Austria: Ebefen; Kessar; Nolvadex; Tamax; Tamofen; Tamoplex; Belgium: Nolvadex; Tamizam; Brazil: Bioxifeno; Estrocur; Kessar; Nolvadex; Tamofen¤; Tamooex¤; Tamoplex; Tamox; Tamoxin; Taxofen; Tecnotax; Canada: Apo-Tamox; Nolvadex; Tamofen; Tamone¤; Tamoplex¤; Chile: Kessar; Nolvadex; Tamolem¤; Taxus; Czech Republic: Nolvadex; Tamifen; Zitazonium; Denmark: Tamofen¤; Finland: Nolvadex¤; Tadex; Tamexin; Tamofen; France: Kessar; Lesporene¤; Nolvadex; Oncotam; Tamofene¤; Germany: Dignotamoxi¤; duratamoxifen¤; Jenoxifen; Kessar; Mandofen; Nolvadex; Nourytam; Tamobeta¤; Tamofen¤; Tamokadin; Tamopham¤; Tamox; Tamoxasta¤; Tamoxigenat¤; Tamoximerck; Tamoxistad; Zemide¤; Zitazonium¤; Greece: Adifen; Defarol¤; Kessar; Nolvadex; Puretam; Tamoplex; Zymoplex; Hong Kong: Apo-Tamox; Nolvadex; Novofen; Tamifen¤; Tamofen¤; Zitazonium; Hungary: Zitazonium; India: Caditam; Cytotam; Mamofen; Nolvadex; Tamodex; Ireland: Clonoxifen¤; Nolgen; Nolvadex; Tamofen¤; Tamox; Israel: Nolvadex; Tamofen; Tamoplex¤; Tamoxen; Tamoxi; Italy: Kessar; Ledertam; Nolvadex; Nomafen; Tamoxene; Virtamox¤; Malaysia: Genox; Nolvadex; Novofen; Tamoplex; Zitazonium; Mexico: Bilem; Cryoxifeno; Kessar; Nolvadex; Ralsifen-X¤; Tamofen¤; Tamoxan; Taxus; Tecnofen; Netherlands: Nolvadex; Tamoplex¤; Norway: Nolvadex; Tamofen¤; New Zealand: Genox; Nolvadex; Tamofen; Portugal: Nolvadex; Tamoxan; Russia: Bilem (Билем); Tamifen (Тамифен); Zitazonium (Зитазониум); South Africa: Kessar; Neophedan; Nolvadex; Tamoplex; Singapore: Apo-Tamox; Nolvadex; Tamofen; Tamoplex¤; Spain: Nolvadex; Oxeprax¤; Sinmaren¤; Yacesal; Sweden: Ledertam¤; Nolvadex; Tamaxin¤; Switzerland: Kessar; Nolvadex; Tamec; Thailand: Gynatam; Nolvadex; Novofen; Tamofen; Tamoplex; Tuosomin; Zitazonium; United Arab Emirates: Tamophar; United Kingdom: Emblon¤; Fentamox¤; Noltam¤; Nolvadex; Oestrifen¤; Soltamox; Tamofen¤; United States: Nolvadex; Soltamox; Venezuela: Nolvadex; Taxus

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Fluorouracil). A white or almost white, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol. A 1% solution in water has apH of 4.5 to 5.0. Protect from light.

The United States Pharmacopeia 31, 2008 (Fluorouracil). A white to practically white, practically odourless, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol; practically insoluble in chloroform and in ether. Store in airtight containers. Protect from light.

Incompatibility. Preparations of fluorouracil are alkaline, and compatibility problems may be expected with acidic drugs and preparations, or those which are unstable in the presence of alkali. Fluorouracil is reported to be incompatible with cytarabine, diazepam, doxorubicin (and presumably other anthracyclines that are unstable at alkaline pH), and calcium folinate. Although fluorouracil has been stated to be incompatible with methotrexate a study of the long-term stability of an admixture of the 2 drugs in sodium chloride 0.9% injection suggests otherwise.

Stability. Despite one report that fluorouracil had limited stability when dissolved in glucose 5% at room temperature (10% loss from solution in 43 hours when stored in PVC and in only 7 hours when stored in glass), others found such a solution to be stable for at least 16 weeks when stored in PVC at 5°. When stored at room temperature in PVC, solutions of fluorouracil may lose water by evaporation, which slowly increases their concentration. Results of a study of fluorouracil and methotrexate admixtures in sodium chloride 0.9% suggest that extended stability (up to 13 weeks) is possible in this diluent at 5° in PVC bags. Commercial solutions of fluorouracil for injection have been reported to be stable for 7 days at 37° in a portable infusion pump, although at 25° one brand showed evidence of precipitation. Fluorouracil solutions may be incompatible with synthetic elastomers: microscopic precipitation has been reported as soon as 4 hours after placement into poly isoprene reservoirs of elastomeric infusers and in polypropylene syringes with an elastomeric joint. Some have questioned the validity of this finding.

Adverse Effects and Treatment

For general discussions see Antineoplastics.

The main adverse effects of fluorouracil are on the bone marrow and the gastrointestinal tract, and may be dose-limiting. Toxicity is schedule dependent: reducing the rate of injection to a slow infusion is associated with less haematological toxicity but does not decrease gastrointestinal toxicity. With protracted continuous infusion in particular, the palmar-plantar erythrodysesthesia syndrome (erythema and painful desquama-tion of the hands and feet) may occur. Gastrointestinal toxicity may be exacerbated if fluorouracil is given with folinic acid.

Leucopenia, thrombocytopenia, stomatitis, gastrointestinal ulceration and bleeding, diarrhoea, or haemorrhage from any site, are signs that treatment should be stopped. The nadir of the white cell count may occur from 7 to 20 days after a dose, and counts usually return to normal after about 30 days. Thrombocytopenia is usually at a maximum 7 to 17 days after a dose. Anaemia may also occur. Nausea and vomiting, rashes, and alopecia are common. Ocular irritation, central neurotoxicity (notably cerebellar ataxia), and myocardial ischaemia have occurred.

Local inflammatory and photo sensitivity reactions have occurred after topical use. Dermatitis and, rarely, erythema multiforme have been reported.

Effects on the eyes. Systemic fluorouracil therapy has been associated with various types of ocular toxicity including several cases of excessive lachrymation and watering of the eyes. In one patient this was associated with symptoms suggesting fibrosis of the tear duct, and possibly representing local irritation due to the presence of fluorouracil in tear fluid, although symptoms have not always resolved on stopping the drug. More seriously a case of bilateral total corneal epithelial erosion has been described. Optic neuropathy, culminating in near blindness, has also occurred in a patient given fluorouracil as part of a combination regimen. Severe ulceration and corneal abscess with hyopyon has followed local injection of fluorouracil into the eye in a diabetic patient with idiopathic band keratopathy.

Effects on the heart. Life-threatening cardiotoxicity (arrhythmias, ventricular tachycardia, and cardiac arrest, secondary to transmural ischaemia) has been reported to occur in 0.55% of patients given fluorouracil, although the incidence of angina and less severe cardiotoxicity associated with coronary artery spasm may be higher. Possible risk factors include pre-existing heart disease or mediastinal radiotherapy, and prolonged infusion of the drug, but symptoms can also occur in patients without these risk factors. Therefore, at present, it is not possible to reliably predict patients at risk. Some suggest that the use of a trometa-mol buffer in the fluorouracil formulation may contribute to the formation of cardiotoxic degradation products.

Effects on the nervous system. Central neurotoxicity, including cerebellar ataxia, confusion, disorientation, and emotional lability is reported to occur rarely in patients receiving fluorouracil, although the incidence may be increased with high-dose or intensive regimens. Patients with disorders of pyrimidine metabolism may be at increased risk of neurotoxicity. It has also been suggested that fluorouracil may produce neurotoxicity by causing thiamine deficiency, and that thiamine may be used to treat it.

Effects on the skin. In addition to reports of fluorouracil-associated dermatitis and photosensitivity a syndrome of erythema, pain, and desquamation of the skin of palms and soles has been reported (the palmar-plantar erythrodysesthesia syndrome). Although particularly associated with continuous infusion the syndrome can also occur after bolus doses. Symptoms generally respond to stopping the drug, but addition of oral pyridoxine to chemotherapy regimens has been reported to prevent or resolve symptoms, as has application of a nicotine patch in one patient.

Rash and confusion developing in an elderly man with malab-sorption and poor nutritional intake who received fluorouracil for a biliary-tract tumour were diagnosed as pellagra. Symptoms responded to nicotinic acid therapy.

Hypersensitivity. Although local hyper sensitivity reactions are included in licensed product information as potential adverse effects of topical fluorouracil, hypersensitivity reactions to systemic fluorouracil have been reported very rarely. For a report of the successful use of fluorouracil in a patient allergic to capecitabine, suggesting that cross-sensitivity does not occur between the two.

Precautions

For general discussions see Antineoplastics. Fluorouracil should be given with care to weak or malnourished patients, to those with a history of heart disease, or to those with hepatic or renal insufficiency. Patients with a history of high-dose pelvic irradiation or treatment with alkylating agents, and those with widespread metastases to the bone marrow should also be treated with extreme caution. Blood cell counts should be determined frequently during therapy. Fluorouracil should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency as this can lead to increased toxicity.

Topical fluorouracil should not be used on mucous membranes. There is a possibility of increased absorption if used excessively or on ulcerated or inflamed skin. Occlusive dressings may increase inflammatory actions. Exposure to UV light during treatment should be avoided. Creams are preferably applied using a non-metal applicator or gloved hand; if bare fingertips are used the hands must be washed immediately afterwards.

Handling and disposal. Fluorouracil is irritant; avoid contact with skin and mucous membranes.

Urine and faeces produced for up to 48 hours and 5 days respectively after an oral dose of fluorouracil should be handled wearing protective clothing.

Metabolic disorders. For reference to increased risk of neurotoxicity in patients with a defect of pyrimidine metabolism given fluorouracil, see under Effects on the Nervous System, above.

Interactions

For a general discussion of antineoplastic drug interactions. The actions of fluorouracil may be modified by other drugs including allopurinol, cimetidine, folinic acid, methotrexate, and metronidazole (see also under Administration, below).

Antineoplastics. Oxaliplatin, which is given with fluorouracil and folinic acid in the treatment of colorectal cancer, reduced fluorouracil clearance in a study of 29 patients with colorectal cancer. The effect was delayed and prolonged, lasting about 15 days, and an increase in toxicity correlated with raised fluorouracil concentrations. The mechanism of this interaction is unclear. In contrast, however, another study found no effect of oxaliplatin on fluorouracil pharmacokinetics; the study was not designed to investigate a delayed effect and the dose of oxaliplatin was lower than that used in the first study.

Sorafenib has been reported to have variable effects on fluorouracil exposure.

For reference to the effect of fluorouracil on the action ofpaclitaxel, see Antineoplastics. For the increased risk of haemolytic-uraemic syndrome that may be seen if fluorouracil is used with mitomycin, see Effects on the Kidneys.

Antiprotozoals. Metroradazole increased the toxicity of fluorouracil in patients with colorectal cancer, apparently by reducing the clearance of the antineoplastic. No enhanced antineoplastic effect was seen with the combination in vitro.

Antivirals. Giving interferon alfa-2b with fluorouracil has produced a marked increase in the initial plasma concentration of fluorouracil and a decrease in fluorouracil clearance. Severe leucopenia, fatal in some cases, has been reported in patients given fluorouracil or fluorouracil prodrugs (such as tegafur) with sorivudine A metabolite of sorivudine appears to inhibit dihydropyrimidine dehydrogenase, the primary enzyme responsible for the inactivation of fluorouracil.

Gastrointestinal drugs. Pretreatment with cimetidine for 4 weeks increased plasma concentrations of fluorouracil after intravenous and oral doses in 6 patients. The effect was probably due to a combination of hepatic enzyme inhibition and reduced hepatic blood flow. No such effect was seen after single doses of cimetidine in 5 patients or pretreatment for just 1 week in 6. Care is required in patients given both drugs together.

Pharmacokinetics

Absorption of fluorouracil from the gastrointestinal tract is unpredictable and fluorouracil is usually given intravenously. Little is absorbed when fluorouracil is applied to healthy skin.

After intravenous injection fluorouracil is cleared rapidly from plasma with a mean half-life of about 16 minutes. It is distributed throughout body tissues and fluids (including crossing the blood-brain barrier to appear in the CSF), and disappears from the plasma within about 3 hours. Within the target cell fluorouracil is converted to 5-fluorouridine monophosphate and floxuridine monophosphate (5-fluorodeoxyuridine monophosphate), the former undergoing conversion to the triphosphate which can be incorporated into RNA while the latter inhibits thymidylate synthetase. About 15% of an intravenous dose is excreted unchanged in the urine within 6 hours. The remainder is inactivated primarily in the liver and is catabolised via dihydropyrimidine dehydrogenase (DPD) similarly to endogenous uracil. A large amount is excreted as respiratory carbon dioxide; urea and other metabolites are also produced.

Chronopharmacology. Plasma concentrations of fluorouracil during continuous intravenous infusion are reported to undergo circadian variations of as much as 50% of the mean, peak concentrations occurring in the middle of the night. The variation may be due to a circadian variation in the activity of the enzyme dihydropyrimidine dehydrogenase in blood, but striking inter-patient variations in peak concentrations of fluorouracil and peak enzyme activity suggest that any adjustment of infusion times would need to be individualised. It has been suggested that pharmacokinetic monitoring should be investigated as a means of individualising fluorouracil doses with the aim of improving efficacy and reducing toxicity.

Uses and Administration

Fluorouracil, an analogue of the pyrimidine uracil, is an antineoplastic that acts as an antimetabolite. After intracellular conversion to the active deoxynucleotide it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. It can also interfere with RNA synthesis.

Fluorouracil is used alone or in combination in the adjuvant and palliative treatment of gastrointestinal cancer. In this setting it may be combined with folinic acid (see Administration, below). Fluorouracil is often given with cyclophosphamide and methotrexate or doxo-rubicin in the adjuvant treatment of breast cancer. It may also be used in the palliation of other malignant neoplasms such as those of the head and neck, liver, and pancreas. In addition, it may be used topically for treating malignant or premalignant lesions of the skin. Its use in these malignancies is further discussed under Choice of Antineoplastic as indicated by the cross-references given below.

Many dosage regimens have been used. Although it is most often given in combination regimens for the treatment of malignancy, many of the licensed dosage regimens relate to single-agent use. Such licensed regimens include:

• by intravenous injection, usual doses of 12 mg/kg daily (to a maximum of 0.8 to 1 g daily) for 3 or 4 days. If there is no evidence of toxicity, this may be followed after 1 day by 6 mg/kg on alternate days for 3 or 4 further doses. An alternative schedule is to give 15 mg/kg intravenously once a week throughout the course. The course may be repeated after 4 to 6 weeks or maintenance doses of 5 to 15 mg/kg to a maximum of 1 g may be given weekly.

• by intravenous infusion, usual doses of 15 mg/kg daily (to a maximum of 1 g daily) being infused in 500 mL of sodium chloride 0.9% or glucose 5% over 4 hours and repeated on successive days until toxicity occurs or a total of 12 to 15 g has been given. Continuous infusion may also be used. The course may be repeated after 4 to 6 weeks.

• by continuous intra-arterial infusion, in doses of 5 to 7.5 mg/kg daily (regional perfusion).

• by mouth, although the parenteral route is generally preferred, a dose of 15 mg/kg, to a maximum of 1 g in one day, has been given once weekly for maintenance.

Suggested regimens with folinic acid include:

• 200 mg/m of folinic acid (as calcium folinate) by slow intravenous injection followed immediately by an intravenous bolus of fluorouracil 370 mg/m; the treatment is given daily for 5 consecutive days, and may be repeated every 4 to 5 weeks

• lower doses of folinic acid (20 mg/m) followed by fluorouracil 425 mg/m for 5 consecutive days, repeated every 4 to 5 weeks (the Mayo regimen)

• an initial dose of 200 mg/m of folinic acid, followed by fluorouracil 400 mg/m as an initial intravenous bolus injection and then 600 mg/m by continuous intravenous infusion. This dosage is given for 2 consecutive days every 2 weeks (the de Gramont regimen)

The white cell count should be determined frequently during treatment with fluorouracil and therapy stopped immediately if the count falls rapidly or if the white cell or platelet count falls below acceptable levels (see also Bonemarrow Depression) or if severe adverse effects occur. Doses should be reduced by up to half in patients with poor nutritional status, impaired bone-marrow, hepatic, or renal function, and within 30 days of major surgery.

Fluorouracil is used topically in the treatment of solar (actinic) keratoses and other superficial tumours and premalignant conditions of the skin including Bowen’s disease and superficial basal cell carcinomas. For actinic keratosis it is usually applied as a 0.5 to 5% cream or as a 1 to 5% solution in propylene glycol once or twice daily for 2 to 4 weeks; the higher strength may be applied for at least 3 to 6 weeks for superficial basal cell carcinomas.

Administration. Modulation of fluorouracil by other drugs has been tried in an effort to enhance its effects, particularly in the treatment of colorectal cancer.

Folinic acidhas been extensively used to modulate the effects of fluorouracil, and has become the agent of choice. Various regimens have been used, modifying the fluorouracil schedule (continuous infusion versus bolus), folinic acid dose (low-dose versus high-dose) and the regimen frequency (monthly, bimonthly, or weekly). Despite numerous studies, the optimum regimen in terms of efficacy and tolerability has yet to be determined.

In the adjuvant setting, a large-scale randomised trial found no difference in efficacy between low-dose and high-dose folinic acid when added to fluorouracil given either once weekly for 30 doses, or for 5 consecutive days per month over 6 months. Fluorouracil and low-dose folinic acid may therefore become the preferred regimen in the adjuvant setting.

In the palliation of advanced disease, meta-analyses have revealed the value of the addition of folinic acid to fluorouracil, and the use of infusions rather than bolus fluorouracil, in terms of response rates. An updated meta-analysis confirmed the benefit of addition of folinic acid to fluorouracil in terms of response rate, and found a small but statistically significant advantage in terms of overall survival. Survival benefit was restricted to trials using the same dose of fluorouracil in the treatment arms (fluorouracil alone versus fluorouracil and folinic acid), suggesting that the benefit of modulation with folinic acid could be compensated by an increase of fluorouracil dose in the fluorouracil alone arm. However, increased toxicity from high-dose fluorouracil might occur. The data for low-dose folinic acid versus high-dose are less clear. In 1 randomised trial, a bimonthly infusion regimen of fluorouracil plus high-dose folinic acid (the de Gramont regimen) was more effective than a monthly bolus regimen of fluorouracil plus low-dose folinic acid. Further studies comparing the effect of high- and low-dose folinic acid added to the same schedule of continuous infusion fluorouracil are required.

Interferon alfa also appears to modify the actions of fluorouracil (see also under Interactions, above), and has been investigated in combination with fluorouracil and folinic acid. Although some early results were promising, later randomised controlled trials failed to show any benefit for the addition of interferon alfa to fluorouracil or fluorouracil plus folinic acid. It is not clear whether interferon beta will prove of any greater benefit.

Based on the results of early adjuvant studies, levamisole was used as standard therapy to modulate fluorouracil, particularly in the USA. However, more recent trials indicate that levamisole is no more effective than placebo when added to fluorouracil, or to fluorouracil plus folinic acid.

Methotrexate has also been used to modulate fluorouracil. Meta-analysis of several studies of fluorouracil preceded by methotrexate found that the combination doubled the response rate to fluorouracil in metastatic colorectal cancer and produced some survival benefits. (Combination in the reverse order, i.e. methotrexate preceded by fluorouracil, may reduce methotrexate toxicity — see under Treatment of Adverse Effects.)

Darier’s disease. Two patients with resistant Darier’s disease receiving long-term oral retinoid therapy responded to treatment with topical fluorouracil applied as a 1% cream once daily. There was complete clearance of skin lesions after 3 weeks of treatment.

Eye disorders. Aside from its use in glaucoma surgery (below), fluorouracil has been used adjunctively in other ocular surgery. It has also shown promising results in the treatment of ocular surface malignancies.

Glaucoma. A regimen of subconjunctival injections of fluorouracil is effective in improving the outcome of glaucoma filtering surgery in selected patients when used as an adjunct to prevent the formation of scar tissue. However, in view of the increased risk of late-onset conjunctival wound leaks caution has been suggested in its use in eyes with a good prognosis. Although one study found that fluorouracil improved the success rate of combined glaucoma filtering surgery and cataract surgery earlier studies had failed to demonstrate any advantage. A systematic review of these and 2 other studies concluded that fluorouracil reduced the risk of surgical failure of trabeculectomy in eyes at high risk of failure, and in those undergoing surgery for the first time, but noted that the methodological quality of the studies was not high, and that this practice has largely been superseded by the use of intra-operative mitomycin. However, a later survey in the UK found that the use of antime-tabolites in glaucoma surgery was much less common than in the USA or Japan, and that fluorouracil was strongly preferred to mitomycin.

Intra-operative topical application of fluorouracil has been tried as an alternative to subconjunctival injection with conflicting results.

Malignant neoplasms. Fluorouracil plays an important role in the adjuvant treatment of gastrointestinal cancer, as discussed, and has been widely used in adjuvant regimens for early breast cancer. It may also be employed in the management of a wide variety of other malignancies including pancreatic endocrine tumours, cancers of the cervix and head and neck, liver metastases, and tumours of the exocrine pancreas. It is reported to have only modest activity in neoplasms of the kidney. In addition, it is sometimes applied topically as part of the management of malignant or pre-malignant lesions of the skin (see Basal Cell and Sq-uamous Cell Carcinoma, or surface neoplasia of the eye.

The role of fluorouracil in chemoradiotherapy of various malignancies has been reviewed.

Toxoplasmosis. For mention of the use of fluorouracil with clindamycin to treat cerebral toxoplasmosis.

Warts. Fluorouracil has been used, as a 1% or, more usually, a 5% cream or solution in the treatment of genital warts (condylomata acuminata). It has been tried as an adjuvant to laser therapy in severe papillomavirus-associated vulvar disease, with variable results, and in men with subclinical or clinically apparent penile lesions. A preparation of fluorouracil 3% in a collagen gel basis, together with adrenaline as a local vasoconstrictor, has been tried by injection into genital warts. A combination of fluorouracil 0.5% and salicylic acid 10% has also been stated to be effective in the topical treatment of common and plantar warts. For a discussion of the various agents, including cytotox-ics such as fluorouracil, employed to produce destruction of warts.

Preparations

British Pharmacopoeia 2008: Fluorouracil Cream; Fluorouracil Injection

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Fluorouracil Cream; Fluorouracil Injection; Fluorouracil Topical Solution.

Single-ingredient Preparations

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

Argentina: Cinco-Fu¤; Efudix; Ifocid¤; Oncofu; Triosules; Australia: Efudix; Fluoroplex¤; Fluroblastin¤; Belgium: Efudix¤; Fluroblastine; Brazil: Killit; Utoral¤; Canada: Adrucil¤; Efudex; Fluoroplex¤; Chile: Efudix; Fluoracilo; Czech Republic: La-Fu; Denmark: Flurablastin; Finland: Flurablastin; France: Efudix; Germany: Actino-Hermal¤; Cytosafe¤; Effluderm¤; Efudix; Fluroblastin¤; Neofluor; O-fluor¤; Onkofluor; Ribofluor; Hong Kong: Efudix¤; Hungary: Efudix; India: Fivefluro; Florac; Fluracil; Ireland: Efudix; Israel: Efudix; Fluracedyl¤; Italy: Efudix; Malaysia: Fluracedyl; Mexico: Efudix; Fiverocil¤; Flurox; Ifacil¤; Rhonuracil¤; Tecflu; Netherlands: Efudix; Fluracedyl; Norway: Flurablastin; Fluracedyl¤; New Zealand: Efudix; Portugal: Cinkef-U; Russia: Flurox (Флурокс); South Africa: Efudix; Fluroblastin; Singapore: Efudix; Spain: Efudix; Sweden: Flurablastin; Fluracedyl; Switzerland: Efudix; Fluroblastine¤; Thailand: Efudix¤; Fivoflu; Fluracedyl¤; Flurox; United Kingdom: AccuSite¤; Efudix; United States: Adrucil; Carac; Efudex; Fluoroplex; Venezuela: Fivoflu

Multi-ingredient Preparations

Austria: Verrumal; Brazil: Efurix; Czech Republic: Verrumal; Germany: Verrumal; Greece: Verruca Hermal; Hong Kong: Verrumal; Hungary: Verrumal; Israel: Verrumal; Verucid; Malaysia: Verrumal; Portugal: Verrucare; Verrumal; Singapore: Verrumal; Switzerland: Verrumal; Thailand: Verrumal

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, International, Japan, US.

European Pharmacopoeia, 6th ed. (Progesterone). Awhite or almost white crystalline powder or colourless crystals. It exhibits polymorphism. Practically insoluble in water freely soluble in dehydrated alcohol sparingly soluble in acetone and in fatty oils. Protect from light.

The United States Pharmacopeia 31, 2008 (Progesterone). A white or creamy-white, odourless, crystalline powder. Practically insoluble in water soluble in alcohol, in acetone, and in dioxan sparingly soluble in vegetable oils. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects

Progesterone and the progestogens may cause gastrointestinal disturbances, changes in appetite or weight, fluid retention, oedema, acne, chloasma (melasma), allergic skin rashes, urticaria, mental depression, breast changes including discomfort or occasionally gynaecomastia, changes in libido, hair loss, hirsutism, fatigue, drowsiness or insomnia, fever, headache, premenstrual syndrome-like symptoms, and altered menstrual cycles or irregular menstrual bleeding. Anaphylaxis or anaphylactoid reactions may occur rarely. Alterations in the serum lipid profile may occur, and rarely alterations in liver-function tests and jaundice. Pain, diarrhoea, and flatulence have followed rectal use. Injection-site reactions have followed parenteral use.

Adverse effects vary depending on the dose and type of progestogen. For example, androgenic effects such as acne and hirsutism are more likely to occur with nor-testosterone derivatives such as norethisterone and norgestrel. These derivatives may also be more likely to adversely affect serum lipids. Conversely, adverse effects on serum lipids appear less likely with gestodene and desogestrel, but these 2 drugs have been associated with a higher incidence of thromboembolism than norethisterone and norgestrel when used in combined oral contraceptives. High doses of progestogens such as those used in treating cancer have also been associated with thromboembolism. For a discussion of the effect of progestogens on the cardiovascular risk profile of menopausal HRT. Breakthrough uterine bleeding is more common with oral progestogen-only contraceptives than when progestogens are used for menstrual irregularities or as part of menopausal HRT.

Some progestogens when given during pregnancy have been reported to cause virilisation of a female fetus. This appears to have been associated with those progestogens with more pronounced androgenic activity such as norethisterone the natural progestogenic hormone progesterone and its derivatives such as dydrogesterone and medroxyprogesterone do not appear to have been associated with such effects. For the adverse effects of progestogens when administered either alone or with oestrogens as contraceptives. For those ofmenopausal HRT.

Carcinogenicity. In a cohort study of women aged 40 to 64 years, the premenopausal use of oral progestogens alone, mainly for benign breast, uterine, and ovarian conditions, and irregular menstruation, was not associated with an increased risk of breast cancer. However, the data did suggest that there was an increased risk for current users of progestogens for longer than 4.5 years (relative risk 1.44, 95% confidence interval 1.03 to 2.00) compared with women who had never used progestogens. Limitations of this study included the lack of analysis of different progestogens or a record of the reasons for progestogen treatment.

Effects on the skin. Auto-immune progesterone dermatitis includes reactions such as eczema, urticaria, and angioedema that usually begin 3 to 10 days before the onset of menstrual flow and end 1 to 2 days into menses, which correlates with raised endogenous progesterone concentrations during the luteal phase of the menstrual cycle. The onset of the condition can be as early as menarche, and many women have never been exposed to exogenous progesterone, but it has also occurred in women with a history of oral contraceptive use. Management has been based on the suppression of endogenous progesterone secretion and oral contraceptives are usually tried first, although they appear to have limited success possibly because of the progestogen component. Other drugs that have been used include corticosteroids, conjugated oestrogens, gonadorelin analogues, androgens, and tamoxifen, but all have significant adverse effects associated with long-term use. Bilateral oophorectomy has been used in severe cases, when drug therapy has been unsuccessful.

A woman with a history of auto-immune progesterone dermatitis developed pruritic, pink, oedematous plaques and macules on the upper thighs, axillae, and buttocks after the use of vaginal progestogen gel during infertility treatment. The reaction was managed with topical corticosteroids. In another woman, with a history of chronic urticaria exacerbated by progesterone, the use of progesterone and various other progestogens as a component of HRT after oophorectomy caused urticaria and angioedema. Desensitisation using micronised progesterone was successful in this case.

Precautions

Progesterone and the progestogens should be used with caution in patients with hypertension, cardiac or renal impairment, asthma, epilepsy, and migraine, or other conditions which may be aggravated by fluid retention. Progestogens can decrease glucose tolerance and diabetic patients should be carefully monitored. They should also be used with care in persons with a history of depression. High doses should be used with caution in patients susceptible to thromboembolism. Progesterone and the progestogens should not be given to patients with undiagnosed vaginal bleeding, nor to those with a history or current high risk of arterial disease and should generally be avoided in hepatic impairment, especially if severe. Unless progestogens are being used as part of the management of breast or genital-tract carcinoma they should not be given to patients with these conditions.

Although progestogens have been given as hormonal support during early pregnancy such use is not now generally advised. However, the use of a progesterone-type progestogen might still be considered for women who are progesterone-deficient. Such use may prevent spontaneous evacuation of a dead fetus, therefore careful monitoring of pregnancy is required. Progestogens should not be used diagnostically for pregnancy testing and should not be given in missed or incomplete abortion.

For precautions to be observed when progestogens are used as contraceptives, see p.2065. For those to be observed when progestogens are used in preparations for menopausal HRT.

Abuse. A case report of abuse of and dependency on progesterone.

Breast feeding. A large study compared a contraceptive progesterone-releasing vaginal ring and a copper IUD for 1 year in breast-feeding women. There was little difference in infant weight gain during the study, although at 12 months the infants of mothers using the IUD were breast-fed less frequently, receiving more supplementary feeding, and were heavier. There was no adverse effect of progesterone on lactation or infant growth. Further smaller studies have also found no adverse effect on lactation or infant growth. The American Academy of Pediatrics has found no reports of adverse effects in breast-fed infants of mothers given progesterone, and therefore considers it to be usually compatible with breast feeding.

Porphyria. Progesterone and progestogens have been associated with acute attacks of porphyria and are considered unsafe in patients with porphyria (but medroxyprogesterone has been used with buserelin to suppress premenstrual exacerbations of porphyria). Progestogens should generally be avoided by all women with porphyria however, where non-hormonal contraception is inappropriate, progestogens may be used with extreme caution if the potential benefit outweighs the risk. The risk of an acute attack is greatest in women who have had a previous attack or are under 30 years of age. Long-acting progestogen preparations should never be used in those at risk.

Pregnancy. In Hungary, where 30% of all pregnant women were given hormonal support therapy with progestogens during the early 1980s, a case-control study suggested that there was a causal relationship between such treatment and hypospadias in their offspring. Mixed results have been reported in other studies of the association between maternal progestogen use and the risk of hypospadias, but the indications and types of progestogens used in early pregnancy have also changed over time (for example, withdrawal bleeding induced by progestogens as a form of pregnancy testing is no longer used, and progestogen luteal support in early pregnancy is no longer recommended for routine use see also Miscarriage, below). Nevertheless, results from a more recent case-control study of deliveries between October 1997 and December 2000 suggested an increase in risk of at least twofold.

There have also been reports of nongenital malformations, including limb reduction defects, neural tube defects, and congenital heart malformations, following intra-uterine exposure to progestogens in early pregnancy. However, numerous analyses of accumulated data have found no evidence of a recognisable malformation syndrome.

For details of individual case reports, see Pregnancy under Dydrogesterone, Hydroxyprogesterone, Norethisterone, and Noretynodrel. For the effects of hormonal contraceptive use during early pregnancy. For the risk of ectopic pregnancy with progestogen-only contraceptives.

Veterinary use. An FAO/WHO expert committee examining the risks from residue of veterinary drugs in foodstuffs established an acceptable daily intake for progesterone, but concluded that there would be no need to specify a numerical maximum residue limit for progesterone in the edible tissues of cattle when products are used as growth promotors according to good practice. However, it should be noted that in the EU the use of ster-oidal hormones such as progestogens in veterinary practice is restricted, and their use as growth promotors is banned.

Interactions

Enzyme-inducing drugs such as carbamazepine, griseofulvin, phenobarbital, phenytoin, and rifampicin may enhance the clearance of progesterone and the progestogens. These interactions are likely to reduce the efficacy of progestogen-only contraceptives, and additional or alternative contraceptive measures are recommended.

Aminoglutethimide markedly reduces the plasma concentrations of medroxyprogesterone acetate and megestrol, possibly through a hepatic enzyme-inducing effect an increase in progestogen dose is likely to be required.

Since progesterone and other progestogens can influence diabetic control an adjustment in antidiabetic dosage could be required. Progestogens may inhibit ciclosporin metabolism leading to increased plasma-ciclosporin concentrations and a risk of toxicity.

Pharmacokinetics

Progesterone has a short elimination half-life and undergoes extensive first-pass hepatic metabolism when given orally oral bioavailability is very low although it may be increased somewhat by an oily vehicle and by micronisation. Progesterone is absorbed when given buccally rectally or vaginally and rapidly absorbed from the site of an oily intramuscular injection. Various derivatives have been produced to extend the duration of action and to improve oral activity. Esters of progesterone derivatives such as hydroxyprogesterone caproate are used intramuscularly, and megestrol acetate is orally active. The ester medroxyprogesterone acetate is used orally and parenterally 19-Nortestoster-one progestogens have good oral activity because the 17-ethinyl substituent slows hepatic metabolism. Progesterone and the progestogens are highly protein bound progesterone is bound to albumin and corticosteroid binding globulin esters such as medroxyprogesterone acetate are principally bound to albumin and 19-nortestosterone analogues are bound to sex-steroid binding globulin and albumin. Progesterone is metabolised in the liver to various metabolites including pregnanediol, which are excreted in the urine as sulfate and glucuronide conjugates. Similarly, progestogens undergo hepatic metabolism to various conjugates, which are excreted in the urine. Progesterone is distributed into breast milk.

Uses and Administration

Progesterone is a natural hormone whereas progestogens are synthetic compounds, derived from progesterone or 19-nortestosterone, with actions similar to those of progesterone. Progestogens derived from 19-nortestosterone are used as hormonal contraceptives, either alone or combined with an oestrogen. The progesterone derivative medroxyprogesterone acetate is also used, and progesterone itself has been used. Progestogens, and sometimes progesterone, are used with oestrogens for menopausal HRT to reduce the increased risk of endometrial hyperplasia and carcinoma that occurs when long-term oestrogen therapy is unopposed.

Similarly, drugs with progestogenic actions may be used in menstrual disorders such as dysmenorrhoea and menorrhagia associated with dysfunctional uterine bleeding (below). Progestogens may also be used in the management of endometriosis. Although progestogens and progesterone have been used for the management of the premenstrual syndrome (below), such a practice is of debatable value.

Progestogens may be valuable in advanced endometrial cancer and have been tried in some other malignancies. The progestogens typically used for malignant disease include medroxyprogesterone acetate, megestrol, and norethisterone. Some progestogens such as megestrol and medroxyprogesterone are used for the cachexia or wasting associated with severe illness including cancer and AIDS.

Progestogens have been widely advocated for either the prevention of recurrent miscarriage or the treatment of threatened miscarriage (below). However, there is little evidence of any benefit from such a practice and the use of progestogens in early pregnancy is not now generally advised, with the exception of the use of progesterone or a progesterone derivative in women who are progesterone deficient (see also Precautions, above). Progesterone is, however, the preferred drug for luteal support in women undergoing assisted reproductive techniques such as IVF (see Infertility).

USES AND ADMINISTRATION OF PROGESTERONE. Progesterone is usually given as an oily intramuscular injection, a vaginal gel or pessaries, or as suppositories. Preparations containing micronised progesterone are also available for oral and vaginal use.

In dysfunctional uterine bleeding or amenorrhoea 5 to 10 mg daily of progesterone may be given by intramuscular injection for about 5 to 10 days until 2 days before the anticipated onset of menstruation. Alternatively, progesterone may be given for amenorrhoea as a vaginal gel at a usual dose of 45 mg on alternate days for up to 6 doses the dose may be increased to 90 mg in those who do not respond to the lower dose. An oral dose of 400 mg given daily at bedtime for 10 days may also be used for amenorrhoea.

In women with a history of recurrent miscarriage and proven progesterone deficiency, twice weekly intramuscular injection (increased to daily if necessary) of 25 to 100 mg of progesterone, from about day 15 of the pregnancy until 8 to 16 weeks, has been used. The dose may be increased to 200 mg daily if necessary. Vaginal doses of micronised progesterone 200 to 400 mg daily, in 2 divided doses, have also been given until week 12 of pregnancy. A similar intramuscular schedule has been used for luteal support in IVF or gamete intra-fallopian transfer techniques with treatment beginning on the day of transfer of embryo or gametes. Alternatively, progesterone may be given vaginally in assisted reproduction, but doses can vary widely depending on the preparation. A vaginal gel may be given at a dose of 90 mg daily it is given for 30 days if pregnancy occurs, and may be continued until there is placental autonomy (up to 10 to 12 weeks). A dose of 90 mg twice daily has been used in women with ovarian failure. A vaginal tablet containing micronised progesterone 100 mg may be given 2 or 3 times daily treatment is started at oocyte retrieval and continued for up to 10 weeks. Some soft capsules containing micronised progesterone may also be suitable for intravaginal use in a dose of 400 to 600 mg daily, in 2 or 3 divided doses, from the day of gonadotrophin administration until week 12 of pregnancy.

Progesterone may be given vaginally or rectally in doses of 200 mg daily to 400 mg twice daily for the management of the premenstrual syndrome. Treatment usually starts on day 12 to 14 of the menstrual cycle and continues until the onset of menstruation. Similar vaginal or rectal doses have also been used in the treatment of puerperal (post-natal) depression.

Progesterone has been given as the progestogen component of menopausal HRT. Soft capsules containing micronised progesterone are available in some countries for oral use, given in a dose of 200 mg daily at bedtime for 12 to 14 days of each month. Alternatively, a dose of 100 mg daily may be given from day 1 to 25 of each cycle, resulting in less withdrawal bleeding. A progesterone-releasing intra-uterine device has been used as a hormonal contraceptive the device contains 38 mg of progesterone and is effective for up to 12 months. A vaginal ring device that releases 10 mg of progesterone daily is used in some countries for contraception in lactating women. The first ring is inserted 6 weeks after delivery then replaced every 90 days.

Administration. A number of progesterone creams for topical application to the skin are promoted in various countries for the management of menopausal symptoms and conditions associated with progesterone deficiency. These are sometimes described as containing ‘natural’ progesterone or phytoprogesterone from plant sources. However, many of these products are available without prescription or medical consultation and there has been some concern about their safety and efficacy. Reviews have found early studies reporting that absorption of progesterone from these creams was minimal. However, a later study using liquid chromatography-tandem spectrometry of whole blood reported that steady-state progesterone exposure was similar for women given either oral micronised progesterone or topical cream. The authors suggested that the differences between their results and previous studies were likely to have been caused by the use of different analytical techniques, and that women using these creams may in fact be exposed to higher systemic concentrations of progesterone than previously thought. Some proponents of topical progesterone therapy have questioned the importance of using serum concentrations as a marker for absorption. A review concluded that available serum-progesterone concentrations probably remain low after topical use and that further studies on the pharmacokinetics of topical progesterone are needed. In terms of efficacy, a number of small controlled studies have not shown progesterone cream to be any better than placebo for the management of menopausal vasomotor symptoms or the prevention of bone loss, and mixed results have been reported regarding the prevention of endometrial proliferation associated with oestrogen therapy.

Menorrhagia. Menorrhagia, or excessive menstrual bleeding, is usually defined as a blood loss exceeding 80 mL per menstrual period, compared with a normal loss of about 30 mL. However, many women consider losses below 80 mL to be excessive particularly if ‘flooding’ occurs. Although not life-threatening, menorrhagia can lead to iron deficiency anaemia and considerably impair quality of life. Menorrhagia may be associated with pelvic disorders such as fibroids or endometriosis, the use of copper IUDs, or some systemic disorders. However, most commonly it is associated with dysfunctional uterine bleeding a term used to denote frequent, prolonged or heavy uterine bleeding for which no specific cause is found (essential, idiopathic, or primary menorrhagia). Both ovulatory (regular) and anovulatory cycles may give rise to dysfunctional uterine bleeding. In general, medical treatment is used initially in women with no underlying uterine abnormalities. The most commonly used drugs are NSATDs, tranexamic acid, combined oral contraceptives, and progestogens, and choice of therapy may be influenced by the contraceptive needs of the patient. Surgery can be used if medical management is ineffective, and may be considered for first-line treatment in selected patients.

NSAIDs such as mefenamic acid, ibuprofen, and naproxen have been widely used. They reduce menstrual blood loss by about 20 to 50%, and there does not seem to be evidence to suggest that one NSAID is more effective than another.^l They are taken only during the menstrual phase, which reduces adverse effects, and probably improves patient compliance they also have the benefit of relieving dysmenorrhoea. Systematic review suggests that NSATDs are less effective than tranexamic acid, danazol, and intra-uterine levonorgestrel in reducing bleeding. NSAIDs are considered a suitable option when hormonal therapy is not acceptable. They should be stopped if symptoms do not improve within three menstrual cycles, but can be used for as long as the patient finds them to be beneficial.

Given during menstruation tranexamic acid reduces menstrual blood loss by about half the benefits of tranexamic therapy have been confirmed by systematic review. Like NSATDs, tranexamic acid is considered a suitable option when hormonal therapy is not acceptable. It should be stopped if symptoms do not improve within three menstrual cycles, but can be used for as long as the patient finds it to be beneficial. Etamsylate has been used for menorrhagia, but it is less effective than NSAIDs and tranexamic acid, and is no longer recommended. In women who require contraception, a combined oral contraceptive appears to be effective, although good evidence of this is actually lacking. It has been suggested that extended-cycle regimens should be considered for women with menorrhagia, as there are fewer bleeding episodes per year of treatment. Traditional therapy with progestogens such as norethisterone or medroxyprogesterone given during the luteal phase appears to be ineffective in women with normal ovulatory cycles, although cyclical therapy may be of benefit in anovulatory patients as it imposes a cycle. Progestogen therapy for 21 days of the cycle results in a significant reduction in menstrual blood loss, but is associated with adverse effects that may limit its acceptability. Long-acting injectable progestogens, such as medroxyprogesterone acetate, reduce menstrual blood loss or induce amenorrhoea when they are used as contraceptives. They have therefore been used for menorrhagia, although specific studies for this indication are lacking.

More recently, a contraceptive levonorgestrel-containing IUD has been shown to be very effective in reducing menstrual blood loss in menorrhagia. UK guidelines suggest that it should be considered first when either hormonal or non-hormonal treatment is acceptable and long-term use is anticipated, although comparative data are scanty. There is also some evidence that it may be an effective alternative to surgery, but data from long-term follow-up are needed. As there can be changes in bleeding pattern associated with this device, particularly in the first few cycles, use for at least 6 months is advised to enable full assessment of benefit.

Danazol is also effective, producing about a 50% reduction in menstrual blood loss, but has significant adverse effects and treatment is usually limited to 3 to 6 months. Gonadorelin analogues are effective for menorrhagia associated with fibroids. When used pre-operatively for endometrial thinning, they produce more consistent results than danazol. Gonadorelin analogues may therefore be considered before surgery or when other options for fibroids are contra-indicated, but ‘add-back’ hormone replacement is recommended for the management of adverse effects from oestrogen deficiency or if they are used for more than 6 months.

In patients who fail to respond to drug treatment, or in whom such therapy is inappropriate, various surgical options exist. Conservative surgical techniques, where the endometrium is ablated or resected, are increasingly being used, and are an effective alternative to hysterectomy. Hysterectomy is the ultimate therapy, but is associated with significant morbidity.

Miscarriage. Threatened miscarriage is a common complication of pregnancy that presents before 20 weeks of gestation as vaginal bleeding, with or without abdominal pain, while the cervix is closed and the fetus is viable. Endogenous progesterone is normally produced by the corpus luteum to maintain pregnancy, and low concentrations have been associated with pregnancy loss. Progestogen therapy has therefore been widely used in the treatment of threatened miscarriage, but there is a paucity of clinical study data to support routine use. Similarly, progestogens have been used prophylactic ally to prevent miscarriage, but studies have suffered from various limitations. A systematic review found no evidence to support routine use, but there was limited evidence to suggest that women with a history of recurrent miscarriage (3 or more consecutive miscarriages) might gain some benefit. The BNF advises that progestogen prophylaxis in women with a history of recurrent miscarriage is not recommended. (See also Pregnancy, above, for reports of hypospadias in the offspring of women given hormonal support therapy.)

Premature labour. Recommendations have been made regarding progesterone therapy for the prevention of premature birth in women at risk of preterm delivery (see under Hydroxyprogesterone Caproate).

Premenstrual syndrome. Progestogen therapy was once popular for premenstrual syndrome, but beneficial responses have not been universally achieved and the theory that progesterone was necessary to correct a hormone imbalance is now losing ground. Progesterone has been given orally, vagi-nally, and rectally, in continuous and luteal phase regimens. However, systematic reviews’ have found no convincing evidence to support its use.

Preparations

British Pharmacopoeia 2008: Progesterone Injection

The United States Pharmacopeia 31, 2008: Progesterone Injectable Suspension Progesterone Injection Progesterone Intrauterine Contraceptive System Progesterone Vaginal Suppositories.

Proprietary Preparations

Argentina: Crinone Faselut Gester Mafel Progest Proluton Utrogestan

Australia: Crinone Proluton

Austria: Utrogestan

Belgium: Crinone Progestogel Utrogestan

Brazil: Crinone Evocanil Utrogestan

Canada: Crinone Prometrium

Chile: Crinone Hormoral Progendo Progering

Czech Republic: Agolutin Crinone Utrogestan

Denmark: Crinone

Finland: Crinone Lugesteron

France: Estima Evapause Progestogel Utrogestan

Germany: Crinone Progestogel Utrogest

Greece: Crinone Promenorea Utrogestan

Hong Kong: Crinone Cyclogest Endometrin Progestogel Utrogestan

Hungary: Utrogestan

India: Crinone Dubagest Naturogest Profine Progest Remens Uterone

Indonesia: Crinone

Ireland: Crinone Utrogestan

Israel: Crinone Endometrin Gestone Utrogestan

Italy: Crinone Esolut Lutogin Progeffik Progestogel Progestol † Prometrium Prontogest

Malaysia: Crinone Cyclogest Utrogestan †

Mexico: Crinone Cuerpo Amarillo Fuerte Gepromi Geslutin Gestageno Premastan Prosphere Utrogestan

The Netherlands: Progestan

Norway: Crinone

New Zealand: Crinone Gestone

Philippines: Crinone

Poland: Luteina

Portugal: Crinone Progenar † Progestogel Utrogestan

Russia: Crinone Progestogel Utrogestan

South Africa: Crinone Cyclogest Utrogestan

Singapore: Crinone Cyclogest Utrogestan

Spain: Crinone Darstin Progeffik Progestogel † Progestosol Utrogestan

Sweden: Crinone

Switzerland: Crinone Progestogel Utrogestan

Thailand: Crinone Cyclogest Gestone † Progestogel Utrogestan

Turkey: Crinone Cyclogest Progestan

UK: Crinone Cyclogest Gestone Utrogestan

USA: Crinone Endometrin Prochieve Progestasert † Prometrium

Venezuela: Crinone Progendo Progestogel Utrogestan.

Multi-ingredient

Argentina: Cristerona Fempack Hosterona Lubriderm Menstrogen Tropivag Plus

Brazil: Ginecoside † Normomensil †

France: Florgynal Synergon Trophigil

Germany: Jephagynon †

Italy: Biormon † Menovis

Malaysia: Duogynon

Mexico: Damax Genofort Lutoginestryl  † Metrigen Fuerte Ominol Primoson † Progediol † Proger †

Portugal: Emmenovis †

Thailand: Duoton Phenoknon †

Turkey: Di-Pro Synergon

Venezuela: Cyclogesterin † Ginecosid.

Drug Approvals

(BANM, US Adopted Name, rINNM)

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Megestrol Acetate). A white or almost white crystalline powder. Practically insoluble in water sparingly soluble in alcohol soluble in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Megestrol Acetate). A white to creamy-white, essentially odourless, crystalline powder. Insoluble in water sparingly soluble in alcohol soluble in acetone very soluble in chloroform slightly soluble in ether and in fixed oils. Protect from light.

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). The weight gain that may occur with megestrol acetate appears to be associated with an increased appetite and food intake rather than with fluid retention. Megestrol acetate may have glucocorticoid effects when given long term.

Effects on carbohydrate metabolism. Megestrol therapy has been associated with hyperglycaemia or diabetes mellitus in AIDS patients being treated for cachexia. It has been suggested that megestrol produces peripheral insulin resistance due to a glucocorticoid action.

Effects on the musculoskeletal system. Severe pain of the hands similar to carpal tunnel syndrome occurred in 4 women while taking megestrol acetate and melphalan megestrol appeared to be responsible.

Osteoporosis and vertebral compression fractures occurred in 2 postmenopausal women taking megestrol for anorexia. In both cases there was evidence of adrenocortical insufficiency that recovered after megestrol therapy was stopped, suggesting that the glucocorticoid effect of megestrol may have contributed to the development of osteoporosis.

Effects on the respiratory system. Hyperpnoea occurred in 2 patients given megestrol acetate 80 mg three times daily.

Glucocorticoid effects. Megestrol has glucocorticoid-like properties that can cause adrenocortical suppression in a significant number of patients. There are also reports of adrenal insufficiency severe enough to require replacement therapy with hydrocortisone.

Porphyria. Megestrol is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Interactions

As for progestogens in general (see Progesterone).

Pharmacokinetics

Megestrol acetate is absorbed from the gastrointestinal tract and peak plasma concentrations occur 1 to 3 hours after an oral dose. Megestrol acetate is highly protein bound in plasma. It undergoes hepatic metabolism, with 57 to 78% of a dose being excreted in the urine and 8 to 30% in the faeces.

Uses and Administration

Megestrol acetate is a progestogen structurally related to progesterone.

It is used for the palliative treatment of some hormone-dependent malignant neoplasms (see below). Oral doses of 40 to 320 mg daily in divided doses may be given in endometrial carcinoma, and doses of 40 mg four times daily or 160 mg once daily may be used in breast cancer.

Megestrol acetate is also used in the treatment of anorexia and cachexia (see below) in patients with cancer or AIDS. The usual dose is 400 to 800 mg daily, as tablets or oral suspension. A suspension of megestrol acetate that has an increased bioavailability is also available (Megace ES Par Pharmaceutical, USA) and is given in a dose of 625 mg in 5 mL daily for anorexia, cachexia, or unexplained significant weight loss in patients with AIDS.

Cachexia. In some patients with severe chronic disorders or malignant neoplasms, anorexia (loss of appetite) forms part of a syndrome of metabolic abnormalities and progressive physical wasting known as cachexia. Improved nutrition and dietary counselling are usually insufficient to reverse cachexia, and drug therapy has been tried to stimulate appetite and promote weight gam.

In cancer-related cachexia, corticosteroids are frequently used for appetite stimulation in patients with advanced malignancies, although they do not appear to promote weight gain. However, because their effect is usually temporary, and adverse effects occur with prolonged use, they tend to be reserved for short-term treatment in patients with a limited life expectancy of weeks. Megestrol has produced weight gain in some randomised controlled studies, although some of this may result from increase in fat mass rather than increase in lean body-mass. It is generally used in patients with a longer life expectancy of months Similar properties have been reported with medroxyprogesterone. A systematic review concluded that only corticosteroids and the progestogens megestrol and medroxyprogesterone had sufficient evidence to support their use in cancer-related anorexia. Anabolic steroids have also been tried, but further evaluation is necessary: a comparison of megestrol or dexamethasone with fluoxymesterone found the latter to be less effective than the progestogen or the corticosteroid. Prokinetic drugs such as metoclopramide may be useful in patients whose symptoms are secondary to decreased gastrointestinal motility, although relief of nausea may not necessarily lead to improved caloric intake or appetite. It has been suggested that NS AIDs might inhibit the effects of pro-inflammatory cytokines associated with weight loss in cancer patients. The addition of ibuprofen improved the response to megestrol in one small study, but more work is needed. There has also been interest in the effects of eicosapentaenoic acid, which may inhibit muscle protein degradation, but study results have been mixed and a systematic review concluded that there was insufficient evidence to recommend the use of eicosapentaenoic acid. Further investigation is needed to confirm its clinical effects, possibly using higher doses or treating for longer periods than have been so far reported. Thalidomide was found to attenuate weight loss in a study of patients with advanced pancreatic cancer, but quality of life and duration of survival were not significantly improved. Other drugs studied but with little, if any, benefit include cannabinoids, cyproheptadine and hydrazine. Other compounds under investigation include the endogenous hormones ghrelin and melatonin.

High-dose megestrol or oxandrolone are effective in HIV-related cachexia, a topic discussed under HIV-associated Wasting.

Hot flushes. Megestrol has been used to treat hot flushes in women with breast cancer (to avoid the potentially tumour-stimulating effects of an oestrogen — see Malignant Neoplasms, under Precautions of HRT), as well as in men with hot flushes after orchidectomy or anti-androgen therapy for prostate cancer. Therapy, which involved low oral doses of 20 mg twice daily, was associated with a decrease in frequency of flushes of 50% or more in about three-quarters of all patients. About 3 years after the study had finished, these patients were asked about any ongoing use of megestrol and the occurrence of hot flushes. Although symptoms still occurred in many of the patients taking megestrol, they were less common and less severe than in those who had stopped therapy, which included some who had stopped because of no perceived benefit. In patients taking megestrol, most were on doses of 20 mg or less daily. Information collected about adverse effects of megestrol revealed unexpected reports of chills, but these were described as being not as disabling as the hot flushes had been.

Malignant neoplasms. Like some other progestogens megestrol acetate is used in endometrial cancer, and it has been reported to have similar efficacy to anastrozole and tamoxifen in postmenopausal women with advanced breast cancer. There was no advantage in terms of response or survival in escalating the standard dose of megestrol (160 mg daily) to 800 or 1600 mg daily in a randomised study in women with breast cancer

Preparations

British Pharmacopoeia 2008: Megestrol Tablets

The United States Pharmacopeia 31, 2008: Megestrol Acetate Oral Suspension Megestrol Acetate Tablets

Proprietary Preparations

Argentina: Megace Megacorp Meltonar Varigestrol

Australia:: Megace

Austria: Megace

Belgium: Megace

Brazil: Femigestrol Gynodal Megestat

Canada: Megace

Chile: Megace Mestrel

Czech Republic: Megace Megaplex

Denmark: Megace

Finland: Megace Megestin

France: Megace

Germany: Megestat

Greece: Megace

Hong Kong: Megace

Hungary: Megace Megesin

India: Endace

Ireland: Megace

Israel: Megace

Italy: Megace Megestil Meprogest

Malaysia: Megace

Mexico: Megace Mestrel

The Netherlands: Megace

Norway: Megace

New Zealand: Megace

Philippines: Megace

Poland: Cachexan Gestar Megace Megalia Megesin

Portugal: Acestrol Megace

Russia: Megaplex

Singapore: Megace

Spain: Borea Maygace Megefren Megostat

Sweden: Megace

Switzerland: Megestat

Thailand: Megace Megaplex Mestrel

Turkey: Megace

UK: Megace

USA: Megace

Venezuela: Megase

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In China.

Profile

Chlorotrianisene is a synthetic nonsteroidal oestrogen structurally related to diethylstilbestrol. It has a prolonged action, and has been given orally for the treatment of menopausal symptoms, female hypogonadism, and prostatic carcinoma.

Single-ingredient Preparations

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

Belgium: Tace¤; Canada: Tace¤; France: Tace¤; Germany: Merbentul¤; Mexico: Estregur¤; Spain: Tace¤; Switzerland: Tace¤; United States: Tace¤