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Drug Approvals

(British Approved Name Modified, rINNM)

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

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

The United States Pharmacopeia 31, 2008 (Medroxyprogesterone Acetate). A white to off-white, odourless, crystalline powder. Insoluble in water sparingly soluble in alcohol and in methyl alcohol soluble in acetone and in dioxan freely soluble in chloroform slightly soluble in ether. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives. Medroxyprogesterone acetate may have glucocorticoid effects when given long term at high doses.

Breast feeding. Medroxyprogesterone is reported to be distributed into breast milk when given as a depot progestogen-only contraceptive. No adverse effects have been seen in breast-fed infants of mothers given medroxyprogesterone, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding. Progestogen-only parenteral contraceptives should not be used until 6 weeks after birth if the woman is breast feeding (see Breast Feeding under Hormonal Contraceptives).

Carcinogenicity. The risk of various cancers associated with the use of depot medroxyprogesterone acetate as a contraceptive has been evaluated by WHO. Overall, there was no increase in risk of breast cancer, although there is some evidence that current or recent use may be associated with a slight increase in risk. There was no significant increased risk of cervical cancer, and a protective effect against endometrial cancer. In contrast to combined oral contraceptives, there was no evidence of a protective effect against ovarian cancer.

Effects on bone density. Use of medroxyprogesterone acetate as a parenteral progestogen-only contraceptive has been associated with reductions in bone density (see under Effects on the Musculoskeletal System). This effect has also been reported after oral doses for menstrual disorders, and is thought to be due to medroxyprogesterone-induced oestrogen deficiency.

Effects on the skin. Acute local skin necrosis has been reported after the intramuscular injection of medroxyprogesterone acetate as a depot contraceptive. A case of pigmented purpura on the lower legs, occurring about 4 months after starting medroxyprogesterone acetate injections, has been described.

Glucocorticoid effects. There have been reports of Cushing’s syndrome induced by medroxyprogesterone acetate in patients receiving long-term therapy with high doses for the treatment of malignant neoplasms or paraphilia. Cushingoid symptoms regressed when treatment was stopped. Medroxyprogesterone possesses glucocorticoid activity and there is a risk of adrenal insufficiency during periods of stress or after sudden withdrawal of treatment. Some consider that patients should be monitored for glucose intolerance and adrenal insufficiency during treatment.

Porphyria. Medroxyprogesterone has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients. However, for a reference to the use of medroxyprogesterone acetate with buserelin acetate in the prevention of premenstrual exacerbations of porphyria in 2 women.

Interactions

As for progestogens in general (see Progesterone). Aminoglutethimide markedly reduces plasma concentrations of medroxyprogesterone so that an increase in medroxyprogesterone dosage is likely to be required.

Pharmacokinetics

Medroxyprogesterone is absorbed from the gastrointestinal tract. In the blood, it is highly protein bound, principally to albumin. It is metabolised in the liver and excreted mainly as glucuronide conjugates in the urine and faeces. It has a half-life of about 16 to 30 hours after oral doses the half-life may be as long as 50 days after intramuscular injection. Medroxyprogesterone is reported to be distributed into breast milk.

Uses and Administration

Medroxyprogesterone acetate is a progestogen structurally related to progesterone, with actions and uses similar to those of the progestogens in general (see Progesterone). It is given orally or, for prolonged action, as an aqueous suspension by intramuscular or subcutaneous injection, depending on the product. It is used for the treatment of menorrhagia and secondary amenorrhoea in oral doses of 2.5 to 10 mg daily for 5 to 10 days starting on the assumed or calculated 16th to 21st day of the menstrual cycle, although treatment may begin on any day in secondary amenorrhoea.

In the treatment of mild to moderate endometriosis usual oral doses are 10 mg three times daily for 90 consecutive days, or 50 mg weekly or 100 mg every 2 weeks by intramuscular injection for at least 6 months. An alternative formulation used for the treatment of pain associated with endometriosis is given in a dose of 104 mg in 0.65 mL by subcutaneous injection once every 12 to 14 weeks.

Medroxyprogesterone acetate is also given by injection as a contraceptive (see under Hormonal Contraceptives). As a progestogen-only contraceptive an intramuscular dose of 150 mg is given every 12 or 13 weeks. A combined contraceptive injection containing medroxyprogesterone acetate 25 mg with estradiol cipionate 5 mg is given monthly as an intramuscular injection. An alternative formulation used as a progestogen-only contraceptive is given as a dose of medroxyprogesterone acetate 104 mg in 0.65 mL by subcutaneous injection once every 12 to 14 weeks. When used as the progestogen component of menopausal HRT, medroxyprogesterone acetate is given orally in a variety of regimens including 1.5, 2.5, or 5 mg daily continuously, 5 or 10 mg daily for 12 to 14 days of a 28-day cycle, and 20 mg daily for 14 days of a 91-day cycle.

Medroxyprogesterone acetate may also be used in the palliative treatment of some hormone-dependent malignant neoplasms. In breast carcinoma (see below) oral doses of 0.4 to 1.5 g daily may be given, although doses up to 2 g daily have been used in the past. Intramuscular medroxyprogesterone acetate has been given in initial doses of 500 mg daily for 4 weeks, then in maintenance doses twice weekly. In endometrial (below) and renal carcinoma oral doses have ranged from 200 to 600 mg daily. Initial doses of 0.6 to 1.2 g weekly have been given by intramuscular injection, reducing to a maintenance schedule of as little as 450 mg monthly. In prostatic carcinoma oral doses have been 100 to 600 mg daily 500 mg has also been given by intramuscular injection, initially twice weekly for 3 months then once weekly for maintenance.

Cachexia. Medroxyprogesterone may improve appetite and food intake, and prevent loss of body-weight in cachexia associated with severe chronic disorders, although information is limited.

Contraception. Medroxyprogesterone acetate has an established use as a parenteral progestogen-only contraceptive. It has also been developed as the progestogenic component of a combined injectable contraceptive and has been investigated as a component of hormonal contraceptives for men. References.

Epilepsy. Early findings suggested that medroxyprogesterone acetate might be of value in the management of catamenial epilepsy. In a later review it was suggested that hormonal manipulation with drugs such as medroxyprogesterone should be reserved for highly selected groups under close supervision.

Male hypersexuality. The anti-androgenic action of medroxyprogesterone has been used for suppression of libido in the control of men with deviant or disinhibited sexual behaviour (see Disturbed Behaviour). Most have received intramuscular medroxyprogesterone acetate doses of about 300 mg weekly have been used, but ranged from 100 mg each month to 500 mg each week in one report of 5 cases, and up to 750 mg each week in another case. Oral treatment with 30 mg daily was also successful in 1 case.

Malignant neoplasms. BREAST. Progestogens are used as second- or third-choice drugs in the hormonal therapy of advanced breast cancer. Some references to the use of medroxyprogesterone acetate in advanced breast cancer are cited below. Comparative studies have shown that patients respond equally well to medroxyprogesterone and either mepitiostane, aminoglutethimide, or oophorectomy.

ENDOMETRIUM. Progestogens are used in the treatment of advanced endometrial carcinoma but there are doubts about their value in the earlier stages of disease. Medroxyprogesterone acetate was effective in a rare case of low-grade endometrial stromal sarcoma. It has also been used in a few patients as adjuvant therapy after surgery and for the treatment of metastatic disease.

Respiratory disorders. Reviews of the use of medroxyprogesterone acetate in obstructive sleep apnoea have concluded that it has a limited role.

Progesterone and, more commonly, medroxyprogesterone acetate are used in the treatment of pulmonary lymphangioleiomyomatosis, a rare disease affecting only women. Anecdotal evidence suggests some patients improve or stabilise on treatment, possibly those with chylous effusions or chylous ascites. However, a more rapid decline in lung function has also been observed with progestogen therapy in some groups. Medroxyprogesterone acetate was reported to be effective in treating congenital central hypoventilation syndrome in 2 children. It has also been used in adults with central hypoventilation resulting from brainstem stroke and other causes. Medroxyprogesterone has also been investigated for its effects on respiration in chronic obstructive pulmonary disease, sometimes with acetazolamide.

Sickle-cell disease. The frequency of painful crises has been reduced in women with homozygous sickle-cell disease given intramuscular depot medroxyprogesterone acetate, and it is now considered to be a suitable contraceptive for this group (see also Sickle-cell Disease, under Precautions of Hormonal Contraceptives.

Preparations

British Pharmacopoeia 2008: Medroxyprogesterone Injection; Medroxyprogesterone Tablets

The United States Pharmacopeia 31, 2008: Medroxyprogesterone Acetate Injectable; Suspension Medroxyprogesterone Acetate Tablets

Single-ingredient Preparations

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

Argentina: Cycrin¤; Depo-Provera¤; Farlutale; Livomedrox; Map An; Medrosterona; Veraplex; Australia: Depo-Provera; Depo-Ralovera; Farlutal¤; Medroxyhexal; Provera; Ralovera; Austria: Depo-Provera¤; Depocon; Farlutal; Prodafem; Provera; Belgium: Depo-Provera; Farlutal; Provera; Brazil: Acemedrox; Acetoflux; Contracep; Cycrin; Depo-Provera; Farlutal; Medroxitest; Progesan; Provera; Tricilon; Canada: Alti-MPA¤; Apo-Medroxy; Depo-Provera; Gen-Medroxy; Novo-Medrone; Proclim¤; Provera; ratio-MPA; Chile: Depo-Prodasone; Farlutal; Farlutes; Prodasone; Provera; Sicrit¤; Czech Republic: Depo-Provera; Provera; Denmark: Depo-Provera; Perlutex; Provera; Finland: Cykrina¤; Depo-Provera; Farlutal; Gestapuran; Lutopolar; Mepastat; Provera; France: Depo-Prodasone; Depo-Provera; Farlutal; Gestoral¤; Prodasone¤; Germany: Clinofem; Clinovir; Depo-Clinovir; Farlutal; G-Farlutal¤; GestaPolar¤; MPA Gyn; MPA-beta; MPA-Noury¤; MPA; Greece: Depo-Provera; Farlutal; Gestoral; Progevera; Provera; Hong Kong: Depo-Provera; Farlutal; Provera; Hungary: Depo-Provera; Provera; India: Depo-Provera; Meprate; Ireland: Depo-Provera; Provera; Israel: Aragest; Depo-Provera; Provera; Italy: Depo-Provera; Farlutal; Lutoral¤; Provera; Malaysia: Depo-Provera; Farlutal¤; Petogen¤; Provera; Veraplex; Mexico: Ciclotal; Cycrin¤; Depo-Provera; Farlutal; Megestrin; Megestron; Progezzard¤; Protarin¤; Provera; Netherlands: Depo-Provera; Farlutal; Provera; Norway: Depo-Provera; Farlutal; Perlutex; Provera; New Zealand: Depo-Provera; Farlutal¤; Provera; Portugal: Depo-Provera; Provera; Russia: Ciclotal (Циклотал); Depo-Provera (Депо-провера); Veraplex (Вераплекс); South Africa: Depo-Provera; Farlutal¤; Petogen; Provera; Singapore: Depo-Provera; Farlutal; Provera; Spain: Depo-Progevera; Farlutal; Progevera 250; Progevera; Sweden: Cykrina¤; Depo-Provera; Farlutal; Gestapuran; Provera; Switzerland: Depo-Provera; Farlutal; Prodafem; Provera¤; Thailand: Contracep; Depo-Gestin; Depo-Progesno; Depo-Progesta; Depo-Provera; Farlutal; Manodepo; Medeton; Provera; United Kingdom: Adgyn Medro¤; Climanor; Depo-Provera; Farlutal; Provera; United States: Amen¤; Curretab¤; Cycrin¤; Depo-Provera; Depo-subQ Provera; Provera; Venezuela: Depo-Provera; Farlutal; Provera

Multi-ingredient Preparations

Argentina: Dilena; Farludiol Ciclo; Farludiol; Periofem Ciclico¤; Periofem Continuo¤; Premelle Ciclico; Premelle Continuo; Australia: Divina¤; Estrapak¤; Menoprem¤; Premia Continuous; Premia Low; Premia; Provelle¤; Austria: Cyclo-Premarin-MPA¤; Cyclo-Premella¤; Femipak; Filena; Perennia; Premarin MPA¤; Premella¤; Sequennia; Tri-Filena¤; Belgium: Diviplus¤; Diviva¤; Premelle Cycle; Premelle; Trivina¤; Brazil: Cyclofemina; Dilena; Menosedan Ciclo; Menosedan Fase; Menosedan MPA; Premarin MPA¤; Premelle Ciclo; Premelle; Prempro Bifasico; Prempro Monofasico; Repogen Ciclo; Repogen Conti; Selecta; Canada: Premplus; Chile: Climatrol Continuo; Climatrol HT Continuo; Climatrol HT; Conpremin Pak Plus; Conpremin Pak; Cyclofem; Enadiol CC; Enadiol MP; Estranova 30 Simple; Estranova CC; Farlupost; Farlutal Estrogeno; Kilios; Novafac 30; Novafac CC; Novafac; Novafem; Prempak; Primaquin MP Continuo; Primaquin MP; Profemina CC; Profemina MP; Czech Republic: Cyclo-Premella; Divina; Diviseq; Indivina; Premella; Denmark: Divina Plus; Divina; Indivina; Klimalet; Klimaxil¤; Trevina; Finland: Divina; Divitren; Indivina; France: Divina; Diviseq; Duova; Precyclan; Germany: Climopax Cyclo; Climopax; CycloPolar¤; Estrafemol; Gianda; Indivina; Osmil; Procyclo; Sisare 28; Sisare; Vitrena; Greece: Divina; Estopause; Premelle Cycle; Premelle; Hong Kong: Dilena; Premelle Cycle; Premelle; Hungary: Cyclo-Premella; Divina; Divitren; Premella; Ireland: Diviseq¤; Femplan-MA¤; Indivina; Premique Cycle; Premique; Tridestra¤; Israel: Meno-MPA¤; Premaril MP; Premaril Plus MP; Italy: Filena; Premelle Combinato; Premelle S¤; Premelle Sequenziale; Malaysia: Plentiva Cycle 5; Plentiva; Premelle; Mexico: Cyclofemina; Dilena; Premelle; Netherlands: Divina¤; Premelle Cycle; Premelle; PremelleLite; Norway: Diviseq¤; Indivina; New Zealand: Menoprem; Premia Continuous; Premia; Provette Continuous¤; Provette Sequential¤; Portugal: Dilena; Medrivas Antibiotico; Medrivas¤; Premelle Cycle; Premelle; Russia: Divina (Дивина); Diviseq (Дивисек); Divitren (Дивитрен); Indivina (Индивина); South Africa: Divina; Premelle; Trivina; Singapore: Premelle Cycle; Premelle; Spain: Medricol¤; Medrivas Antib; Medrivas; Perifem; Premelle Ciclico; Premelle; Sweden: Divina Plus; Divina; Indivina; Premelle Sekvens; Premelle; Trivina; Switzerland: Cyclo-Premella ST; Cyclo-Premella¤; Diviseq; Indivina; OestroTabs Plus Cyclic¤; Premella; Premia; Triaval; Thailand: Indivina; Premelle Cycle; Premelle; United Kingdom: Improvera¤; Indivina; Premique Cycle; Premique; Tridestra; United States: Lunelle¤; Premphase; Prempro; Venezuela: Climatrol HT Ciclico; Climatrol HT Continuo; Premelle Ciclico; Premelle Continuo; Premelle Plus Continuo

(British Approved Name, rINN)

Follicle Stimulating Hormone-releasing Factor; GnRH; Gonadoliberin; Gonadoreliini; Gonadorelina; Gonadoréline; Gonadorelinum; Gonadotrophin-releasing Hormone; Hoe-471; LH/FSH-RF;LH/FSH-RH; LH-RF; LH-RH; Luliberin; Luteinising Hormone-releasing Factor.

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-L-arginyl-L-prolylglycinamide.

Гонадорелин

Gonadorelin Acetate

Drug Approvals

(BANM, US Adopted Name, rINNM)

Abbott-41070; Acetato de gonadorelina; Gonadolrelin-acetát;Gonadoreliiniasetaatti; Gonadorelinacetat; Gonadorelin-acetát; Gonadoréline, acétate de; Gonadorelini acetas; Gonadorelinoacetatas.

Гонадорелина Ацетат

Pharmacopoeias. In Europe, Japan, and US for veterinary use only.

The United States Pharmacopeia 31, 2008 (Gonadorelin Acetate). A white to slightly yellowish powder. Soluble in water sparingly soluble in methyl alcohol. Store in airtight containers at a temperature of not more than 8°.

European Pharmacopoeia, 6th ed. (Gonadorelin Acetate). The acetate form of a hypothalamic peptide that stimulates the release of follicle-stimulating hormone and luteinising hormone from the pituitary gland. It is obtained by chemical synthesis. A white or slightly yellowish powder soluble in water and in 1% v/v glacial acetic acid sparingly soluble in methyl alcohol. Store in airtight containers at a temperature of 2° to 8°. Protect from light.

Gonadorelin Hydrochloride

Drug Approvals

(BANM, US Adopted Name, rINNM)

AY-24031; Gonadoréline, Chlorhydrate de; Gonadorelini Hydrochloridum; Hidrocloruro de gonadorelina.

Гонадорелина Гидрохлорид

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Gonadorelin Hydrochloride). A synthetic polypeptide hormone having the property of stimulating the release of the luteinising hormone from the hypothalamus. It is extremely hygroscopic. Protect from exposure to moisture and store in airtight well-sealed containers, in a desiccator.

Adverse Effects

Gonadorelin and its analogues are generally well tolerated but may cause gastrointestinal adverse effects, usually nausea and abdominal pain or discomfort. There may be headache or lightheadedness, and an increase in menstrual bleeding. Continued therapy with gonadorelin analogues results in paradoxical suppression of the pituitary gonadal axis in premenopausal women this may produce menopausal symptoms, including vaginal dryness, hot flushes, and loss of libido. If sufficiently prolonged the suppression of circulating oestrogens may lead to osteoporosis. In men, hot flushes and sexual dysfunction can occur, and breast swelling and tenderness have been reported infrequently with gonadorelin analogues. Long-term treatment can also cause a loss of bone mineral density in men. Other adverse effects reportedly associated with gonadorelin analogue therapy, and presumably related to changes in the hormonal milieu, include mood changes, nervousness, palpitations, acne and dry skin, changes in scalp and body hair, alterations in liver function tests and blood lipids, and decreased glucose tolerance. Arthral-gia and paraesthesias have been reported. Ovarian hyperstimulation (as seen with chorionic gonadotrophin), although rare, has occurred in women given gonadorelin.

Reactions or pain may occur at the site of injection with rash (local or generalised), thrombophlebitis, swelling, or pruritus. Hypersensitivity reactions, including bronchospasm and anaphylaxis, have been reported. Other effects may be a consequence of the particular use of gonadorelin or its analogues. Tumour flare, due to an initial surge in testosterone concentrations, has been reported in the initial stages of treatment for cancer of the prostate and prophylactic anti-androgen therapy may be added. Flare may manifest as an increase in bone pain occasionally there has been spinal cord compression, or a worsening of urinary-tract symptoms with haematuria and urinary obstruction. Acute degeneration of submucous fibroids with severe bleeding has been reported following use of leuprorelin. An initial increase in signs and symptoms has also been reported in women with breast cancer receiving gonadorelin analogues hypercalcaemia has occurred in those with metastatic disease. In girls being treated for precocious puberty, vaginal bleeding may occur in the first month of treatment because of initial ovarian stimulation followed by treatment-induced oestrogen withdrawal.

Hypersensitivity. Acquired hypersensitivity led to an anaphylactic reaction after an intravenous dose of gonadorelin in a man who had been receiving pulsatile subcutaneous gonadorelin therapy for 10 weeks.

Osteoporosis. Long-term use of a gonadorelin analogue results in oestrogen deficiency-associated osteoporosis and various drugs have been investigated for their ability to reduce this effect. Parathyroid hormone has been reported to prevent bone loss in small studies ofyoung women receiving nafarelin. ‘Add-back’ therapy with tibolone or oestrogen plus progestogen has also had beneficial effects on bone mineral density in women receiving gonadorelin analogues. However, studies have used various combination regimens and it is not possible to determine which is most effective. There is less information available about the management of osteoporosis in men receiving gonadorelin analogues as androgen deprivation therapy, but measures have included supplemental calcium and vitamin D, and the use of bisphosphonates. Raloxifene is also under investigation in both women and men.

Pituitary apoplexy. Pituitary apoplexy has been reported after endocrine stimulation testing using gonadorelin. A review of 14 cases found that 2 patients had received gonadorelin alone but most had also received protirelin (thyrotropin-releasing hormone). The onset of initial symptoms was within 2 hours and pituitary tumour haemorrhage was much more common than infarction alone.

Precautions

Gonadorelin or its analogues should not generally be used in patients with pituitary adenoma as haemor-rhagic infarction (pituitary apoplexy) has sometimes occurred. It has also been recommended that patients with weight-related amenorrhoea should not receive these drugs until their weight is corrected. Although at least one manufacturer recommends that gonadorelin should not be used in women with polycystic ovary disease or with endometriotic cysts, gonadorelin and its analogues have been used for ovulation induction in polycystic disease and produced improvement in uterine fibroids gonadorelin analogues have also been used with benefit in endometriosis. Gonadorelin analogues may increase cervical resistance, making it difficult to dilate the cervix for intra-uterine surgical procedures. Gonadorelin or its analogues should be stopped if the patient becomes pregnant. Contraceptive measures should be taken to protect against unwanted ovulation. Men at risk from tumour flare should be carefully monitored in the first month of therapy.

Interactions

Drugs affecting pituitary secretion of gonadotrophin s may alter the response to gonadorelin or its analogues other hormonal therapy and corticosteroids can affect the response. Spironolactone and levodopa can stimulate gonadotrophins while phenothiazines, dopamine antagonists, digoxin, and sex hormones can inhibit gonadotrophin secretion.

Pharmacokinetics

Gonadorelin is poorly absorbed from the gastrointestinal tract. It has a terminal plasma half-life of only 10 to 40 minutes after intravenous injection. It is hydrolysed in the plasma and excreted in the urine as inactive metabolites.

Gonadorelin analogues are absorbed after oral, intramuscular, intranasal, or rectal doses and have a longer half-life.

Uses and Administration

Gonadorelin is a synthetic form of hypothalamic gonadotrophin-releasing hormone. It stimulates the synthesis and release of follicle-stimulating hormone and, in particular, luteinising hormone in the anterior lobe of the pituitary. The secretion of endogenous gonado-trophin-releasing hormone is pulsatile and is controlled by several factors including circulating sex hormones. Gonadotrophic hormones (gonadotrophins), released from the pituitary gland in response to gonadorelin, stimulate secretion of sex hormones from the gonads. A single dose of gonadorelin or one of its analogues has the effect of increasing circulating sex hormones continued use leads to down-regulation of gonadorelin-receptor synthesis in the pituitary and results in a paradoxical reduction in sex-hormone secretion. Gonadorelin may be given as the base, acetate, or hydrochloride, and the dose may be expressed in terms of any of these.

Gonadorelin is used in the diagnosis of hypothalamic-pituitary-gonadal dysfunction. Assessment is usually based on the response to a dose of gonadorelin of 100 micrograms by intravenous or subcutaneous injection. In females, where possible, it should be given early in the follicular stage of the menstrual cycle. In the UK, the BNFC includes a single dose of 2.5 micrograms/kg, to a maximum of 100 micrograms, for children from the age of 1 year. Gonadorelin is also used in the treatment of amenorrhoea and infertility associated with hypogonadotrophic hypogonadism. Weight-related amenorrhoea should have been corrected by diet. Treatment in such conditions is based on an intermittent pulse pump providing 5 to 20 micrograms over one minute every 90 minutes, either subcutaneously or intravenously, for up to 6 months or until conception. Gonadorelin or, more usually, its analogues such as buserelin, goserelin, leuprorelin, nafarelin, and trip-torelin (which are more potent and have a longer duration of action) are used in cryptorchidism, malignant neoplasms (especially of the prostate), and in delayed and precocious puberty.

Benign prostatic hyperplasia. The gonadorelin analogues have been tried in the management of benign prostatic hyperplasia but are considered unsatisfactory for indefinite use. See also under Leuprorelin Acetate, and Nafarelin Acetate.

Cryptorchidism. Although surgery remains the treatment with the best success rate, primary hormonal therapy with gonadorelin or an analogue is widely used for cryptorchidism. Systematic reviews’ suggest a success rate of about 20% overall, although this may be reduced when care is taken to exclude retractile testes. There is some suggestion that medical treatment given either before or after surgery can improve the patient’s fertility index, a predictor of future fertility.

Delayed and precocious puberty. For mention of the use of gonadorelin or its analogues in delayed and precocious puberty, and respectively. Benefit in delayed puberty is most likely in those cases where it is secondary to hypogonadism.

Diagnosis of hypothalamic and pituitary dysfunction.

Gonadorelin may be used in the diagnosis of hypothalamic -pituitary -gonadal dysfunction such as in hypogonadism, delayed puberty, and precocious puberty.

Disturbed behaviour. Gonadorelin analogues such as leuprorelin or triptorelin may be tried in men with paraphilias.

Endometriosis. Gonadorelin analogues are effective in the management of endometriosis, but the need for long-term therapy to prevent recurrence limits their value, because of the risk of osteoporosis. ‘Add-back’ therapy (hormone replacement) may be given in an attempt to reduce bone mineral density loss and vasomotor symptoms.

Fibroids. Uterine fibroids (leiomyomas) are benign tumours of uterine smooth muscle. They are found in about 25% of women, most of whom are aged in their 30s or 40s when the condition becomes symptomatic. Fibroids may give rise to menstrual problems, particularly menorrhagia, pelvic discomfort, infertility, and miscarriage. Although small fibroids may not require treatment, the management of symptomatic fibroids has traditionally been surgical. However, because fibroids are oestrogen responsive, gonadorelin analogues have also been tried as medical treatment for their ability to induce a hypogonadotrophic hypogonadal state. These drugs produce a significant reduction in uterine and fibroid volume, and amenorrhoea, but when treatment stops uterine and fibroid volume tend to return to pretreatment values. The hypoestrogenism produced during treatment also causes menopausal symptoms such as hot flushes and vaginal dryness, and bone loss may occur. Giving oestrogens or progestogens, once the uterine fibroid size has significantly reduced, has been tried as ‘add-back’ therapy to counteract these adverse effects. Tibolone has also been reported to reduce bone loss and vasomotor symptoms. Subcutaneous injection of long-acting depot preparations of gonadorelin or its analogues appears to be the preferred method and is considered a valuable pre-operative adjunct to surgery, simplifying the procedure by reducing uterine and fibroid volume and intra-operative blood loss, as well as correcting pre-operative iron-deficiency anaemia. However, concern has been expressed that the use of gonadorelin analogues for treating fibroids may complicate the differentiation of benign and malignant growths.

Other drugs that are under investigation for fibroids include gonadorelin antagonists such as cetrorelix and ganirelix, and mife-pristone. Danazol and gestrinone have also been tried in a small number of patients.

Growth retardation. The use of a gonadorelin analogue to delay precocious puberty may improve the final height of children with the disorder. However, the use of a gonadorelin analogue with growth hormone in short but otherwise normal children is controversial — see under Triptorelin.

Infertility. Gonadorelin and its analogues are used in the management of infertility related to hypogonadotrophic hypogonadism in both women and men. Some further references are given below. See also under Buserelin Acetate, Leuprorelin Acetate, and Nafarelin Acetate. For mention of the use of gonadorelin and its analogues in the management of infertility in polycystic ovary syndrome, see below.

Malignant neoplasms. Gonadorelin analogues are used in the treatment of prostatic cancer where they provide an alternative to orchidectomy in the management of advanced disease. They may also be used for ovarian ablation in premenopausal women with breast cancer. Gonadorelin analogues have been tried in neoplasms of the endometrium and ovary, but their use is much less well established. Analogues used include buserelin, goserelin, leuprorelin, and triptorelin.

Mastalgia. Gonadorelin analogues such as goserelin may be effective in severe refractory mastalgia.

Polycystic ovary syndrome. Gonadorelin and its analogues have been used in the management of infertility associated with polycystic ovary syndrome (see Infertility), even though some product information contra-indicates their use in this syndrome.

Pulsatile gonadorelin has been tried for ovulation induction but rates of ovulation and pregnancy are poor when it is used alone in women with polycystic ovary syndrome. Pretreatment with a gonadorelin analogue for pituitary desensitisation before starting pulsatile gonadorelin has shown some benefit in patients with polycystic ovary syndrome who have high levels of luteinising hormone. However, there is only limited clinical data from small short-term trials and case series on the use of pulsatile gonadorelin in these women.

Gonadorelin analogues may be used for pituitary desensitisation before the use of gonadotrophins for ovulation induction, and there is a suggestion that this strategy may improve pregnancy rates compared with gonadotrophins alone in women with polycystic ovary syndrome. Gonadorelin analogues are used also in ovarian stimulation protocols for assisted reproduction techniques.

Women with polycystic ovary syndrome are at increased risk of ovarian hyperstimulation syndrome and must be carefully monitored throughout the use of ovulation induction regimens.

Porphyria. For mention of the use of gonadorelin analogues to suppress cyclic premenstrual exacerbations of acute porphyria, see Buserelin, Nafarelin, and Triptorelin.

Premenstrual syndrome. In women in whom other drug treatments for premenstrual syndrome are ineffective, use of a gonadorelin analogue, usually with HRT as ‘add-back’ therapy to prevent menopausal symptoms, may be considered. Short-term therapy (3 months) has been used to confirm the diagnosis of premenstrual syndrome, or to predict the response to bilateral oophorectomy when this is being considered. Some references to the use of gonadorelin analogues in premenstrual syndrome are given below.

Preparations

The United States Pharmacopeia 31, 2008: Gonadorelin for Injection.

Proprietary Preparations

Argentina: Luteoliberina

Austria: Kryptocur Lutrele Relefact LH-RH

Belgium: HR †

Brazil: Parlib

Canada: Lutrepulse

Czech Republic: Relefact LH-RH

France: Lutrele Stimu-LH

Germany: Kryptocur Lutrele Relefact LH-RH

Greece: Relefact LH-RH

Hong Kong: Relisorm L

Hungary: Relisorm I

Israel: Lutrele Relefact LH-RH

Italy: Kryptocur Lutrele

The Netherlands: Cryptocur HR † Lutrele Relefact LH-RH

New Zealand: HR

South Africa: HR †

Spain: Luforan

Sweden: Lutrele

Switzerland: Kryptocur Lutrele Relisorm L

United Kingdom: HR †

USA: Factrel

Drug Approvals

(British Approved Name, rINN)

Pharmacopoeias. In Japan and US.

The United States Pharmacopeia 31, 2008 (Diethylstilbestrol Diphosphate). An off-white, odourless, crystalline powder. Sparingly soluble in water soluble in alcohol and in dilute alkali. Store in airtight containers at a temperature not exceeding 21°.

Fosfestrol Sodium

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In British, which specifies xH₂0.

British Pharmacopoeia 2008 (Fosfestrol Sodium). A white or almost white powder. Freely soluble in water practically insoluble in dehydrated alcohol and in ether. A 5% solution in water has a pH of 7.0 to 9.0. Protect from light.

Adverse Effects and Precautions

As for Diethylstilbestrol.

After intravenous injection of fosfestrol sodium there may be a temporary burning sensation in the perineal region and pain at the site of bony metastases. Slow infusion is not recommended as cytotoxic concentrations of the drug may not be achieved.

Uses and Administration

Fosfestrol is a synthetic nonsteroidal oestrogen that requires dephosphorylation to diethylstilbestrol before it is active. It is used in the treatment of malignant neoplasms of the prostate.

Fosfestrol and its sodium salt have both been used, and doses of fosfestrol sodium may be expressed in terms of either the base or the salt anhydrous fosfestrol sodium 300 mg is equivalent to about 250 mg of fosfestrol. Expressed in terms of fosfestrol sodium, initial doses of 600 to 1200 mg daily by slow intravenous injection over about 1 hour may be given for 5 to 10 days, followed by 300 mg daily for 10 to 20 days. Injections should be given preferably with the patient lying down. Maintenance intravenous doses of fosfestrol sodium 300 to 600 mg may be given, reduced gradually over several months from dosing 4 times a week to once weekly. Fosfestrol sodium may also be given orally. If initial doses cannot be given intravenously, doses of 360 to 480 mg three times daily have been given orally. For maintenance therapy, doses of 120 to 240 mg three times daily may be used, and gradually reduced to 240 mg daily.

Preparations

British Pharmacopoeia 2008: Fosfestrol Injection Fosfestrol Tablets

The United States Pharmacopeia 31, 2008: Diethylstilbestrol Diphosphate Injection.

Proprietary Preparations

Argentina: Fosfostilben Honvan

Austria: Honvan

Belgium: Honvan

Brazil: Ronvan †

Canada: Honvol

France: ST-52 †

Germany: Honvan

Greece: Honvan

Hong Kong: Honvan

India: Honvan

Mexico: Honvan †

The Netherlands: Honvan †

Port Honvan †

Spain: Honvan

Switzerland: Honvan

Folitropina FSH.

ATC Vet — QG03GA90.

Follitropin Alfa

Drug Approvals

(British Approved Name, rINN)

Folitropin Alfa; Folitropina alfa; Follitropine Alfa; Follitropinum Alfa.

Фоллитропин Альфа

Follitropin Beta

Drug Approvals

(British Approved Name, rINN)

Folitropin Beta; Folitropina beta; Follitropine Bêta; FollitropinumBeta; Org-32489.

Фоллитропин Бета

Units

80 units of human pituitary follicle-stimulating hormone are contained in about 4.17micrograms (with 5 mg of mannitol and 1 mg human serum albumin) in one ampoule ofthe first International Standard (1986). 138 units of recombinant human follicle-stimulating hormone for bioassay are contained in one ampoule of the first International Standard (1995).

Adverse Effects and Precautions

As for Human Menopausal Gonadotrophins.

Spongiform encephalopathies. In a few countries, gonadotrophins derived from cadaver pituitary glands have been used in the treatment of infertility, and a small number of patients are reported to have acquired Creutzfeldt-Jakob disease from such preparations.^l However, most countries have preferred to use gonadotrophins derived from urine, and these in their turn are being replaced with recombinant products such preparations appear to carry negligible risk of transmitting prion disease.

Pharmacokinetics

Follitropins alfa and beta are slowly absorbed after subcutaneous or intramuscular injection, with an absolute bioavailability of about 70 to 80%. Peak plasma concentrations of follitropin beta have been stated to occur about 12 hours after subcutaneous or intramuscular injection. Accumulation occurs with repeated doses, reaching a steady state within 3 to 5 days. Follitropins are slowly eliminated from the body, with a terminal half-life ranging from 12 to 70 hours. About one-eighth of a dose of follitropin alfa is reported to be excreted in the urine.

Uses and Administration

Follicle-stimulating hormone is secreted by the anterior lobe of the pituitary gland, with another gonadotrophin, luteinising hormone. These gonadotrophins stimulate the normal functioning ofthe gonads and the secretion of sexhormones in both men and women. In women, follicle-stimulating hormone stimulates the development and maturation ofthe follicles and ova in men it has a role in sperma-togenesis.

Recombinant human follicle-stimulating hormones (follitropins alfa or beta) are used in the treatment of female infertility due to anovulation, in women who have not responded to clomifene therapy. Follitropins are also used for the stimulation of spermatogenesis in the management of male infertility caused by hypogonadotrophic hypogonadism (see Infertility). The dosage and schedule of treatment for female infertility must be determined according to the needs of each patient it is usual to monitor response by studying the patient’s urinary oestrogen excretion or by ultrasonic visualisation of follicles or both. In menstruating patients treatment should be started within the first 7 days ofthe menstrual cycle.

• Treatment is usually begun with 75 to 150 units daily by subcutaneous or intramuscular injection for 7 or 14 days if there is no response, dosage is increased at 7- or 14-day intervals until an adequate but not excessive response is achieved.

• Treatment is then stopped and followed after 1 or 2 days by a single dose of chorionic gonadotrophin 5000 to 10 000 units to induce ovulation.

It has been suggested in UK licensed product information for follitropin alfa that a daily dose of 225 units is the usual maximum, and that if a patient fails to respond adequately after 4 weeks of treatment that cycle should be abandoned and the patient should subsequently begin the next cycle at a higher starting dose. Follitropins are also used as part of IVF or other assisted reproductive technologies.

• For this purpose doses of 150 to 225 units daily are generally given, for at least 4 days, commencing on the second or third day ofthe menstrual cycle. Thereafter the dose may be adjusted individually based on ovarian response to a usual maximum of about 450 units adequate follicular development generally occurs within about 5 to 10 days of treatment.

• Pituitary downregulation with a gonadorelin analogue may be used with follitropin therapy, in which case the gonadorelin analogue is generally begun about 2 weeks before follitropin, and the 2 are then continued together until follicular development is adequate.

• A single dose of up to 10 000 units of chorionic gonadotrophin is then given to induce final follicular maturation and oocyte retrieval performed about 35 hours later.

Follitropins are used for the stimulation of spermatogenesis in the management of male infertility caused by hypogonadotrophic hypogonadism. Before starting follitropin therapy, chorionic gonadotrophin is given to raise serum testosterone concentrations to the normal range, which may take 3 to 6 months. A dose of follitropin alfa or beta of 150 units subcutaneously three times weekly is then used, with continued chorionic gonadotrophin doses of follitropin alfa up to 300 units three times weekly may be required. Treatment is continued for at least 4 months, and more than 18 months of treatment may be needed. A dose of follitropin beta 75 units daily or two or three times weekly, by subcutaneous or intramuscular injection, has been used similarly.

Other substances with follicle-stimulating activity are used similarly: these include human menopausal gonadotrophins, which have both luteinising and follicle-stimulating activity, and urofollitropin.

Preparations

Proprietary Preparations

Argentina: Gonal † Puregon

Australia: Gonal † Puregon

Austria: Gonal † Puregon

Belgium: Gonal † Puregon

Brazil: Gonal † Puregon

Canada: Gonal † Puregon

Chile: Gonal-F Puregon

Czech Republic: Gonal † Puregon

Denmark: Gonal † Puregon

Finland: Gonal † Puregon

France: Gonal † Puregon

Germany: Gonal † Puregon

Greece: Gonal † Puregon

Hong Kong: Gonal † Puregon

Hungary: Gonal † Puregon

India: Gonal †

Indonesia: Gonal † Puregon

Ireland: Gonal † Puregon

Israel: Gonal † Puregon

Italy: Gonal † Puregon

Malaysia: Gonal † Puregon

Mexico: Gonal † Puregon

The Netherlands: Gonal † Puregon

Norway: Gonal † Puregon

New Zealand: Gonal † Puregon

Philippines: Gonal † Puregon

Poland: Gonal † Puregon

Portugal: Gonal † Puregon

Russia: Gonal † Puregon

South Africa: Gonal † Puregon

Singapore: Gonal † Puregon

Spain: Gonal † Puregon

Sweden: Gonal † Puregon

Switzerland: Gonal † Puregon

Thailand: Gonal † Puregon

Turkey: Gonal † Puregon

United Kingdom: Gonal † Puregon

USA: Follistim Gonal †

Venezuela: Gonal † Puregon

Multi-ingredient

Czech Republic: Pergoveris

Portugal: Pergoveris

UK: Pergoveris

Drug Approvals

(British Approved Name, rINN)

Pharmacopoeias. In China, and US. Europe includes the hemihydrate.

European Pharmacopoeia, 6th ed. (Estradiol Hemihydrate). A white or almost white crystalline powder or colourless crystals. Practically insoluble in water sparingly soluble in alcohol soluble in acetone slightly soluble in dichloromethane.

The United States Pharmacopeia 31, 2008 (Estradiol). White or creamy-white, odourless, hygroscopic small crystals or crystalline powder. Practically insoluble in water soluble 1 in 28 of alcohol, 1 in 435 of chloroform, and 1 in 150 of ether soluble in acetone, in dioxan, and in solutions of fixed alkali hydroxides sparingly soluble in vegetable oils. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Estradiol Acetate

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

Drug Nomenclature

Estradiol Benzoate

(British Approved Name Modified, rINNM)

Drug Nomenclature

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

European Pharmacopoeia, 6th ed. (Estradiol Benzoate). An almost white crystalline powder or colourless crystals. It exhibits polymorphism. Practically insoluble in water sparingly soluble in acetone freely soluble in dichloromethane slightly soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Estradiol Benzoate). A white to off-white, crystalline powder. Insoluble in water soluble in alcohol and in acetone slightly soluble in ether. Store in airtight containers. Protect from light.

Estradiol Cipionate

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Estradiol Cypionate). A white to practically white crystalline powder, odourless or has a slight odour. Insoluble in water soluble 1 in 40 of alcohol, 1 in 7 of chloroform, and 1 in 2800 of ether soluble in acetone and in dioxan sparingly soluble in vegetable oils. Store in airtight containers. Protect from light.

Estradiol Dipropionate

Drug Approvals

(British Approved Name Modified, rINNM)

Estradiol Enantate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Estradiol Hexahydrobenzoate

Drug Approvals

(British Approved Name Modified, rINNM)

Estradiol Phenylpropionate

Drug Approvals

(British Approved Name Modified, rINNM)

Estradiol Valerate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Estradiol Valerate). A white or almost white, crystalline powder or colourless crystals. Practically insoluble in water soluble in alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (Estradiol Valerate). A white crystalline powder which is usually odourless or may have a faint fatty odour. Practically insoluble in water soluble in benzyl benzoate, in dioxan, in methyl alcohol, and in castor oil sparingly soluble in arachis oil and in sesame oil. Store in airtight containers. Protect from light.

Adverse Effects

The adverse effects of estradiol and other oestrogens are related, in part, to dose and duration of therapy, and to the gender and age of the recipient. In addition, adverse effects may be modified by a progestogen in combined oral contraceptives or menopausal HRT. Whether adverse effects of natural and synthetic oestrogens differ, and whether the dosage route has an effect, is less clear.

The adverse effects of oestrogens used in hormonal contraceptives are considered in detail starting. Those of oestrogens used in HRT are considered in detail starting. The use of oestrogens in children may cause premature closure of the epiphyses resulting in decreased final adult height.

Large doses of oestrogens used in palliation of cancers have also been associated with nausea, fluid retention, venous and arterial thrombosis, and cholestatic jaundice. In men, they cause impotence and feminising effects such as gynaecomastia. In women, they may cause withdrawal bleeding, and, when used for breast cancer, they have caused hypercalcaemia and bone pain.

Effects on the skin. Transdermal patches in which estradiol is dissolved in the adhesive matrix may cause fewer skin reactions than those releasing estradiol from an alcoholic reservoir.

Precautions

The precautions for the use of estradiol and other oestrogens used as menopausal HRT are considered in detail starting. Those for oestrogens used in hormonal contraceptives are considered in detail starting.

High doses of oestrogen used in treating malignant disease should be used cautiously in patients with cere-brovascular disorders, coronary artery disease, or venous thromboembolism. They may exacerbate hypercalcaemia of malignancy. Oestrogens should be used with caution in children because premature closure of the epiphyses may occur resulting in inhibited linear growth and small stature. Oestrogens have been reported to interfere with some diagnostic tests such as those for thyroid function and glucose tolerance.

Breast feeding. Estradiol has been detected in breast milk after the use of pessaries containing 50 or 100 mg of estradiol. The American Academy of Pediatrics considers that estradiol is usually compatible with breast feeding.

Cosmetic use. Use of cosmetic products containing oestrogens has led to adverse effects such as precocious puberty in children and gynaecomastia or postmenopausal bleeding in adults. Such products have been used by a greater proportion of African Americans than any other ethnic group in the USA, and it has been hypothesised that this may have contributed to the observations of earlier onset of puberty in girls’ and increased risk of breast cancer in young women

Porphyria. Oestrogens are considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrfnogenicity.

Pregnancy. Although gross abnormalities of the genito-urinary tract have been reported in the male offspring of women who took diethylstilbestrol during pregnancy there is conflicting evidence as to whether the oestrogen produced an increased risk of abnormalities, infertility, or testicular cancer in such offspring. The male fetus is normally protected from the feminising effects of the natural oestrogens in the uterine environment by the early development of the testes and the secretion of male hormones. However, there has been considerable concern about a rising incidence of disorders of the male reproductive tract, and a reduction in sperm counts, which has been noted in the last 20 to 30 years. It has been hypothesised that overexpo-sure of male fetuses to environmental oestrogens derived from pollutants such as pesticides and plastics may be responsible for this decline, although some dispute this A systematic review of epidemiological data found no strong evidence to link fetal exposure to oestrogens (as pharmaceuticals or pollutants) with reduced sperm count, cryptorchidism, or hypospadias, although there was some evidence to support a possible link with testicular cancer.

For discussion of the lack of effects of hormonal contraceptives on the fetus, including evidence that they are unlikely to increase the risk of hypospadia in the male fetus, see Pregnancy, under Precautions of Hormonal Contraceptives.

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

There is concern about the effect of environmental oestrogens on male fertility and development, see Pregnancy, above.

Interactions

Interactions involving estradiol and other oestrogens used in menopausal HRT are covered. Interactions for oestrogens used in hormonal contraceptives are covered.

Pharmacokinetics

In general, estradiol and other oestrogens are readily absorbed from the gastrointestinal tract and through the skin or mucous membranes. However, the natural unconjugated oestrogens such as estradiol undergo extensive first-pass metabolism in the gastrointestinal tract and liver after oral doses. They are, therefore, generally not orally active, although a micronised preparation of estradiol has sufficient bioavailability (3 to 5%) to be orally active. Estradiol is metabolised in part to less active oestrogens such as estriol and estrone. Synthetic oestrogens produced by alkylation of the C17 position, such as ethinylestradiol, are more slowly metabolised and are therefore orally active. Conjugated oestrogens, which are essentially oestrogen metabolites, are also orally active because they are hydrolysed by enzymes in the lower gastrointestinal tract allowing absorption of the active oestrogen. Vaginal, transdermal, intranasal, or parenteral use of oestrogens also avoids first-pass hepatic metabolism. Plasma-estradiol concentrations are reported to reach a peak 1.5 to 2 hours after an oral dose, and again at about 8 hours due to enterohepatic recycling. Estradiol esters are rapidly hydrolysed to free estradiol when given orally. After intramuscular injection of the esters, absorption is prolonged.

Oestrogens are extensively bound to plasma proteins. Naturally occurring oestrogens such as estradiol are principally bound to sex-hormone binding globulin. Conversely, ethinylestradiol is mostly bound to albumin.

Oestrogens are metabolised in the liver. A variety of sulfate and glucuronide conjugates are formed, and these are excreted in the urine and the bile. Those excreted in the bile undergo enterohepatic recycling or are excreted in the faeces.

Uses and Administration

Estradiol is the most active of the naturally occurring oestrogens (for further details). Estradiol and its semisynthetic esters and other natural oestrogens are primarily used as menopausal HRT whereas synthetic derivatives such as ethinylestradiol and mestranol have a major role as components of combined oral contraceptives (see Hormonal Contraceptives). Estradiol may also be used as replacement therapy for female hypogonadism or primary ovarian failure. Replacement therapy (‘add-back’ therapy) may also be given to women in whom the pituitary-ovarian axis is suppressed by therapy with gonadorelin or its analogues.

Estradiol hemihydrate 1.03 mg is equivalent to about 1 mg of the anhydrous substance.

For menopausal HRT oral preparations or transdermal patches of estradiol are commonly used. Other transdermal formulations, subcutaneous implants, and a nasal spray are also available. Intramuscular injections were formerly used. In women with a uterus, a progestogen is also required, given cyclically or continuously, usually by mouth although some combined transdermal preparations are available. Local vaginal estradiol preparations are used specifically for the treatment of menopausal atrophic vaginitis these are generally recommended for short-term use only, if given without a progestogen in women with a uterus, although specific recommendations vary between products.

For use by mouth estradiol or estradiol valerate are normally given doses are 1 or 2 mg daily cyclically or more often continuously. Estradiol acetate may be given in an initial dose of 450 micrograms daily, increasing if necessary to 0.9 or 1.8 mg once daily.

Estradiol may be used topically as transdermal skin patches to provide a systemic effect a variety of patch-es are available which release between 25 and 100 micrograms of estradiol every 24 hours. A low-dose patch supplying 14 micrograms daily is also available specifically for the prevention of postmenopausal osteoporosis in women at significant risk with this low dose, the addition of a 14-day course of progestogen in women with a uterus is only required once every 6 to 12 months. Depending on the preparation, patches are replaced once or twice weekly. Each new patch is applied to a different area of skin in rotation, usually below the waistline patches should not be applied on or near the breasts. Topical gel preparations are also used for systemic effect. The usual applied dose is 0.25 to 1.5 mg of estradiol daily, depending on the preparation, but up to 3 mg daily may be required for control of menopausal symptoms in some women. The gel should not be applied on the face or on or near the breasts, vagina, or vulval region. A topical emulsion is also available estradiol hemihydrate 8.7 mg is applied daily to provide a systemic estradiol dose of about 50 micrograms. A transdermal spray has also been developed, delivering a single dose of estradiol 1.53 mg onto the skin. It should be applied to the skin of the inner surface of the forearm, and the dose may be increased up to 3 sprays once daily in the morning, at separate sites on the forearm, according to response.

A nasal spray is available, delivering 150 micrograms of estradiol hemihydrate per spray. The usual initial dose is 150 micrograms daily (1 spray in 1 nostril). After 2 or 3 cycles the dose may be adjusted according to response the usual maintenance dose is 300 micrograms daily (1 spray in each nostril once daily) but may range from 150 micrograms once daily up to 450 to 600 micrograms daily in 2 divided doses.

In order to prolong the duration of action subcutaneous implants of estradiol may be used. The dose of estradiol is generally 25 to 100 mg with a new implant being given after about 4 to 8 months according to oestrogen concentrations.

Estradiol may be used locally either as 25-microgram vaginal tablets, at an initial dose of one tablet daily for 2 weeks followed by a maintenance dose of one tablet twice a week, or as a 0.01% vaginal cream, in initial amounts of 2 to 4 g of cream daily for 1 to 2 weeks followed by half the initial dose for a similar period, then a maintenance dose of 1 g up to 3 times weekly. A local delivery system using a 3-month vaginal ring contains 2 mg of estradiol hemihydrate, and delivers about 7.5 micrograms of estradiol per 24 hours. Another 3-month vaginal ring system, which contains estradiol acetate, releases either 50 or 100 micrograms of estradiol daily, and is used for the relief of both local and systemic postmenopausal symptoms. Intramuscular injections of estradiol benzoate or valer-ate esters have been used as oily depot solutions, usually given once every 3 to 4 weeks. The cipionate, di-propionate, enantate, hexahydrobenzoate, phenylpropionate, and undecylate esters have been used similarly. The enantate and cipionate esters are used as the oestrogen component of combined injectable contraceptives.

Estradiol and other oestrogens have sometimes been used in higher doses for palliative treatment in prostate cancer and breast cancer in men and postmenopausal women.

Administration, buccal and sublingual administration.

Estradiol is absorbed through the buccal route, and has been reported to improve postmenopausal vasomotor symptoms. A pharmacokinetic study of micronised estradiol found the sublingual route resulted in more rapid absorption, a higher peak concentration, and more rapid elimination, than oral dosage. Sublingual micronised estradiol has been studied for the management of postpartum depression.

IMPLANTS. There may be a striking interpatient variation in blood-estradiol concentrations in women receiving estradiol implants, and symptoms of oestrogen deficiency have re-appeared in some patients even though serum-estradiol concentrations were within or above the physiological range. After debate on the appropriateness of using serum concentrations of estradiol as a guide to implant use, rather than symptoms, it is now recommended that estradiol concentration should be monitored during therapy.

Cyclical progestogen may be required for a prolonged period after removal of estradiol implants in women with a uterus.

INTRANASAL ADMINISTRATION. The intranasal route for estradiol HRT has been reviewed. It appears to be comparable in efficacy to oral or transdermal use in the treatment of meno-pausal symptoms. As with transdermal application, the intranasal route avoids intestinal and hepatic first-pass metabolism.

TRANSDERMAL ADMINISTRATION. Transdermal estradiol given via patches applied to the skin has been reviewed. This method of delivery has certain advantages over the oral route in that gastrointestinal and hepatic first-pass metabolism is

avoided, liver enzymes are not stimulated (although this may also mean that beneficial effects on serum lipids are absent), and the prolonged drug release from the patch means less frequent application is necessary and hence patient compliance may be improved. For oestrogen replacement in menopausal and postmenopausal women estradiol patches are used continuously or in a cyclical manner, with added progestogen for part of the cycle in those women with an intact uterus. This does not lead to drug accumulation and produces blood-estradiol concentrations and estradiol to estrone ratios similar to those normally observed in premenopausal women. The patch is well tolerated with skin irritation being the main problem. Patches are as effective as oral oestrogens in treating menopausal and postmenopausal symptoms such as flushing and vaginal atrophy and in preventing osteoporosis. Combined HRT patches, providing both estradiol and a progestogen, have also been developed.

Estradiol is also effective when applied topically to the skin as a gel or emulsion.

Depression. The use of oestrogen therapy in the treatment of premenopausal women with postnatal depression has been shown to be effective. However, although such therapy could be a useful adjunct to conventional treatment (see Depression), the risk of serious adverse effects including thrombosis may limit its value.

Whether oestrogens are of benefit in older women, typically with depression associated with the menopause, is less clear. Some studies of transdermal estradiol have reported benefit, whereas other studies of transdermal or oral dosage have not found it to be effective. Whether the presence of a progestogen in combination HRT would reduce any purported benefit is also unclear. Antidepressants remain the standard of care in perimen-opausal or postmenopausal women with clinical depression.

Gender reassignment. Oestrogens are used in male-to-female transsexuals to develop and maintain secondary sexual characteristics. Although ethinylestradiol and conjugated oestrogens have been used for this purpose, and there is some evidence that such use can improve vascular function, others consider ethinylestradiol too thrombogenic at the doses required [typically 50 to 100 micrograms daily or more] and suggest that estradiol, as the valerate in oral doses of 2 to 4 mg daily, or transdermally as a patch supplying 100 micrograms daily, is the oestrogen of choice. Cyproterone acetate is usually also given for its anti-androgenic effect.

Growth disorders. Supraphysiological doses of oestrogens inhibit somatic growth and have been used, with a cyclical progestogen, to reduce final height in girls with constitutional tall stature, although such treatment has declined markedly with changing social norms. In early reports, diethylstilbestrol was used, but this is an unsuitable choice because of the increased risk of cancer. Ethinylestradiol has been given in the past in doses of up to 500 micrograms daily, but doses of 50 to 100 micrograms daily came to be preferred, although lower doses may be equally effective. Conjugated oestrogens have also been used, and a study reported that doses of 7.5 to 11.25 mg daily resulted in an average decrease of about 5 cm from final predicted height. In practice, doses as low as 625 micrograms daily have been used. Reported height reductions have ranged from 2 to 10 cm but studies are difficult to compare. Treatment has generally been continued until closure of the epiphyses, but the effects of oestrogen therapy may be influenced by both chronological and bone age at the onset of treatment, duration of treatment, the oestrogen used and its dose, and the point of final height assessment. High-dose oestrogen therapy is also associated with adverse effects such as weight gain, headache, nausea, and pigmentation of the areolae or nipples, and there can be adverse changes to haemostatic and lipid measures. A retrospective cohort review has also reported that girls who had been treated with high-dose oestrogens were more likely to report fertility problems in later life than similar girls who had not been treated.

Oestrogen therapy has occasionally been used to help promote growth in girls with constitutional delayed puberty.

Haemorrhagic disorders. Limited evidence supports the use of oestrogens in various bleeding disorders. There have been mixed results from small studies of oestrogens, given alone or with a progestogen, in patients with hereditary haemorrhagic telangiectasia the use of a combined oral contraceptive has been suggested as a suitable option for fertile women with symptomatic epistaxis. There are also some reports of bleeding being reduced in patients with gastrointestinal vascular malformations from other causes. Conjugated oestrogens have been used in haemorrhagic disorders associated with chronic renal failure and haemorrhagic cystitis.

Lactation inhibition. Synthetic oestrogens (e.g. quinestrol) and nonsteroidal oestrogens (e.g. diethylstilbestrol) were historically used to suppress lactation. However, this use is now considered inappropriate because of an increased risk of puerperal thromboembolism.

Premenstrual syndrome. Premenstrual syndrome (PMS) presents as a variable combination of psychological and somatic symptoms occurring during the luteal phase of the menstrual cycle, which resolve during, and immediately after, menstruation. Another term, premenstrual dysphoric disorder, has been proposed to cover severe cyclical mood disorder that is functionally incapacitating. Whereas about 20 to 40% of women have complaints that may be classified as PMS, only 3 to 8% meet criteria for premenstrual dysphoric disorder. The term premenstrual tension (PMT) has sometimes been applied to the psychological symptoms. Many symptoms of PMS are the same as normal premenstrual symptoms, but are more severe. The aetiology of PMS is not fully understood, although it is thought that affected women may be more sensitive to the effects of normal hormonal fluctuations on CNS neurotransmitter function.

Initial management includes non-medical interventions such as education and support, counselling, stress management, relaxation techniques, and exercise caffeine and salt restriction are of unproven benefit. The herbal remedy agnus castus has been found to be of benefit For patients with moderate to severe symptoms, a number of drugs have been tried with varying degrees of success objective assessment of efficacy has been hampered by varying diagnostic criteria, a marked placebo response, and difficulties in obtaining reproducible responses. Treatment may be aimed at modifying the menstrual cycle or treating specific symptoms.

In women with mainly psychological symptoms, SSRIs can be helpful. Fluoxetine and sertraline have been shown in controlled studies to alleviate both psychological and somatic symptoms in women with PMS, and may be given intermittently (only in the luteal phase) or continuously. If treatment with one SSRI is ineffective or not tolerated, another SSRI or venlafaxine may be substituted. ‘^e There is limited information on the use of S S-RIs for PMS in adolescents, and precautions regarding suicidal ideation in young adults should be considered. Clomipramine, a nonselective serotonin reuptake inhibitor, has been tried for PMS with some success. The anxiolytic alprazolam has also been used, but use of this and other benzodiazepines should be restricted to the luteal phase of the cycle in selected patients to minimise the risk of dependence and tolerance.

Abdominal bloating and swelling associated with PMS has traditionally been thought to be due to sodium and water retention. However, in most women with these symptoms there is no evidence of an increase in body-weight or in body sodium or total water, and use of diuretics is therefore not justified. Nevertheless, in women with appreciable weight gain and abdominal bloating in the luteal phase, the aldosterone antagonist spironol-actone may be useful. Another symptom of PMS, cyclical mastalgia, is discussed.

Pyridoxine has been tried on the basis that it is a cofactor in neu-rotransmitter (specifically serotonin) synthesis, and has been found to relieve depression induced by oral contraceptives in selected patients. However, its efficacy in PMS is equivocal, and high daily doses have been associated with neurotoxicity. Calcium supplementation may relieve symptoms of PMS.

Treatments that modify the menstrual cycle have often been used in women with PMS. In general, drugs with proven efficacy such as danazol, oestrogen implants, and gonadorelin analogues are reserved for women with severe PMS unresponsive to other treatments, because of their adverse effects. Progestogen therapy was once popular, but beneficial responses have not been universally achieved and the theory that progesterone was necessary to correct a hormone imbalance is now losing ground. In addition, a systematic review of clinical trials found no evidence to support the use of progesterone or progestogens for PMS. Combined oral contraceptives have met with limited success. They may be useful in some women for the control of somatic symptoms, but in others, PMS is caused or exacerbated by them. There is some suggestion that combined contraceptives containing dros-pirenone may be more effective in managing PMS than those containing progestogens such as levonorgestrel or norethister-one. Consideration should be given to continuous rather than cyclical use. Perimenopausal women may benefit from oestrogen delivered from transdermal patches. In women with a uterus, use with a cyclical progestogen is required to avoid endometrial hyperplasia unfortunately, the progestogen may be associated with the return of symptoms. Possible strategies to minimise this include the use of a less androgenic progestogen, reducing the frequency with which it is given, or using an intra-uterine device to deliver the progestogen locally. Danazol can be useful, but there is concern over its adverse effects on lipids during long-term use and over the risk of masculinisation of a female fetus should pregnancy occur. For patients with severe symptoms not amenable to other treatments, gonadorelin analogues such as goserelin can be used to eliminate ovarian function, ‘add-back’ treatment with oestrogen plus progestogen being given to protect against the adverse effects of oestrogen deficiency including osteoporosis. This treatment is very effective for both physical and psychological symptoms. Short-term use (3 months) of a gonadorelin analogue alone has been used to confirm the diagnosis of PMS, or to predict the response to bilateral oophorectomy.

Preparations

British Pharmacopoeia 2008: Estradiol and Norethisterone Acetate Tablets; Estradiol and Norethisterone Tablets; Estradiol Injection; Estradiol Transdermal Patches

The United States Pharmacopeia 31, 2008: Estradiol and Norethindrone Acetate Tablets; Estradiol Cypionate Injection; Estradiol Injectable Suspension; Estradiol Pellets; Estradiol Tablets; Estradiol Transdermal System; Estradiol Vaginal Cream; Estradiol Valerate Injection.

Proprietary Preparations

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

Argentina: Aerodiol; Climaderm¤; Disequens; Estraderm; Estradot; Estreva; Estring¤; Estrofem; Etrosteron; Eutocol; Evorel; Fem 7; Ginatex; Hormodiol; Lindisc; Oestro Gel; Progynon; Progynova; Replasyn; Ronfase; Rontagel; Transdiol¤; Trial Gel; Trial Sat; Australia: Aerodiol; Climara; Dermestril; Estraderm; Estradot; Estring¤; Estrofem; Femtran; Menorest; Primogyn Depot; Progynova; Sandrena; Vagifem; Zumenon; Austria: Aerodiol; Climara; Cycloderm; Dermestril; Duokliman; Estracutan; Estraderm; Estradot; Estramon; Estring¤; Estrofem; Estrogel; FemSeven; FemSieben; Klimapur; Klimareduct; Linoladiol; Menorest; Merimono; Oesclim¤; Progynon; Progynova; Sandrena¤; Sterigin; Substitol¤; Systen; Vagifem; Zerella; Zumenon; Belgium: Aerodiol; Climara; Dermestril; Estraderm; Estreva; Estrofem; Feminova; Meno-Implant; Oestrogel; Progynova; Systen; Vagifem; Vivelle; Zumenon; Brazil: Aerodiol; Avicis; Benzo-Ginoestril; Climaderm; Estradelle; Estraderm; Estradot; Estreva; Estrofem; Fem 7; Ginedisc¤; Hormodose; Lindisc; Menorest¤; Merimono; Natifa; Oesclim¤; Oestrogel¤; Primogyna; Reglovar¤; Riselle; Sandrena; Systen; Canada: Climara; Delestrogen; Estrace; Estraderm; Estradot; Estring; Estrogel; Femogex¤; Oesclim; Vagifem; Vivelle¤; Chile: Climaderm; Cyclobiol; Dermatrans; Enadiol; Epiestrol; Estranova E; Estreva; Farlutes; Fem 7; Femalon; Femiderm; Femidott; Ginoderm; Mirion; Oesclim¤; Primaquin; Primofol Depot¤; Primogyna¤; Progynova; Sandrena; Transvital; Vagifem; Czech Republic: Agofollin; Climara; Dermestril; Divigel; Elleste; Estrace; Estraderm; Estrahexal; Estreva; Estrimax; Estring; Estrofem; Fem 7; Linoladiol N; Menorest; Neofollin; Octodiol; Oesclim; Oestrogel; Riselle; Systen; Vagifem; Denmark: Aerodiol; Climara; Divigel; Estraderm; Estring; Estrofem; Estrogel; Evorel; Femanest; FemSeven¤; Menorest¤; Progynon; Sandrena; Vagifem; Vivelle Dot; Finland: Climara; Dermestril; Divigel; Estraderm; Estradot; Estrena; Estring; Estrofem; Estrogel; Evorel; FemSeven; Menorest¤; Merimono; Progynova; Vagifem; Zumenon; France: Aerodiol; Benzo-Gynoestryl¤; Climara; Delidose; Dermestril; Estraderm; Estrapatch; Estrofem; Evafilm¤; Femsept; Menorest; Oesclim; Oestrodose; Oestrogel; Oromone; Progynova; Provames; Systen; Thais; Vivelledot; Germany: Aerodiol; Cerella¤; Cutanum; Dermestril; Ephelia; Estrabeta; Estraderm; Estradot; Estramon; Estreva; Estrifam; Estring; Estronorm; Evorel; Fem 7; Femoston mono; Gynokadin; GynPolar; Linoladiol N; Menorest; Merimono; Pantostin; Progynon B¤; Progynon Depot 100¤; Progynon Depot 10; Progynon Depot 40¤; Progynova; Sandrena; Sisare mono; Tradelia; Vagifem; Greece: Aerodiol; Dermestril; Estraderm TTS¤; Estradot; Estramon; Estring¤; Estrofem; Estrogel; Menorest; Oesclim¤; Oestrogel; Vagifem; Hong Kong: Aerodiol¤; Bisteron¤; Dermestril; Estraderm; Estreva; Estrofem; Fem 7¤; Oestrogel; Progynova; Hungary: Calidiol; Dermestril; Divigel; Estraderm; Estradot; Estramon; Estrimax; Estrofem; Linoladiol N; Oesclim; Oestrogel; Systen; Triaklim; Vagifem; India: Estraderm; Ireland: Aerodiol; Climara; Dermestril; Divigel; Epiestrol¤; Estraderm; Estradot; Estramon¤; Estrofem; Evorel; Fematab; Fematrix¤; Menorest¤; Oestrogel; Progynova¤; Vagifem; Israel: Climara¤; Dermestril; Estraderm; Estrofem; Evorel; Meno-Patch¤; Oestrodose; Oestrogel; Progynova; Vagifem; Italy: Aerodiol; Armonil; Benztrone¤; Climara; Dermestril; Ephelia; Epiestrol; Esclima; Estraderm; Estroclim; Estrodose; Estrofem; FemSeven; Gelestra; Ginaikos; Menorest; Progynon B¤; Progynon Depot¤; Progynova; Sandrena; Sprediol; Systen; Vagifem; Zerella; Malaysia: Divigel; Estrofem; Oestrogel; Progynova; Trisequens; Mexico: Armistor; Benzo-Ginestryl; Climaderm; Essventia; Estraderm; Estramon; Estreva; Evorel; Fem 7; Ginedisc; Oestrogel; Primogyn; Sandrena; Systen; Monaco: Estreva; Netherlands: Aerodiol; Climara; Dermestril; Dimenformon¤; Estraderm; Estradot; Estring¤; Estrofem; Fem 7; Femring; Meno-Implant; Menorest; Progynon Depot 100¤; Progynon Depot 10¤; Progynova; Sandrena; Systen; Vagifem; Zumenon; Norway: Climara; Estraderm; Estradot; Estring; Evorel; Menorest¤; Progynova; Vagifem; New Zealand: Aerodiol; Climara; Estraderm; Estring¤; Estrofem; Femtran; Progynova; Sandrena¤; Vagifem¤; Portugal: Climara; Dermestril; Estraderm; Estradot; Estrofem; Estronar¤; Menorest; Vagifem; Zumenon; Russia: Climara (Климара); Divigel (Дивигель); Estrimax (Естримакс); Estrofem (Естрофем); Oestrogel (Естрожель); South Africa: Climara; Estraderm; Estring; Estro-Pause; Estrofem; Evorel; Femigel; Menorest¤; Primogyn Depot; Progynova; Vagifem; Singapore: Divigel; Estraderm; Estreva; Estrofem; Fem 7¤; Oestrogel; Progynova; Vagifem; Spain: Absorlent; Alcis; Cliogan; Dermestril; Endomina; Esotran¤; Esprasone; Estraderm; Estradot; Estroffik; Evopad; Menorest¤; Meriestra; Oestraclin; Oestrodose¤; Progynon Depot¤; Progynova; Vagifem; Sweden: Climara; Divigel; Estraderm; Estradot; Evorel; Femanest; FemSeven; Menorest¤; Oesclim; Oestring; Progynon; Vagifem; Switzerland: Aerodiol; Cerina; Climara; Dermestril; Divigel; Epiestrol¤; Estraderm; Estradot; Estramon; Estreva; Estring; Estrofem N; Fem 7; FemSeven¤; Menorest; Oestrogel; Progynon Depot 100¤; Progynon Depot 10¤; Progynova; Sandrena; Systen; Vagifem; Zumenon; Thailand: Climara; Divigel; Estrofem; Oestrogel; Progynon; Progynova; Vagifem; United Kingdom: Adgyn Estro¤; Aerodiol; Bedol; Benztrone¤; Climaval; Dermestril¤; Elleste-Solo; Estraderm; Estradot; Estring; Evorel; Fematrix; FemSeven; FemTab; Menorest¤; Menoring¤; Oestrogel; Progynova; Sandrena; Vagifem; Zumenon; United States: Alora; Climara; Deladiol¤; Delestrogen; depGynogen; Depogen; Dioval¤; Dura-Estrin¤; Duragen¤; E-Cypionate¤; Esclim; Estra-D¤; Estra-L¤; Estrace; Estraderm; Estrasorb; Estring; Estro-Cyp¤; Estrogel; Estroject¤; FemPatch; Femring; Femtrace; Gynodiol; Gynogen¤; Menaval¤; Menostar; Vagifem; Valergen; Vivelle; Venezuela: Aerodiol; Climaderm; Estraderm; FemSeven

Multi-ingredient Preparations

Argentina: Activelle; Angeliq; Atrimon; Ciclocur; Climene; Cristerona; Dilena; Dos Dias N; Estalis Sequi; Estalis; Estracomb; Estragest; Evorel Conti; Evorel Sequi; Farludiol Ciclo; Farludiol; Fem 7 Combi; Fempack; Gynodian Depot; Hosterona; Kliogest; Lubriderm; Menstrogen; Mesigyna; Perlutal; Plenifem¤; Prefest; Primosiston; Supligol NF; Supligol¤; Totelle Ciclico; Totelle Continuo; Trial Combi; Trial Gest; Trial Pack¤; Trisequens; Australia: Angeliq; Climen; Divina¤; Estalis Continuous; Estalis Sequi; Estracombi; Estrapak¤; Femoston; Kliogest; Kliovance; Primodian Depot¤; Trisequens; Austria: Activelle; Climabelle; Climen; Climodien; Cyclacur; Estalis Sequens; Estalis; Estandron¤; Estracomb; Estragest¤; Femipak; Femoston Conti; Femoston; Femphascyl conti; Femphascyl; FemSeven Combi; Filena; Gravibinon¤; Gynodian Depot; Ichth-Oestren¤; Kliogest; Lafamme; Liseta; Mericomb; Merigest; Minique; Novofem; Ostrolut¤; Perikliman; Primodian Depot¤; Totelle cyclo¤; Tri-Filena¤; Trisequens; Belgium: Activelle; Climen; Climodien; Cyclocur; Dimenformon; Diviplus¤; Diviva¤; Estracombi; Feminova Plus; Femoston Conti; Femoston; Kliogest; Novofem; Totelle Cycle; Trisequens; Trivina¤; Brazil: Activelle; Cicloprimogyna; Ciclovular¤; Cliane; Climene; Cyclofemina; Dilena; Elamax; Estalis SQ; Estalis; Estandron P; Estracomb; Estragest; Evitas¤; Femineo; Femoston Conti; Femoston; Gestadinona; Ginecoside¤; Ginedisc 50 Plus¤; Hormoginase¤; Kliogest; Lindisc Duo¤; Mericomb; Merigest; Mesigyna; Natifa Pro; Normomensil¤; Perlutan; Postoval; Prefest; Preg-Less; Progest¤; Suprema; Systen Conti; Systen Sequi; Trinestril; Trisequens; Unalmes; Uno-Ciclo; Canada: Climacteron; Duogex LA¤; Estalis Sequi; Estalis; Estracomb; Estrand¤; Neo-Pause¤; Chile: Activelle; Agurin; Avaden; Cliane; Climene; Cyclofem; Enadiol CC; Enadiol MP; Enadiol Neta; Estandron Prolongado; Estracomb; Estragest; Estranova 30 Simple; Estranova CC; Farlupost; Fem 7 Combi; Femoston Conti; Femoston; Ginefolin; Gravidinona¤; Gynodian Depot; Kilios; Kliogest; Mesigyna; Novafem; Postoval; Primaquin MP Continuo; Primaquin MP; Progyluton; Totelle Continuo; Totelle; Trisequens; Unalmes¤; Czech Republic: Activelle; Aknefug; Alpicort F; Avaden; Climara Duo; Climen; Convaden; Cyclo-Menorette; CycloOstrogynal; Divina; Diviseq; Estalis Sequi; Estalis; Estrace Plus; Estrace-C; Estracomb; Estragest; Femoston; Folivirin; Gynodian Depot; Indivina; Kliane; Klimodien; Klimonorm; Kliogest; Linoladiol-H N; Pausogest; Systen Conti; Systen Sequi; Triaklim; Trisequens; Denmark: Activelle; Climen; Climodien; Cyclo-Progynon; Divina Plus; Divina; Estracomb; Evo-Conti; Evo-Sequi; Femanor; Femasekvens; Indivina; Klimalet; Klimaxil¤; Kliogest; Novofem; Nuvelle; Ostranorm¤; Totelle; Trevina; Trinorm¤; Trisekvens; Finland: Activelle; Climara Duo¤; Cyclabil; Divina; Divitren; Estalis Sekvens; Estalis; Estracomb¤; Evorel Conti; Evorel Sequi; Femilar; Femoston Conti; Femoston; FemSeven Combi; Indivina; Kliogest; Mericomb; Merigest; Novofem; Senikolp¤; Totelle Sekvens; Trisekvens; France: Activelle; Avadene; Climaston; Climaston; Climene; Climodiene; Divina; Diviseq; Duova; FemseptCombi; Gravibinan¤; Gynodian Depot¤; Kliogest; Naemis; Novofemme; Successia¤; TOM¤; Trisequens; Germany: Acetonal Vaginale¤; Activelle; Aknefug-Emulsion¤; Alpicort F; Androfemon¤; Climen; Climodien; Clionara; Crinohermal fem; Cyclo-Menorette; Cyclo-Progynova; CycloOstrogynal; CycloPolar¤; Ell-Cranell¤; Estalis Sequi; Estracomb; Estrafemol; Estragest; Fem 7 Combi; Femoston Conti; Femoston; Fissan-Brustwarzensalbe¤; Gianda; Gravibinon¤; Gynamon; Gynodian Depot; Ichth-Oestren¤; Indivina; Jephagynon¤; Klimonorm; Kliogest N; Lafamme; Linoladiol-H N; Lynandron¤; Malun¤; Mericomb; Merigest; NeoOstrogynal; NeyNormin N (Revitorgan-Dilutionen N Nr 65); Novofem; Osmil; Ostronara; Ovatest¤; Primodian Depot¤; Primosiston¤; Procyclo; Sebohermal¤; Sisare 28; Sisare; Syngynon¤; Trisequens; Vitrena; Greece: Activelle; Angeliq; Climodien; Cyclacur; Divina; Estalis; Estopause; Estracomb TTS; Femaston; Kliogest; Nuvelle¤; Systen Conti; Systen Sequi; Trisequens; Hong Kong: Activelle; Climen 28; Dilena; Estracomb; Femoston; Hormonin; Klimonorm¤; Kliogest; Progestrol¤; Trisequens; Hungary: Activelle; Alpicort F; Climen; Cyclo-Menorette; Divina; Divitren; Estracomb; Estragest; Femoston; Klimodien; Klimonorm; Kliogest; Linoladiol-H N; Pausogest; Trisequens; India: Kemicetine Antiozena; Mixogen; Ireland: Activelle; Cyclo-Progynova¤; Diviseq¤; Estalis Sequi; Estalis; Estracombi; Estrapak¤; Evorel Conti; Femoston Conti; Femoston; Femplan-MA¤; Indivina; Kliogest; Novofem; Nuvelle; Tridestra¤; Trisequens; Israel: Activelle; Evorel Conti; Evorel Sequi; Kliogest; Meno-MPA¤; Meno-Net¤; Novofem; Progyluton; Trisequens; Italy: Ablacton¤; Activelle; Biormon¤; Climen; Clym-Depositum¤; Combiseven; Cyclacur¤; Duo-Ormogyn¤; Estalis Sequi; Estandron¤; Estiamen B¤; Estiamen¤; Estracomb; Femoston Conti; Femoston; Filena; Gravibinan; Gynodian Depot; Kliogest; Menovis; Nuvelle TS¤; Nuvelle; Pausene; Primodian Depot¤; Tesor-C¤; Totelle; Trisequens; Malaysia: Activelle; Climen; Femoston; Klimonorm; Kliogest; Progyluton; Mexico: Anafertin; Binodian; Cliane; Climene; Cyclofemina; Damax; Despamen; Dilena; Estracomb; Estrapak¤; Evorel Conti; Ginoplan¤; Gravidinona; Lutalmin; Lutoginestryl F; Mesigyna; Metrigen Fuerte; Ominol¤; Patector; Perludil; Perlutal; Prefest; Primosiston; Primoson-F; Progediol; Proger-F; Progyluton; Totelle Continuo; Totelle Secuencial; Yectames; Monaco: Trioestrine-Retard¤; Netherlands: Activelle; Angeliq; Avaden; Climene; Cyclocur; Dimenformon Prolongatum¤; Divina¤; Estandron Prolongatum; Estracomb; Fem 7 Sequi; Femoston; Kliogest; Naemis; Novofem; Trisequens; Zumeston¤; Norway: Activelle; Climen; Climodien; Cyclabil; Diviseq¤; Estalis Sekvens; Estalis; Estracomb¤; Indivina; Kliogest; Novofem; Totelle Sekvens; Trisekvens; New Zealand: Cliane; Estrapak¤; Kliogest; Kliovance; Nuvelle; Trisequens; Portugal: Activelle; Cicnor; Climara Duo; Climen; Climodien; Dilena; Emmenovis; Estalis Sequi; Estalis; Estracomb; Femoston 1/5; Femoston 2/10; Kliogest; Nuvelle; Progyluton; Trisequens; Russia: Climen (Климен); Climodien (Климодиен); Cyclo-Progynova (Цикло-прогинова); Divina (Дивина); Diviseq (Дивисек); Divitren (Дивитрен); Femoston (Фемостон); Femoston 1/5 (Фемостон 1/5); Gynodian Depot (Гинодиан Депо); Indivina (Индивина); Klimonorm (Климонорм); Pausogest (Паузогест); Triaklim (Триаклим); Trisequens (Трисеквенс); South Africa: Activelle; Angeliq; Climen; Divina; Estracombi; Estro-Pause N; Evorel Conti; Evorel Sequi; Femoston; Kliogest; Mixogen; Postoval; Prefesta; Primodian Depot; Trisequens; Trivina; Singapore: Activelle; Climen; Estracomb; Femoston; Kliogest; Progyluton; Trisequens; Spain: Ablacton¤; Absorlent Plus; Activelle; Auroclim; Climen; Climodien; Clisin; Dinatrofon¤; Duofemme; Emenovister¤; Endomina Plus; Estalis Sequi; Estalis; Estandron Prolongado¤; Estracomb; Gynodian Depot¤; Merigest Sequi; Merigest; Mevaren; Nuvelle; Perifem; Primodian Depot¤; Primosiston Fuerte¤; Progyluton; Topasel; Trisequens; Sweden: Activelle; Climodien; Cyclabil; Divina Plus; Divina; Estalis Sekvens; Estalis; Estracomb¤; Evorel Micronor; Femanor; Femasekvens; Indivina; Kliogest; Novofem; Totelle Sekvens; Totelle; Trisekvens; Trivina; Switzerland: Activelle; Alpicort F; Climen; Cyclacur; Diviseq; Estalis Sequi; Estalis; Estandron Prolongatum¤; Estracomb; Estragest; Fem 7 Combi; Femoston Conti; Femoston; Gravibinon¤; Gynodian Depot; Indivina; Kliogest N; Linoladiol¤; Mericomb; Merigest; Novofem; OestroTabs Plus Cyclic¤; Primodian Depot¤; Primosiston¤; Systen Conti; Systen Sequi; Triaval; Trisequens; Tyliculine¤; Thailand: Activelle; Climen; Cyclo-Progynova; Duoton; Indivina; Klimonorm; Kliogest¤; Primodian Depot; Trisequens¤; United Kingdom: Adgyn Combi¤; Angeliq; Climagest; Climesse; Clinorette; Cyclo-Progynova 1 mg; Cyclo-Progynova 2 mg; Elleste Duet Conti; Elleste-Duet; Estracombi; Estrapak¤; Evorel Conti; Evorel Pak¤; Evorel Sequi; Femapak; Femoston Conti; Femoston; FemSeven Conti; FemSeven Sequi; FemTab Continuous¤; FemTab Sequi; Hormonin; Indivina; Kliofem; Kliovance; Novofem; Nuvelle Continuous; Nuvelle TS¤; Nuvelle; Tridestra; Trisequens; United States: Activella; Andro/Fem¤; ClimaraPro; CombiPatch; Deladumone¤; depAndrogyn¤; Depo-Testadiol; Depotestogen; Duo-Cyp¤; Duratestrin¤; Estra-Testrin¤; Lunelle¤; Prefest; T-E Cypionate¤; Test-Estro¤; Testaval 90/4¤; Valertest¤; Venezuela: Cliane; Climene; Estracomb; Estragest; Ginecosid; Gynodian Depot; Mesigyna; Primosiston; Progyluton

(British Approved Name, rINN)

Drug Nomenclature

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

Busereliini; Buserelina; Buserelinas; Busereline; Buserelinum; Buszerelin; S74-6766.

(6-O-tert-Butyl-D-serine)-des-10-glycinarnideg-onadorelin ethylamide; 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-O-tert-butyl-D-seryl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide.

C₆₀H₈₆N_l6O_l3 = 1239.4.

CAS — 57982-77-1.

ATC — L02AE01.

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Buserelin). A white or slightly yellowish hygroscopic powder. Sparingly soluble in water and in dilute acids. Store at 2° to 8°. Protect from light and moisture.

Buserelin Acetate

Drug Approvals

(BANM, US Adopted Name, rINNM)

Acetato de buserelina; Buserelin Asetat; Busereline, Acetate de; Buserelini Acetas; Hoe-766

D-Ser (Bu^t)⁶ Pro⁹ NEt LHRH acetate.

C₆₀H₈₆N_l6O_l3,C₂H₄O₂= 1299.5.

CAS — 68630-75-1.

ATC — L02AE01.

Adverse Effects and Precautions

As for Gonadorelin.

Interactions

As for Gonadorelin.

Pharmacokinetics

Buserelin is completely absorbed after subcutaneous injection, with peak plasma concentrations occurring about 1 hour after a dose. It accumulates in liver and kidneys as well as in the anterior pituitary. It is metabolised by tissue peptidases and is excreted in urine and bile as unchanged drug and metabolites. The half-life after injection is stated to be about 80 minutes.

Uses and Administration

Buserelin is an analogue of gonadorelin with similar properties. It is used for the suppression of testosterone in the treatment of malignant neoplasms of the prostate it is also used in the treatment of endome-triosis and as an adjunct to ovulation induction with go-nadotrophins in the treatment of infertility. It has been used in precocious puberty and tried in the treatment of uterine fibroids (see below). Buserelin is usually given as the acetate but doses are expressed in terms of the base 105 micrograms of buserelin acetate is equivalent to about 100 micrograms of buserelin. In advanced prostatic carcinoma doses of 500 micrograms are injected subcutaneously every 8 hours for 7 days. On the eighth day treatment is changed to the nasal route 100 micrograms is sprayed into each nostril 6 times daily (usually before and after meals). An acceptable response should be achieved within 4 to 6 weeks. Since there is an initial increase in circulating testosterone, an anti-androgen such as cy-proterone acetate may be given for at least 3 days before beginning buserelin therapy, and continued for at least 3 weeks, to avoid the risk of a disease flare. Long-acting subcutaneous depot preparations that release buserelin over a 2- or 3-month period are also available.

In endometriosis a dose of 150 micrograms is sprayed into each nostril three times daily. The usual duration of therapy is 6 months, which should not be exceeded.

In infertility, pituitary desensitisation before ovulation induction with gonadotrophins is achieved by giving 150 micrograms intranasally four times daily, beginning either in the early follicular phase (day 1) or midluteal phase (day 21) of the menstrual cycle. Alternatively, 200 to 500 micrograms may be given daily as a subcutaneous injection. Therapy should be continued until pituitary downregulation occurs, which normally takes 1 to 3 weeks if necessary 300 micrograms four times daily intranasally, or 500 micrograms twice daily subcutaneously may be given. Gonadotrophin treatment is then added to buserelin therapy until an appropriate stage of follicular development, when both are withdrawn and chorionic gonadotrophin is given to induce ovulation.

Endometriosis. Gonadorelin analogues such as buserelin have a role in the management of endometriosis, but the need for long-term therapy limits their value because of the risk of osteoporosis ‘add-back’ therapy (hormone replacement) can be used to prevent this. References.

Fibroids. Like other gonadorelin analogues buserelin has been used to reduce the volume of uterine fibroids. References.

Infertility. Buserelin is given with gonadotrophic hormone therapy for induction of ovulation and as an aid to improving IVF procedures. Buserelin with gonadotrophic hormones has been found to result in pregnancies in women previously unresponsive to clomifene citrate, although there may be a greater risk of multiple births.

The regimens used in IVF may be characterised according to how long the gonadorelin analogue is given for:

• long, 2 weeks or more

• short, 8 to 10 days

• ultrashort, 3 days

A comparative study of such regimens found that the best results in all age groups were consistently associated with the long buserelin protocol The timing of buserelin dosage may also be important. Starting buserelin in the midluteal phase of the cycle has been reported to produce more rapid pituitary down regulation and higher pregnancy rates from IVF than when buserelin was begun in the early follicular phase.

For a general discussion of the management of infertility.

Malignant neoplasms. The long-term use of buserelin in men decreases the testicular concentration of testosterone. For this reason it is used in the treatment of prostatic cancer, which is androgen-dependent. Gonadorelin analogues are an effective alternative to orchidectomy, sometimes combined with an anti-androgen for enhanced effect, and play a maj or role in the management of advanced, incurable disease.

Other reports of malignant neoplasms treated with buserelin include its use in metastatic breast cancer.

Porphyria. Buserelin given with medroxyprogesterone acetate suppressed cyclic and premenstrual exacerbations of porphyria in 2 patients. Doses used were 300 micrograms buserelin intranasally in the evenings of days 1 to 21 of the menstrual cycle and 10 mg medroxyprogesterone acetate daily by mouth from day 12 to 21. Both patients were free from porphyric attacks during the reported 11 months of treatment. Intranasal buserelin has also been used in 1 patient to prevent premenstrual exacerbation of coproporphyria. The initial dose of 900 micrograms daily could be tapered to 150 micrograms daily, with only 1 minor attack in 5 years of treatment. The authors of this report also noted a number of case reports of buserelin used in acute intermittent porphyria.

Premenstrual syndrome. For reference to the use of buserelin or other gonadorelin analogues (with HRT to prevent menopausal symptoms) in women unresponsive to other drug treatment, see under Gonadorelin.

Preparations

Proprietary Preparations

Argentina: Suprefact

Austria: Suprecur Suprefact

Belgium: Suprefact

Brazil: Suprefact

Canada: Suprefact

Czech Republic: Suprecur † Suprefact

Denmark: Suprecur Suprefact

Finland: Suprecur Suprefact

France: Bigonist Suprefact

Germany: Profact Suprecur

Greece: Suprefact

Hong Kong: Suprecur

Hungary: Suprefact

Ireland: Suprecur Suprefact

Israel: Suprefact

Italy: Suprefact

Japan: Suprecur

Malaysia: Suprefact

Mexico: Suprefact

The Netherlands: Suprecur Suprefact

Norway: Suprecur Suprefact

New Zealand: Suprefact

Portugal: Suprefact

South Africa: Suprefact

Singapore: Suprefact

Spain: Suprefact

Sweden: Suprecur Suprefact

Switzerland: Suprefact

Thailand: Suprefact

Turkey: Suprecur Suprefact

UK: Suprecur Suprefact

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Leuprolide; Leuproreliini; Leuprorelina; Leuprorelinas; Leuproreline; Leuprorelinum.

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide.

C₅₉H₈₄N₁₆O_l2= 1209.4.

CAS — 53714-56-0.

ATC — L02AE02.

Pharmacopoeias. In> Europe.

European Pharmacopoeia, 6th ed. (Leuprorelin). A synthetic nonapeptide analogue of the hypothalamic peptide gonadorelin. It is obtained by chemical synthesis and is available as an acetate. A white or almost white, hygroscopic, powder. Store in airtight containers at a temperature not exceeding 30°. Protect from light.

Leuprorelin Acetate

Drug Approvals

(British Approved Name Modified, rINNM)

INNs in main languages (French, Latin, and Spanish): Abbott-43818; Acetato de leuprorelina; Leuprolide Acetate (USAN); Leuproreliiniasetaatti; Leuprorelinacetat; Leuproreline, Acetate de; Leuprorelini Acetas; Loprorelin Asetat; TAP-144.

C₅₉H₈₄N_l6O_l2C₂H₄0₂ = 1269.5.

CAS — 74381-53-6.

ATC — L02AE02.

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Leuprolide Acetate). Store in airtight containers at a temperature not exceeding 30°.

Adverse Effects and Precautions

As for Gonadorelin. Thrombocytopenia and leucopenia have been reported rarely.

Benign intracranial hypertension. Increased intracranial pressure associated with leuprorelin treatment has been reported in a few isolated cases.

Effects on the eyes. Leuprorelin may be associated with blurred vision, usually lasting 1 to 2 hours after injection, but in rare instances longer. Haemorrhage or occlusion of intra-ocular blood vessels, ocular pain, and lid oedema have also been reported but the association is less well established.

Hypersensitivity. An anaphylactic reaction started within 5 minutes of the injection of a leuprorelin depot formulation in a patient with prostate cancer. Recurrent anaphylaxis developed in another patient given a depot injection of leuprorelin acetate for endometriosis, requiring both acute and chronic management.

Local reactions. Local reactions, including erythema, pain, induration, granulomas, and sterile abscess are particularly associated with depot injections of gonadorelin analogues such as leuprorelin and triptorelin they may also occur with subcutaneous daily injection. It has been suggested that the depot vehicle, a lactic acid-glycolic acid copolymer, may be responsible for many, although not all, such reactions. Reactions are claimed to be more prevalent in children than in adults: an incidence of about 5% of patients has been suggested. Reactions are apparently idiosyncratic and may occur at any time during therapy, may be intermittent, or may never recur

Pituitary apoplexy. Pituitary apoplexy occurred shortly after the injection of a depot formulation of leuprorelin for the treatment of prostate cancer in 2 patients with occult pituitary adenomas. In a woman receiving leuprorelin daily in preparation for oocyte donation, symptoms began after the third dose. Signs and symptoms in these cases included headache, visual disturbances, generalised weakness, nausea and vomiting, and haem-orrhagic necrosis of themacroadenoma.

Interactions

As for Gonadorelin.

Pharmacokinetics

Leuprorelin acetate is not active when given orally but is well absorbed on subcutaneous or intramuscular injection. After a parenteral dose it has an elimination half-life of about 3 hours.

Uses and Administration

Leuprorelin is an analogue of gonadorelin with similar properties. Continuous administration is used for the suppression of gonadal sex hormone production in the treatment of malignant neoplasms ofthe prostate, in central precocious puberty, and in the management of endometriosis and uterine fibroids. It is also given before uterine surgery for endometrial reduction, and may be used in the treatment of breast cancer in premenopausal women. Leuprorelin is used as the acetate.

In the palliative treatment of advanced prostate cancer, leuprorelin acetate may be given by subcutaneous injection in a usual single daily dose of 1 mg. It is also given subcutaneously or intramuscularly as depot preparations but the dosage and route of these may differ between countries. In the USA, the dose is 7.5 mg monthly, 22.5 mg every 3 months, or 30 mg every 4 months, given subcutaneously or intramuscularly, depending on the preparation. A depot preparation of 45 mg given subcutaneously once every 6 months is also used. In the UK, leuprorelin acetate may also be used in advanced prostate cancer, as well as medical treatment of locally advanced cancer, as an adjuvant to surgery in locally advanced cancer at high risk of progression, or as an adjuvant to radiotherapy in high-risk localised or locally advanced disease. A dose of 3.75 mg may be given once a month, by subcutaneous or intramuscular injection, or 11.25 mg may be given subcutaneously every 3 months. A nonbiodegradable titanium alloy implant, which is inserted subcutaneously into the inner part ofthe upper arm, is also available in the USA for advanced disease. It contains 72 mg of leuprorelin acetate and delivers the drug at a controlled rate of 120 micrograms daily. After 12 months it must be removed, but can be replaced by another implant to continue therapy. An anti-androgen such as cyproterone acetate may be given for several days before beginning leuprorelin therapy and continued for about 3 weeks, to avoid the risk of a disease flare.

For the management of endometriosis and uterine fibroids, leuprorelin acetate 3.75 mg monthly may be given as a single depot injection, intramuscularly or subcutaneously. Alternatively, 11.25 mg may be given as an intramuscular depot every 3 months. Treatment is begun during the first 5 days of the menstrual cycle, and may be continued for up to 6 months for endometriosis, while in women with anaemia due to uterine fibroids it is continued, with iron supplementation, usually for up to 3 months. To prepare for uterine surgery including endometrial ablation or resection, a single 3.75 mg depot injection may be given 5 to 6 weeks before the procedure, or monthly for 3 to 4 months before surgery for uterine fibroids.

In the management of central precocious puberty leuprorelin acetate has been given by intramuscular depot injection in a dose of 300 micrograms/kg every 4 weeks, adjusted according to response. Doses of 50 micrograms/kg daily by subcutaneous injection, adjusted according to response, have also been used. Leuprorelin acetate has also been given in other sex-hormone-related disorders.

Benign prostatic hyperplasia. For a discussion ofthe management of benign prostatic hyperplasia, including mention of the use of gonadorelin analogues and the view that they are unsatisfactory for indefinite therapy. References to the use of leuprorelin.

Disturbed behaviour. Leuprorelin has been used in the treatment of men with paraphilias. Case series have reported reductions in abnormal sexual thoughts and behaviours.

Endometriosis. Gonadorelin analogues are effective in the management of endometriosis but the need for long-term therapy to prevent recurrence limits their value because of the risk of osteoporosis ‘add-back’ hormone replacement therapy can be used to prevent this. References to the use of leuprorelin.

Fibroids. Gonadorelin analogues may be of some benefit as an adjunct or alternative to surgery in women with uterine fibroids, although there has been some concern that this might complicate the diagnosis of malignancy. References to the use of leuprorelin.

Hirsutism. The mainstay of drug treatment for hirsutism has been an anti-androgen, usually cyproterone acetate or spironolactone. Although gonadorelin analogues have been used, and are effective, they must be given parenterally or nasally and may produce menopausal effects, notably osteoporosis. References to the use of leuprorelin.

Infertility. Gonadorelin analogues are used in the treatment of infertility. References to the use of leuprorelin.

Malignant neoplasms. Gonadorelin analogues are used as an alternative to orchidectomy in the management of advanced malignant neoplasms of the prostate. Such therapy is as effective as orchidectomy in prolonging survival combination of leuprorelin or other gonadorelin analogues with nonsteroidal anti-androgens to produce maximal androgen blockade produces only modest additional benefit. Intermittent maximal androgen blockade is being studied in an attempt to improve results, and leuprorelin is also under investigation as neoadjuvant therapy in localised disease. Leuprorelin is also used for ovarian ablation in premenopausal women with breast cancer. There are also isolated reports of endometrial cancer, and ovarian cancer responding to leuprorelin, but the role of the gonadorelin analogues in these conditions is much less well established.

Precocious puberty. The gonadorelin analogues have replaced other agents as the drugs of choice for the treatment of central precocious puberty. References to the use of leuprorelin.

Premenstrual syndrome. For reference to the use of leuprorelin or other gonadorelin analogues (with HRT to prevent menopausal symptoms) in women unresponsive to other drug therapy, see under Gonadorelin.

Preparations

Proprietary Preparations

Argentina: Eligard Lectrum Lupron Reliser †

Australia: Eligard Lucrin

Austria: Enantone Trenantone

Belgium: Depo-Eligard Lucrin

Brazil: Lectrum Lorelin Lupron Reliser

Canada: Eligard Lupron

Chile: Lupron

Czech Republic: Eligard Lucrin

Denmark: Enantonf Procren

Finland: Eligard Enanton Procren

France: Eligard Enantone Lucrin †

Germany: Eligard Enantone Enantone-Gyn Trenantone Uno-Enantone †

Greece: Daronda Elityran Leuprol

Hong Kong: Enantone Lorelin Lucrirr †

Hungary: Eligard Lucrin

India: Lupride

Indonesia: Endrolin Lectrum Tapros

Ireland: Prostap

Israel: Lucrin

Italy: Enantone

Japan: Leuplin Lupron

Malaysia: Lucrin

Mexico: Lectrum Lorelin Lucrin Reliser †

The Netherlands: Daronda Eligard Lucrin

Norway: Enanton Procren

New Zealand: Eligard Lucrin

Philippines: Luprolex

Poland: Eligard Lucrin Depot

Portugal: Eligard Lucrin

Russia: Lucrin

South Africa: Lucrin

Singapore: Lucrin

Spain: Eligard Ginecrin Procrin

Sweden: Eligard Enanton Procren

Switzerland: Eligard Lucrin

Thailand: Enantone

Turkey: Lucrin

UK: Prostap

USA: Eligard Lupron Viadur †

Venezuela: Lupron Reliser †

The symbol † denotes a preparation no longer actively marketed.

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish): Dihydrospinenone; Drospinenon; Drospirenona; Drospirenone; Drospirenoni; Drospirenonum; SH-470; ZK-30595.

(6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3′,4′,6,6a,7,8,9,10,11,12,13,14,15,15a,16-Hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa[6,7:15,16]cyclopenta[α]phenanthrene-17,2′(5′H)-furan]-3,5′(2H)-dione.

C₂₄H₃₀O₃ = 366.5.

CAS — 67392-87-4.

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Drospirenone). A white to off-white powder. Practically insoluble in water and in hexane sparingly soluble in alcohol and in ethyl acetate soluble in methyl alcohol and in acetone freely soluble in dichloromethane. Store in airtight containers at a temperature of 20° to 25°, excursions permitted between 15° and 30°.

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives, p.2059. Drospirenone has antimineralocorticoid activity and therefore should not be used in patients at risk of hyperkalaemia, such as those with renal or hepatic impairment or adrenal insufficiency.

Effects on the cardiovascular system. As with combined oral contraceptives containing other progestogens, there are reports of thrombotic and ischaemic events in patients taking a preparation of ethinylestradiol and drospirenone. The extent of risk associated with hormonal contraceptives that contain drospirenone is mentioned under Venous Thromboembolism.

Renal impairment. US licensed product information for preparations containing drospirenone contra-indicates its use in renal impairment, and in the UK it is contra-indicated in severe impairment. A study of women with renal impairment that was mild (creatinine clearance 50 to 80 mL/minute) or moderate (30 to 50 mL/min) found a trend toward increasing drospirenone exposure with decreasing creatinine clearance. Serum-potassium concentrations were not significantly altered by drospirenone, despite the concomitant use of other drugs that can also potentially increase potassium concentrations including beta blockers and ACE inhibitors.

Interactions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives, and Hormone Replacement Therapy. Because drospirenone has antimineralocorticoid activity, it may potentially exacerbate the effects of drugs that can increase serum-potassium, such as ACE inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, potassium-sparing diuretics, or NSAIDs. Drospirenone may also reduce blood pressure, such that antihypertensive treatment may require adjustment.

Diuretics. The pharmacokinetics of hydrochlorothiazide were not affected by the addition of drospirenone and estradiol in a placebo-controlled study of 36 hypertensive postmenopausal women. However, those given the combination in this study developed lower blood pressure and higher serum-potassium concentrations, which was attributed to the antimineralocorticoid effect of drospirenone. Nontheless, there were no cases of hyperkalaemia. It has been suggested that these potential antihypertensive and potassium-sparing effects might be beneficial in women requiring treatment for both menopausal symptoms and hypertension (see also Menopausal Disorders).

NSAIDs. Drospirenone has the potential to exacerbate the effects of other drugs, such as NSAIDs, that can increase serum potassium. Licensed product information suggests that a clinical effect is unlikely in practice, although the use of a number of such drugs together or the presence of renal impairment may increase the risk. In a small study of healthy postmenopausal women, there was no evidence that potassium concentrations were any higher during concomitant use of indometacin with a combination of drospirenone plus estradiol compared with indometacin alone.

Pharmacokinetics

After oral doses, drospirenone is rapidly absorbed with a bioavailability of about 76%. It is about 97% bound to plasma proteins, though it does not bind to sex hormone binding globulin or corticosteroid binding globulin. It is extensively metabolised with a terminal half-life of about 30 to 40 hours. The metabolites are excreted in the urine and faeces.

Uses and Administration

Drospirenone is a structural analogue of spironolactone it has the effects of a progestogen (see Progesterone) with antimineralocorticoid and anti-androgenic activity. It is used as the progestogenic component of combined oral contraceptives, usually in a dose of 3 mg daily with ethi-nylestradiol 30 micrograms, for 21 days of each 28-day cycle. A combination of drospirenone 3 mg with ethinylestradiol 20 micrograms, given daily for 24 days of each 28-day cycle, may also be used for contraception and for the management of premenstrual dys-phoric disorder or moderate acne in women who also require an oral contraceptive. Drospirenone is also used as the progestogenic component of menopausal HRT in a continuous dosage regimen of 0.5 or 2 mg daily.

Menopausal disorders. Drospirenone is used as the progestogenic component of menopausal HRT. The antimineralocorticoid effect of drospirenone has also been investigated and found to lower blood pressure in postmenopausal women with treated and untreated hypertension.

Premenstrual syndrome. The combination of drospirenone with ethinylestradiol has been studied in the management of premenstrual syndrome. A systematic review of 5 studies found some evidence that the combination may be useful in the treatment of premenstrual dysphoric disorder. However, it was not known whether the effect lasted beyond 3 cycles of treatment, whether the combination was effective for less severe symptoms, or whether combinations using drospirenone were any better than combined contraceptives containing other progestogens.

Preparations

Proprietary Preparations

Argentina: Diva Total.

Multi-ingredient

Argentina: Angeliq Damsel Diva Divina Equifem Gad-ofem Isis Isis Fe Kala Kirumelle Maxima Yasmin Yasminelle

Australia: Angeliq Yasmin

Austria: Allurene Angeliq Yasmin Yirala

Belgium: Angeliq Yasmin

Brazil: Angeliq Elani Yasmin YAZ

Canada: Yasmin

Chile: Angeliq Dahlia Femelle Yasmin

Czech Republic: Angeliq Belanette Yadine Yasminelle

Denmark: Angemin Yasmin

Finland: Angeliq Yasmin

France: Angeliq Jasmine Jasminelle

Germany: Angeliq Petibelle Yasmin

Greece: Angeliq Yasmin

Hong Kong: Angeliq Yasmin

Hungary: Angeliq Yadine Yasminelle

Indonesia: Angeliq Yasmin

Ireland: Angeliq Yasmin

Israel: Angeliq Yasmin

Italy: Angeliq Yasmin

Malaysia: Yasmin

Mexico: Angeliq Yasmin

The Netherlands: Allurene Angeliq Belanette Liofora Yasmin Yasminelle Yira

Norway: Yasmin

New Zealand: Yasmin

Philippines: Angeliq Yasmin

Poland: Angeliq Yasmin Yasminelle

Portugal: Angeliq Petibelle Yasmin Yasminelle

Russia: Angeliq Yarina

South Africa: Angeliq Yasmin

Singapore: Yasmin

Spain: Angeliq Yasmin Yira

Sweden: Angemin Yasmin

Switzerland: Yasmin

Thailand: Angeliq Yasmin

Turkey: Angeliq Yasmin

UK: Angeliq Yasmin

USA: Angeliq Yasmin YAZ

Venezuela: Yasmin

Drug Approvals

(British Approved Name, rINN)

INNs in other languages (French, Latin, and Spanish): DES; Diethylstilbestrol; Diethylstilbestrolum; DiethylstiIboestrol; Dietilestilbestrol; Dietilstilbostrolis; Dietylstilbestrol; Dietyylistilbestroli; NSC-3070; Stilbestrol; Stilboestrol.

(E)-αβ-Diethylstilbene-4-4′-diol.

C_l8H₂₀O₂ = 268.4.

CAS — 56-53-1.

ATC — G03CB02; L02AA01.

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Diethylstilbestrol). A white or almost white crystalline powder. Practically insoluble in water freely soluble in alcohol dissolves in solutions of alkali hydroxides. Protect from light.

The United States Pharmacopeia 31, 2008 (Diethylstilbestrol). A white, odourless, crystalline powder. Practically insoluble in water soluble in alcohol, in chloroform, in ether, in fatty oils, and in dilute alkali hydroxides. Store in airtight containers. Protect from light.

Diethylstilbestrol Dipropionate

Drug Approvals

(British Approved Name Modified, rINNM)

INNs in other languages (French, Latin, and Spanish): Diethylstilbestrol, Dipropionate de; Diethylstilbestroli; Dipropionas; Dipropionato de dietilestilbestrol; Stilboestrol; Dipropionate.

(E)-αβ-Diethylstilbene-4,4′-diol dipropionate.

C₂₄H₂₈O₄ = 380.5

CAS — 130-80-3.

ATC — G03CB02; L02AA01.

Adverse Effects and Precautions

Dose-related adverse effects of diethylstilbestrol include nausea, fluid retention, and arterial and venous thrombosis, and these effects are common at the doses used for palliation of cancer. Impotence and gynaeco-mastia occur in men, and withdrawal bleeding may occur in women, as may hypercalcaemia and bone pain in women treated for breast cancer. Diethylstilbestrol should be used with caution in those with cardiovascular disease or renal or hepatic impairment. Use of diethylstilbestrol is contra-indicated if pregnancy is suspected.

Adverse effects and precautions of oestrogens in general (steroidal compounds) are covered under Estradiol.

Historically, high doses of diethylstilbestrol and related substances were used for ‘hormonal support’ in pregnant women to try to prevent miscarriages and preterm births, most commonly in the USA. This practice was later shown to be ineffective. Adverse effects on the genito-urinary tract of offspring of these women have been noted. In particular, an increased incidence of changes in the cervix and vagina including adenosis and rarely clear-cell adenocarcinoma has been seen in postpubertal daughters of women who received diethylstilbestrol or related substances during pregnancy (see below). A possible increased incidence of abnormalities of the genital tract and of abnormal spermatozoa has been reported in male offspring similarly exposed (see below). The recipients themselves appear to be at a small increased risk of breast cancer (see below).

Carcinogenicity. BREAST. No statistically significant difference in the incidence of breast cancer was found among a group of 693 women given diethylstilbestrol during pregnancy 25 years earlier compared with a control group of 668 who were not. This finding was, however, criticised on the basis that the study lacked the statistical power to reject the null hypothesis. In another study the incidence of breast cancer in 3033 women who had taken diethylstilbestrol in pregnancy during the period 1940 to 1960 was compared with the incidence in a comparable group of unexposed women. This study involved over 85 000 women-years of follow-up in each group and it was found that the incidence of breast cancer per 100 000 women-years was 134 in the exposed group and 93 in the unexposed group (a relative risk of 1.4). The authors concluded that in those women given diethylstilbestrol there was a moderately increased incidence of breast cancer but that some unrecognised concomitant of exposure could not be excluded as a possibility for the increase. Although this study suggested that the risk increased over time, subsequent follow-up, while confirming a modest increase in risk overall, did not confirm a higher risk in these women as time went on. Further follow-up and analysis of the combined data from these cohort studies confirmed a modest increase in risk of breast cancer associated with diethylstilbestrol (relative risk 1.27, 95% confidence interval 1.07 to 1.52). Another large population cohort study suggested that the risk of fatal breast cancer might also be increased in women who had been given diethylstilbestrol. Two cases of breast cancer in premenopausal women exposed to diethylstilbestrol in utero have raised the possibility that the risk of breast cancer may be increased in these women, in addition to the known genito-urinary risk (see below under Pregnancy, Effects on Female Offspring). However, a cohort study involving 4536 women exposed in utero found no increased risk of other cancers overall, and did not show an increased risk of breast cancer (relative risk 1.18 95% confidence intervals 0.56 to 2.49). A later study of further follow-up of this cohort, plus additional data from another group, found that although the risk overall and for younger women was not increased, from the age of 40 years the risk increased to 1.91 (95% confidence interval 1.09 to 3.33). The risk appeared to increase further with greater age, but the relatively small number of cases in women aged 50 years and over made this harder to establish.

GENITO-URINARY TRACT. See below under Pregnancy, Effects on Female Offspring.

KIDNEY. Renal carcinoma was associated with the long-term use of diethylstilbestrol for prostate cancer in 2 men.

LIVER. Hepatic angiosarcoma developed in a 76-year-old man who had received diethylstilbestrol 3 mg daily for 12 years. Hepatoma developed in another elderly man who had received a similar dose for 4.5 years.

Effects on the blood. Adverse haematological effects reported with diethylstilbestrol have included severe bone-marrow changes in a 71-year-old man given diethylstilbestrol in a massive dose of 150 mg daily for 7 years and fatal immune haemo-lytic anaemia in a 69-year-old man given weekly infusions of diethylstilbestrol 1 g for 9 weeks. The latter reaction was due to an IgG antibody specific for diethylstilbestrol.

Pregnancy. EFFECTS ON FEMALE OFFSPRING. The DESAD (Diethylstilbestrol and Adenosis) Project carried out by the National Cancer Institute in the USA led to several reports linking exposure to diethylstilbestrol in utero to adverse genital-tract effects. It was reported that of nearly 300 young females with clear-cell adenocarcinoma of the genital tract, more than 80% had been exposed in utero to diethyl-stilbestrol-type hormones. Patients had been aged 7 to 28 years at the time of diagnosis. Doses and duration of treatment varied widely the association existed for both 1.5 mg of diethylstilbestrol daily throughout pregnancy and variable amounts for a week or more during the first trimester. Vaginal adenosis, rare in unexposed young women, was present in about a third of those exposed in the first 4 months of pregnancy, and cervical ectropion in more than two-thirds. Vaginal epithelial changes were most closely associated with early exposure to diethylstilbestrol, with the total dose, and with the duration of exposure their incidence decreased with age. The risk of cancer in the first 25 years after exposure was small. Fertility did not appear to be impaired in women who had been exposed in utero to diethylstilbestrol but the relative risk of an unfavourable outcome of pregnancy in such a group was 1.69. However, of the women who became pregnant, 81% of those exposed to diethylstilbestrol and 95% of control subjects had at least one full-term live birth. In a review of vaginal adenosis and its association with maternal diethylstilbestrol ingestion during pregnancy it was noted that the link between diethylstilbestrol and particularly the benign changes in the vagina and cervix (adenosis) seemed well established. The association between this drug and the development of genital malignancies was less clear, and the very low incidence in the prospective studies in the USA supported this concept. The problem was rare in the UK, but clinicians should be aware that it existed. Cases of vaginal adenosis in young women should be investigated and screened appropriately, and preferably referred to centres where colposcopic expertise was available. Treatment of simple vaginal adenosis should be avoided.

Later reviews have highlighted the fact that adverse effects were still emerging in women who had been exposed to diethylstilbestrol in utero several decades before. The need for thorough medical screening of such women was emphasised genital-tract examination was particularly important. It was pointed out that many women exposed to diethylstilbestrol in utero were in the reproductive stage of their lives and warranted special observation since a diethylstilbestrol-damaged genital tract posed a potential problem during pregnancy. It has also been suggested, for example, that such women are at increased risk of developing pre-eclampsia.

There has been concern about the possibility of transgenerational effects on the grandchildren of women given diethylstilbestrol during pregnancy. There has been very little reported on female offspring of exposed women, but there were no breast or gynaecological abnormalities found on examination of 28 daughters (over 15 years of age) of women who had been exposed in utero and had in many cases cervical and/or vaginal changes characteristic of diethylstilbestrol exposure. Limited data from a Dutch cohort of 16 284 mothers and 8934 sons suggested that the male offspring of exposed women may in turn be at greatly increased risk of hypospadias, although the absolute risk was small. A case-control study also found an increased risk, but of a much smaller magnitude, and another cohort study (including DESAD data) found no support for a greatly increased risk of hypospadias. The earlier cohort study that reported the greatly increased risk may have been affected by factors related to infertility, as the study was done in a cohort of subfertile women, about half of whom had undergone IVF.

Further information on the adverse effects of diethylstilbestrol in females exposed to the drug in utero can be obtained from the references listed below. For mention of the possible increased risk of breast cancer in these women, see Carcinogenicity.

EFFECTS ON MALE OFFSPRING. The effects of exposure to diethylstilbestrol in utero have been studied in male offspring. Problems in passing urine and abnormalities of the penile urethra were found to be more common in young males exposed to diethylstilbestrol in utero than in controls in one study. In another, genital tract abnormalities such as epidi-dymal cysts, capsular induration, and defective testicles occurred in 41 of 163 diethylstilbestrol-exposed men compared with 11 of 168 controls sperm counts and motility were also reduced in exposed males. In contrast, comparison of 828 men exposed to diethylstilbestrol in utero with 676 unexposed men suggested that, overall, diethylstilbestrol exposure did not result in an increased risk of genito-urinary abnormalities, infertility, or testicular cancer. It was suggested that previously reported increased frequencies of such abnormalities may have resulted from a selection bias and/or from a difference in diethylstilbestrol usage. Another study in 253 exposed men found that although there was an increased incidence of congenital malformations of the genitalia (18 cases compared with 5 of 241 controls), this was not associated with any decrease in fertility or impairment of sexual function. An analysis of the combined data from 4 cohorts suggested that there was a small increase in the risk of infertility (relative risk 1.3, 95% confidence interval 1.0 to 1.6) in men who had been exposed to diethylstilbestrol, but that overall this was not associated with an increased likelihood of never fathering a pregnancy or live birth, and did not affect the number of pregnancies or live births. Data from these 4 cohorts was also analysed for the development of cancer. The overall rates of cancer were similar to those in unexposed men and to national rates. The rate of testicular cancer was increased in men who had been exposed to diethylstilbestrol in utero, but this finding did not reach statistical significance and was limited to only one of the cohorts. Further follow-up will be needed as these men approach the age at which most cancers are diagnosed.

For reference to possible effects on the male grandchildren of women who took diethylstilbestrol (the offspring of women exposed in utero) see Effects on Female Offspring, above.

Veterinary use. In the EU, the use of diethylstilbestrol or other stilbenes in veterinary medicine is banned unless prior steps are taken to ensure the treated animal and its products are not available for human or animal consumption.

Pharmacokinetics

Diethylstilbestrol is readily absorbed from the gastrointestinal tract. It is slowly metabolised in the liver and excreted in the urine and faeces, mainly as the glu-curonide.

Uses and Administration

Diethylstilbestrol is a synthetic nonsteroidal oestrogen that has been used in the palliation of breast and prostate cancer.

Daily oral doses of 10 to 20 mg are occasionally used in the palliative treatment of malignant neoplasms of the breast in postmenopausal women. The usual oral dose in carcinoma of the prostate is 1 to 3 mg daily higher doses were formerly given. Diethylstilbestrol has also been used in the treatment of pros-tatic carcinoma in the form of its diphosphate salts (see Fosfestrol).

Diethylstilbestrol has been used as pessaries in the short-term management of menopausal atrophic vaginitis.

Preparations

British Pharmacopoeia 2008: Diethylstilbestrol Pessaries Diethylstilbestrol Tablets

The United States Pharmacopeia 31, 2008: Diethylstilbestrol Injection Diethylstilbestrol Tablet.

Proprietary Preparations

Argentina: Novo Fosfostilben

Brazil: Destilbenol

France: Distilbene

Ireland: Boestrol

Mexico: Dimeprost.

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Dehydrostilbestrol; Dienestrol; Dienestroli; Dienestrolis; Dienestrolum; Dienoestrol; Dienoestrolum; Dienosztrol; Oestrodienolum.

(E,E)-4,4′-[Di(ethylidene)ethylene]diphenol 4,4′-(1,2-Diethylidene-1,2-ethanediyl)bisphenol.

C_l8H_l80₂ = 266.3.

CAS — 84-17-3 (dienestrol); 13029-44-2 ((E,E)-dienestrol).

ATC — G03CB01

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Dienestrol). A white or almost white, crystalline powder. Practically insoluble in water freely soluble in alcohol and in acetone dissolves in dilute solutions of alkali hydroxides. Protect from light.

The United States Pharmacopeia 31, 2008 (Dienestrol). Colourless, white, or practically white needle-like crystals, or white or practically white crystalline powder. It is odourless. Practically insoluble in water soluble in alcohol, in acetone, in ether, in methyl alcohol, in propylene gly-col, and in solutions of alkali hydroxides slightly soluble in chloroform and in fatty oils.

Profile

Dienestrol is a synthetic nonsteroidal oestrogen structurally related to diethylstilbestrol. It has been used as a 0.01% cream in the treatment of menopausal atrophic vaginitis. If used on a long-term basis in women with a uterus a progestogen is required.

Dienestrol diacetate has been used as an ingredient of topical preparations for skin disorders.

Porphyria. Dienestrol is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals or in-vitro systems.

Preparations

The United States Pharmacopeia 31, 2008: Dienestrol Cream.

Proprietary Preparations

Denmark: Sexadien †

USA: Ortho-Dienestrol