Concentrate for intravenous infusion, natalizumab 20 mg/mL, net price 15-mL vial = £1130.00. Counselling, liver toxicity, progressive multifocal leucoencephalopathy, and hypersensitivity, patient alert card
Electrolytes Na+ 2.3 mmol/vial
Siltuximab
Siltuximab is a monoclonal antibody that inhibits interleukin-6 receptor binding. It is licenced for the treatment of multicentric Castleman’s disease (MCD) in patients who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Castleman’s disease is a rare disorder of the lymphatic system that causes an abnormal cell growth in lymph nodes causing benign tumours.
Monitor neutrophil and platelet count, and haemoglobin levels prior to each dose of siltuximab treatment for the first 12 months and thereafter prior to every third dosing cycle. Consider delaying treatment if required neutrophil, platelet, and haemoglobin levels not achieved — consult product literature for details.
Infusion-related side-effects are reported commonly with siltuximab; resucitation facilities should be available during treatment. Siltuximab therapy should be discontinued permanently in the event of a severe infusion-related reaction, anaphylaxis, a severe allergic reaction, or the occurence of cytokine-release syndrome. Mild to moderate infusion-related reactions may improve by temporarily reducing the rate or stopping the infusion. When restarting treatment, a reduced infusion rate and the administration of antihistamines, paracetamol, and corticosteroids should be considered. Consider discontinuation of siltuximab if more than 2 doses are delayed due to treatment-related toxicities during the first 48 weeks — for full details consult product literature.
SILTUXIMAB
Indications see notes above
Cautions see notes above and consult product literature; treat infection prior to treatment and monitor for infection during treatment; severe infection — withhold treatment until resolved; use with caution in patients at increased risk of gastrointestinal perforation; promptly investigate those presenting with symptoms suggestive of gastrointestinal perforation; hepatic impairment; live vaccines should not be given concurrently or within 4 weeks before starting siltuximab treatment; interactions: Appendix 1 (siltuximab)
Pregnancy manufacturer advises avoid unless potential benefit outweighs risk; women of childbearing potential should use effective contraception during and for 3 months after treatment
Breast-feeding manufacturer advises avoid — no information available
Side-effects see notes above; also abdominal pain, weight gain, hypertension, localised oedema, hypertriglyceridaemia, infections including upper respiratory tract infection and nasopharyngitis, renal impairment, hypoglobulinaemia, neutropenia, thrombocytopenia, maculopapular rash, pruritus, hypersensitivity reactions (including infusion-related reaction and anaphylaxis); also reported increased haemoglobin levels, hepatitis B reactivation
Dose
By intravenous infusion, ADULT over 18 years, 11 mg/kg every 3 weeks
Sylvant® (Janssen-Cilag) 
Intravenous infusion, powder for reconstitution, siltuximab, net price 100-mg vial =£415.00, 400-mg vial=£1661.00
Teriflunomide
Teriflunomide is a metabolite of leflunomide which has immunomodulating and anti-inflammatory properties. It is licensed for the treatment of adults with relapsing-remitting multiple sclerosis. Teriflunomide should be initiated and supervised by a physician experienced in the management of multiple sclerosis.
The Scottish Medicines Consortium has advised (February 2014) that the use of teriflunomide (Aubagio®) in NHS Scotland is restricted to use in patients with relapsing-remitting multiple sclerosis who do not have highly active disease, and only as an alternative to treatment with interferon beta or glatiramer acetate.
NICE guidance
Teriflunomide for treating relapsing-remitting multiple sclerosis (January 2014)
Teriflunomide is recommended for the treatment of adults with active relapsing-remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years), in adults who
do not have highly active or rapidly evolving severe relapsing-remitting multiple sclerosis and
the manufacturer provides teriflunomide with the discount agreed in the patient access scheme
TERIFLUNOMIDE
Note Teriflunomide is a metabolite of leflunomide
Indications see notes above
Cautions adult over 65 years; impaired bone-marrow function (avoid if severe) including anaemia, leucopenia or thrombocytopenia; significant alcohol consumption; latent tuberculosis; hypoproteinaemia (avoid if severe); switching between other immunomodulating drugs; persistent cough or dyspnoea — assess for interstitial lung disease and consider suspending treatment; severe infection — delay or suspend treatment until resolved; signs or symptoms of serious skin reactions (including ulcerative stomatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) — discontinue treatment; monitor full blood count (including differential white cell count and platelet count) before treatment and as clinically indicated during treatment; monitor blood pressure before treatment and periodically thereafter; an accelerated elimination procedure is recommended following discontinuation due to serious adverse effects (consult product literature and see Accelerated Elimination Procedure below); interactions: Appendix 1 (teriflunomide)
Hepatic monitoring Monitor liver function before treatment and every 2 weeks for first 6 months then every 8 weeks thereafter or as clinically indicated (pre-existing liver disease may increase risk). Increase to weekly monitoring if alanine aminotransferase (ALT) is 2–3 times the upper limit of reference range; discontinue treatment if signs or symptoms of hepatic injury, or if liver enzymes exceed 3 times the upper limit of reference range
Accelerated elimination procedure To aid drug elimination in case of serious adverse effect or before conception (see also Pregnancy below), stop treatment and give either colestyramine 8 g (reduce to 4 g if not tolerated) 3 times daily for 11 days or activated powdered charcoal 50 g every 12 hours for 11 days. After the accelerated elimination procedure a plasma concentration of less than 20 micrograms/litre (measured on 2 occasions at least 14 days apart) and a waiting period of one and a half months are necessary before conception. Use of non-oral contraception is recommended during the accelerated elimination procedure — consult product literature
Contra-indications significantly impaired bone-marrow function (including anaemia, neutropenia, leucopenia, or thrombocytopenia); severe immunodeficiency; severe hypoproteinaemia; serious infection
Hepatic impairment avoid in severe impairment; see also Hepatic Monitoring above
Pregnancy avoid — toxicity in animal studies; effective contraception essential for women of child-bearing potential during treatment and for up to 2 years after treatment (see also Accelerated Elimination Procedure above)
Breast-feeding present in milk in animal studies — manufacturer advises avoid
Side-effects diarrhoea, nausea, vomiting, gastroenteritis, weight loss, hypertension, respiratory tract infection, laryngitis, anxiety, paraesthesia, peripheral neuropathy, sciatica, carpal tunnel syndrome, hyperaesthesia, neuralgia, menorrhagia, urinary tract infection, cystitis, neutropenia, leucopenia, pollakiuria, elevated liver enzymes, musculoskeletal pain, myalgia, oral infection, alopecia, rash, acne, tinea pedis; less commonly anaemia, thrombocytopenia; very rarely interstitial lung disease, pancreatitis; important: accelerated elimination procedure recommended following discontinuation due to serious adverse effects (consult product literature and see Accelerated Elimination Procedure above)
Dose
ADULT over 18 years, 14 mg once daily
NICE Technology Appraisal
NICE recommended. See Teriflunomide for treating relapsing-remitting multiple sclerosis (January 2014)
8.3 Sex hormones and hormone antagonists in malignant disease
Hormonal manipulation has an important role in the treatment of breast, prostate, and endometrial cancer, and a more marginal role in the treatment of hypernephroma. These treatments are not curative, but may provide excellent palliation of symptoms in selected patients, sometimes for a period of years. Tumour response, and treatment toxicity should be carefully monitored and treatment changed if progression occurs or side-effects exceed benefit.
8.3.1 Oestrogens
Diethylstilbestrol is sometimes used to treat prostate cancer, but it is not usually used first-line because of its side-effects. It is occasionally used in postmenopausal women with breast cancer. Toxicity is common and dose-related side-effects include nausea, fluid retention, and venous and arterial thrombosis. Impotence and gynaecomastia always occur in men, and withdrawal bleeding may be a problem in women. Hypercalcaemia and bone pain may also occur in breast cancer.
Ethinylestradiol is the most potent oestrogen available; unlike other oestrogens it is only slowly metabolised in the liver. Ethinylestradiol is licensed for the palliative treatment of prostate cancer.
DIETHYLSTILBESTROL
(Stilboestrol)
Indications see notes above
Cautions cardiovascular disease
Hepatic impairment avoid; see also Combined Hormonal Contraceptives (section 7.3.1)
Pregnancy in first trimester, high doses associated with vaginal carcinoma, urogenital abnormalities, and reduced fertility in female offspring; increased risk of hypospadias in male offspring
Side-effects sodium retention with oedema, thromboembolism, jaundice, feminising effects in men; see also notes above
Dose
Breast cancer, 10–20 mg daily
Prostate cancer, 1–3 mg daily
Diethylstilbestrol (Non-proprietary) 
Tablets, diethylstilbestrol 1 mg, net price 28 = £107.79; 5 mg, 28 = £192.67
ETHINYLESTRADIOL
(Ethinyloestradiol)
Indications see notes above; other indications (section 6.4.1.1)
Cautions see section 6.4.1.1; interactions: Appendix 1 (oestrogens)
Contra-indications see section 6.4.1.1
Hepatic impairment avoid; see also Combined Hormonal Contraceptives (section 7.3.1)
Side-effects see section 6.4.1.1
Dose
Prostate cancer (palliative), 0.15–1.5 mg daily
8.3.2 Progestogens
Progestogens have a role in the treatment of endometrial cancer; their use in breast cancer and renal cell cancer has declined. Progestogens are now rarely used to treat prostate cancer. Medroxyprogesterone or megestrol are usually chosen and can be given orally; high-dose or parenteral treatment cannot be recommended. Side-effects are mild but may include nausea, fluid retention, and weight gain.
MEDROXYPROGESTERONE ACETATE
Indications see notes above; contraception (section 7.3.2.2); other indications (section 6.4.1.2)
Cautions see section 6.4.1.2; loss of vision during treatment (discontinue treatment if papilloedema or retinal vascular lesions); interactions: Appendix 1 (progestogens)
Contra-indications see section 6.4.1.2 and notes above
Hepatic impairment avoid; see also oral Progestogen-only Contraceptives (section 7.3.2.1)
Pregnancy avoid — genital malformations and cardiac defects reported; see also Parenteral Progestogen-only Contraceptives (section 7.3.2.2)
Breast-feeding present in milk — no adverse effects reported; see also Parenteral Progestogen-only Contraceptives (section 7.3.2.2)
Side-effects see section 6.4.1.2 and notes above; glucocorticoid effects at high dose may lead to a cushingoid syndrome; also constipation, diarrhoea, dry mouth, vomiting, indigestion; adrenergic-like effects, congestive heart failure, hypertension, palpitation, tachycardia; confusion, euphoria, loss of concentration, nervousness, hyperpyrexia; hypercalcaemia; cervical erosions, galactorrhoea; raised white blood cell count, raised platelet count; vision disorders, retinal thrombosis
Dose
See preparations below
Provera® (Pharmacia) 
Tablets, medroxyprogesterone acetate 100 mg (scored), net price 60-tab pack = £29.98, 100-tab pack = £49.94; 200 mg (scored), 30-tab pack = £29.65, 400 mg, 30-tab pack = £58.67
Dose endometrial and renal cell cancer, 200–600 mg daily; breast cancer, 0.4–1.5 g daily
Tablets, medroxyprogesterone acetate 2.5 mg, 5 mg and 10 mg, see section 6.4.1.2
MEGESTROL ACETATE
Indications see notes above
Cautions see under Medroxyprogesterone acetate (section 6.4.1.2) and notes above; interactions: Appendix 1 (progestogens)
Contra-indications see under Medroxyprogesterone acetate (section 6.4.1.2) and notes above
Hepatic impairment manufacturer advises caution in severe impairment
Pregnancy avoid; reversible feminisation of male fetuses reported in animal studies; risk of hypospadias in male fetuses and masculinisation of female fetuses
Breast-feeding discontinue breast-feeding
Side-effects see under Medroxyprogesterone acetate (section 6.4.1.2) and notes above; vomiting, constipation, diarrhoea, carpal tunnel syndrome, adrenal insufficiency. Cushing’s syndrome, urinary frequency, tumour flare (with or without hypercalcaemia), and asthenia
Dose
Breast cancer, 160 mg once daily
Megace® (Swedish Orphan) 
Tablets, scored, megestrol acetate 160 mg (off-white), 30-tab pack = £19.52
NORETHISTERONE
Indications see notes above; other indications (section 6.4.1.2)
Cautions see section 6.4.1.2 and notes above; interactions: Appendix 1 (progestogens)
Contra-indications see section 6.4.1.2 and notes above
Hepatic impairment avoid; see also oral Progestogen-only Contraceptives (section 7.3.2.1)
Pregnancy masculinisation of female fetuses and other defects reported; see also oral Progestogen-only Contraceptives (section 7.3.2.1)
Breast-feeding higher doses may suppress lactation and alter milk composition — use lowest effective dose; see also oral Progestogen-only Contraceptives (section 7.3.2.1)
Side-effects see section 6.4.1.2 and notes above
Dose
Breast cancer, 40 mg daily, increased to 60 mg daily if required
8.3.3 Androgens
Testosterone esters (section 6.4.2) have largely been superseded by other drugs for breast cancer.
8.3.4 Hormone antagonists
8.3.4.1 Breast cancer
The management of patients with breast cancer involves surgery, radiotherapy, drug therapy, or a combination of these.
For operable breast cancer, treatment before surgery (neoadjuvant therapy) reduces the size of the tumour and facilitates breast-conserving surgery; hormone antagonist therapy (e.g. letrozole) is chosen for steroid hormone-receptor-positive breast cancer and chemotherapy for steroid hormone-receptor-negative tumours or for younger women.
Early breast cancer All women should be considered for adjuvant therapy following surgical removal of the tumour. Adjuvant therapy is used to eradicate the micrometastases that cause relapses. Choice of adjuvant treatment is determined by the risk of recurrence, steroid hormone-receptor status of the primary tumour, and menopausal status.
Adjuvant therapy comprises cytotoxic chemotherapy and hormone-antagonist therapy. Women with steroid hormone-receptor-positive breast cancer are considered for hormone-antagonist therapy (preceded by cytotoxic chemotherapy if necessary) whilst women with steroid hormone-receptor-negative breast cancer should be considered for cytotoxic chemotherapy.
Aromatase inhibitors act predominantly by blocking the conversion of androgens to oestrogens in the peripheral tissues. They do not inhibit ovarian oestrogen synthesis and should not be used in premenopausal women. Anastrozole and letrozole are non-steroidal aromatase inhibitors; exemestane is a steroidal aromatase inhibitor. Aromatase inhibitors are usually prescribed as initial adjuvant therapy in postmenopausal women with oestrogen-receptor-positive tumours; tamoxifen, an oestrogen-receptor antagonist, is used if an aromatase inhibitor is not appropriate. Adjuvant hormone antagonist therapy should generally be continued for 5 years following removal of the tumour. In postmenopausal women considered for extended adjuvant therapy, 5 years of tamoxifen is followed by letrozole for a further 2–3 years.
Trastuzumab (section 8.1.5) is licensed for use in early breast cancer which overexpresses human epidermal growth factor-2 (HER2) in women who have received surgery, chemotherapy and radiotherapy (as appropriate).
Premenopausal women with oestrogen-receptor-positive breast cancer who decline chemotherapy may benefit from treatment with goserelin (section 8.3.4.2) or ovarian ablation.
Advanced breast cancer Treatment of advanced breast cancer depends on the patient’s drug history and an assessment of disease severity. Aromatase inhibitors, such as anastrozole or letrozole, are the preferred treatment in postmenopausal women with oestrogen-receptor-positive advanced breast cancer, a long disease-free interval following treatment for early breast cancer, and disease limited to bone or soft tissues; tamoxifen can be used if aromatase inhibitors are not suitable. Progestogens, such as medroxyprogesterone acetate (section 8.3.2), may be used after aromatase inhibitors and tamoxifen in postmenopausal women.
Tamoxifen should be considered for pre- and perimenopausal women with oestrogen-receptor-positive breast cancer not previously treated with tamoxifen. Ovarian suppression is used in pre- and perimenopausal women who have had disease progression despite treatment with tamoxifen. The gonadorelin analogue goserelin (section 8.3.4.2) is licensed for advanced breast cancer in pre- and perimenopausal women suitable for hormone manipulation.
Trastuzumab emtansine can be used alone for treating HER2-positive, unresectable, locally advanced breast cancer previously treated with trastuzumab and a taxane, or when there is disease recurrence during or following adjuvant therapy (section 8.1.5).
Cytotoxic chemotherapy is indicated for advanced steroid hormone-receptor-negative tumours and for aggressive disease, particularly when metastases involve visceral sites (e.g. the liver) or if the disease-free interval following treatment for early breast cancer is short.
Cytotoxic drugs used in breast cancer An anthracycline combined with fluorouracil (section 8.1.3) and cyclophosphamide (section 8.1.1), and sometimes also with methotrexate (section 8.1.3) is effective. Cyclophosphamide, methotrexate, and fluorouracil can be useful if an anthracycline is inappropriate (e.g. in cardiac disease).
Metastatic disease The choice of chemotherapy regimen will be influenced by whether the patient has previously received adjuvant treatment and the presence of any co-morbidity.
For women who have not previously received chemotherapy, an anthracycline (such as doxorubicin or epirubicin) alone or in combination with another cytotoxic drug is the standard initial therapy for metastatic breast disease.
Patients with anthracycline-refractory or resistant disease should be considered for treatment with a taxane (section 8.1.5) either alone or in combination with trastuzumab if they have tumours that overexpress HER2. Other cytotoxic drugs with activity against breast cancer include capecitabine (section 8.1.3), mitoxantrone, mitomycin (both section 8.1.2), and vinorelbine (section 8.1.4). Trastuzumab alone (section 8.1.5) is an option for chemotherapy-resistant cancers that overexpress HER2. Trastuzumab emtansine can be used as monotherapy in HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, or when there is disease recurrence during or following adjuvant therapy (section 8.1.5). Trastuzumab and trastuzumab emtansine are not interchangeable.
The use of bisphosphonates (section 6.6.2) in patients with metastatic breast cancer may reduce pain and prevent skeletal complications of bone metastases.
ANASTROZOLE
Indications adjuvant treatment of oestrogen-receptor-positive early invasive breast cancer in postmenopausal women; adjuvant treatment of oestrogen-receptor-positive early breast cancer in postmenopausal women following 2–3 years of tamoxifen therapy; advanced breast cancer in postmenopausal women which is oestrogen-receptor-positive or responsive to tamoxifen
Cautions laboratory test for menopause if doubt; susceptibility to osteoporosis (assess bone mineral density before treatment and at regular intervals)
Contra-indications not for premenopausal women
Hepatic impairment avoid in moderate to severe impairment
Renal impairment avoid if creatinine clearance less than 20 mL/minute
Pregnancy avoid
Breast-feeding avoid
Side-effects hot flushes, vaginal dryness, vaginal bleeding, hair thinning, anorexia, nausea, vomiting, diarrhoea, headache, arthralgia, arthritis, bone fractures, bone pain, rash (including Stevens-Johnson syndrome), cutaneous vasculitis; asthenia and drowsiness — may initially affect ability to drive or operate machinery; slight increases in total cholesterol levels reported; very rarely allergic reactions including angioedema and anaphylaxis
Dose
1 mg daily
Anastrozole (Non-proprietary) 
Arimidex® (AstraZeneca) 
Tablets, f/c, anastrozole 1 mg, net price 28-tab pack = £68.56
The Scottish Medicines Consortium has advised (August 2005 and October 2006) that anastrozole (Arimidex®) is accepted for restricted use within NHS Scotland, within the licensed indications, for early breast cancer and early invasive breast cancer.
EXEMESTANE
Indications adjuvant treatment of oestrogen-receptor-positive early breast cancer in postmenopausal women following 2–3 years of tamoxifen therapy; advanced breast cancer in postmenopausal women in whom anti-oestrogen therapy has failed
Cautions interactions: Appendix 1 (exemestane)
Contra-indications not indicated for premenopausal women
Hepatic impairment manufacturer advises caution
Renal impairment manufacturer advises caution
Pregnancy avoid
Breast-feeding avoid
Side-effects nausea, vomiting, abdominal pain, dyspepsia, constipation, anorexia; dizziness, fatigue, headache, depression, insomnia; hot flushes, sweating; alopecia, rash; less commonly drowsiness, asthenia, and peripheral oedema; rarely thrombocytopenia, leucopenia
Dose
25 mg daily
NICE Technology Appraisal
NICE not recommended. See Everolimus in combination with exemestane for treating advanced HER2-negative hormone-receptor-positive breast cancer after endocrine therapy (August 2013)
Aromasin® (Pharmacia) 
Tablets, s/c, exemestane 25 mg, net price 30-tab pack = £88.80, 90-tab pack = £266.40. Label: 21
The Scottish Medicines Consortium has advised (October 2005) that exemestane (Aromasin®) is accepted for restricted use within NHS Scotland as an adjuvant treatment in postmenopausal women with oestrogen-receptor-positive invasive early breast cancer, following 2–3 years of initial adjuvant tamoxifen therapy.
FULVESTRANT
Indications treatment of oestrogen-receptor-positive metastatic or locally advanced breast cancer in postmenopausal women in whom disease progresses or relapses while on, or after, other anti-oestrogen therapy
Hepatic impairment manufacturer advises caution in mild to moderate impairment; avoid in severe impairment
Renal impairment manufacturer advises caution if creatinine clearance less than 30 mL/minute — no information available
Pregnancy manufacturer advises avoid — increased incidence of fetal abnormalities and death in animal studies
Breast-feeding manufacturer advises avoid — present in milk in animal studies
Side-effects nausea, vomiting, diarrhoea; venous thromboembolism; anorexia, headache, asthenia; urinary-tract infections; hot flushes; back pain; rash, injection-site reactions, hypersensitivity reactions; less commonly vaginal haemorrhage, vaginal candidiasis, and leucorrhoea
Dose
By deep intramuscular injection into buttock, 500 mg every 2 weeks for the first 3 doses, then 500 mg every month
Note 500 mg dose should be administered as one 250-mg injection (slowly over 1–2 minutes) into each buttock
Faslodex® (AstraZeneca) 
Injection (oily), fulvestrant 50 mg/mL, net price 2 × 5-mL (250-mg) prefilled syringe = £522.41
LETROZOLE
Indications first-line treatment in postmenopausal women with hormone-dependent advanced breast cancer; adjuvant treatment of oestrogen-receptor-positive invasive early breast cancer in postmenopausal women; advanced breast cancer in postmenopausal women (naturally or artificially induced menopause) in whom other anti-oestrogen therapy has failed; extended adjuvant treatment of hormone-dependent invasive breast cancer in postmenopausal women who have received standard adjuvant tamoxifen therapy for 5 years; neo-adjuvant treatment in postmenopausal women with localised hormone-receptor-positive, human epidermal growth factor-2 negative breast cancer where chemotherapy is not suitable and surgery not yet indicated
Cautions susceptibility to osteoporosis (assess bone mineral density before treatment and at regular intervals)
Contra-indications not indicated for premenopausal women
Hepatic impairment manufacturer advises caution in severe impairment
Renal impairment manufacturer advises caution if creatinine clearance less than 10 mL/minute
Pregnancy avoid (isolated cases of birth defects reported); manufacturer advises effective contraception required until postmenopausal status fully established (return of ovarian function reported in postmenopausal women)
Breast-feeding manufacturer advises avoid
Side-effects nausea, vomiting, abdominal pain, hypertension, hot flushes, fatigue, dizziness, headache, dyspepsia, constipation, diarrhoea, depression, anorexia, appetite increase, weight changes, vaginal bleeding, hypercholesterolaemia, alopecia, increased sweating, rash, dry skin, peripheral oedema, arthralgia, musculoskeletal pain, osteoporosis, bone fracture; less commonly cerebrovascular events, cardiac events, palpitation, tachycardia, dyspnoea, cough, insomnia, anxiety, memory impairment, dysaesthesia, taste disturbance, pruritus, urticaria, thrombophlebitis, urinary frequency, urinary-tract infection, vaginal discharge, breast pain, pyrexia, mucosal dryness, stomatitis, cataract, eye irritation, blurred vision, tumour pain, arthritis, leucopenia, general oedema; rarely pulmonary embolism, arterial thrombosis; also reported hepatitis, toxic epidermal necrolysis
Dose
2.5 mg daily
Letrozole (Non-proprietary) 
Tablets, letrozole 2.5 mg, net price 14-tab pack = £1.88, 28-tab pack = £3.32
TAMOXIFEN
Indications see under Dose and notes above; mastalgia [unlicensed indication] (section 6.7.2)
Cautions occasional cystic ovarian swellings in premenopausal women; increased risk of thromboembolic events, especially when used with cytotoxics (see also below); endometrial changes (important: see below); porphyria, interactions: Appendix 1 (tamoxifen)
Endometrial changes Increased endometrial changes, including hyperplasia, polyps, cancer, and uterine sarcoma reported; prompt investigation required if abnormal vaginal bleeding including menstrual irregularities, vaginal discharge, and pelvic pain or pressure in those receiving (or who have received) tamoxifen. Patients should be informed of the risk of endometrial cancer and told to report relevant symptoms promptly
Contra-indications treatment of infertility contra-indicated if personal or family history of idiopathic venous thromboembolism or genetic predisposition to thromboembolism
Pregnancy avoid — possible effects on fetal development; effective contraception must be used during treatment and for 2 months after stopping
Breast-feeding suppresses lactation; avoid unless potential benefit outweighs risk
Side-effects hot flushes, vaginal bleeding and vaginal discharge (important: see also Endometrial Changes under Cautions), suppression of menstruation in some premenopausal women, pruritus vulvae, gastro-intestinal disturbances, headache, light-headedness, tumour flare, decreased platelet counts; occasionally oedema, rarely hypercalcaemia if bony metastases, alopecia, rashes, uterine fibroids; also visual disturbances (including corneal changes, cataracts, retinopathy); leucopenia (sometimes with anaemia and thrombocytopenia), rarely neutropenia; hypertriglyceridaemia reported rarely (sometimes with pancreatitis); thromboembolic events reported (see below); liver enzyme changes (rarely fatty liver, cholestasis, hepatitis); rarely interstitial pneumonitis, hypersensitivity reactions including angioedema, Stevens-Johnson syndrome, bullous pemphigoid; see also notes above
Risk of thromboembolism Tamoxifen can increase the risk of thromboembolism particularly during and immediately after major surgery or periods of immobility (consider interrupting treatment to initiate anticoagulant measures). Patients should be made aware of the symptoms of thromboembolism and advised to report sudden breathlessness and any pain in the calf of one leg
Dose
Breast cancer, 20 mg daily
Anovulatory infertility, 20 mg daily on days 2, 3, 4 and 5 of cycle; if necessary the daily dose may be increased to 40 mg then 80 mg for subsequent courses; if cycles irregular, start initial course on any day, with subsequent course starting 45 days later or on day 2 of cycle if menstruation occurs
TOREMIFENE
Indications hormone-dependent metastatic breast cancer in postmenopausal women
Cautions hypercalcaemia may occur (especially if bone metastases and usually at beginning of treatment); avoid in acute porphyria (but see section 9.8.2); history of severe thromboembolic disease; interactions: Appendix 1 (toremifene)
Endometrial changes Increased endometrial changes, including hyperplasia, polyps and cancer reported. Abnormal vaginal bleeding including menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated
Contra-indications endometrial hyperplasia, QT prolongation (avoid concomitant administration of drugs that prolong QT interval), electrolyte disturbances (particularly uncorrected hypokalaemia), bradycardia, heart failure with reduced left-ventricular ejection fraction, history of arrhythmias
Hepatic impairment elimination decreased in hepatic impairment — avoid if severe
Pregnancy avoid
Breast-feeding avoid
Side-effects nausea, vomiting; oedema; depression, dizziness, fatigue; sweating, hot flushes, vaginal bleeding or discharge (important: see Cautions); rash; less commonly anorexia, constipation, increased weight, thromboembolic events, dyspnoea, insomnia, headache, endometrial hypertrophy; very rarely jaundice, transient corneal opacity, and alopecia
Dose
60 mg daily
8.3.4.2 Gonadorelin analogues and gonadotrophin-releasing hormone antagonists
Metastatic cancer of the prostate usually responds to hormonal treatment aimed at androgen depletion. Standard treatments include bilateral subcapsular orchidectomy or use of a gonadorelin analogue (buserelin, goserelin, histrelin, leuprorelin, or triptorelin). The gonadotrophin-releasing hormone antagonist, degarelix is also available. Response in most patients lasts for 12 to 18 months. No entirely satisfactory therapy exists for disease progression despite this treatment (hormone-refractory prostate cancer), but occasional patients respond to other hormone manipulation e.g. with an anti-androgen. Bone disease can often be palliated with irradiation or, if widespread, with strontium or prednisolone (section 6.3.2).
Gonadorelin analogues
Gonadorelin analogues are as effective as orchidectomy or diethylstilbestrol (section 8.3.1) but are expensive and require parenteral administration, at least initially. They cause initial stimulation then depression of luteinising hormone release by the pituitary. During the initial stage (1–2 weeks) increased production of testosterone may be associated with progression of prostate cancer. In susceptible patients this tumour ‘flare’ may cause spinal cord compression, ureteric obstruction or increased bone pain. When such problems are anticipated, alternative treatments (e.g. orchidectomy) or concomitant use of an anti-androgen such as cyproterone acetate or flutamide (see below) are recommended; anti-androgen treatment should be started before the gonadorelin analogue. Gonadorelin analogues are also used in women for breast cancer (section 8.3.4.1) and other indications (section 6.7.2).
The Scottish Medicines Consortium has advised (June 2009) that histrelin (Vantas®) is accepted for restricted use within NHS Scotland for the palliative treatment of advanced prostate cancer in patients with an anticipated life expectancy of at least one year in whom annual administration will offer advantages.
Cautions Men at risk of tumour ‘flare’ (see above) should be monitored closely during the first month of therapy. Caution is required in patients with metabolic bone disease because reduced bone mineral density can occur. The injection site should be rotated.
Side-effects The gonadorelin analogues cause side-effects similar to the menopause in women and orchidectomy in men and include hot flushes and sweating, sexual dysfunction, vaginal dryness or bleeding, and gynaecomastia or changes in breast size. Signs and symptoms of prostate or breast cancer may worsen initially (managed in prostate cancer with anti-androgens, see above). Other side-effects include hypersensitivity reactions (rashes, pruritus, asthma, and rarely anaphylaxis), injection site reactions (see Cautions), headache (rarely migraine), visual disturbances, dizziness, arthralgia and possibly myalgia, hair loss, peripheral oedema, gastro-intestinal disturbances, weight changes, sleep disorders, and mood changes.
BUSERELIN
Indications advanced prostate cancer; other indications (section 6.7.2)
Cautions diabetes, hypertension, depression; see also notes above
Side-effects see notes above; worsening hypertension, palpitation, glucose intolerance, altered blood lipids, thrombocytopenia, leucopenia, nervousness, fatigue, memory and concentration disturbances, anxiety, increased thirst, hearing disorders, musculoskeletal pain; nasal irritation, nose bleeds and altered sense of taste and smell (spray formulation only)
Dose
By subcutaneous injection, 500 micrograms every 8 hours for 7 days, then intranasally, 1 spray into each nostril 6 times daily (see also notes above)
Counselling Avoid use of nasal decongestants before and for at least 30 minutes after treatment.
Suprefact® (Sanofi-Aventis) 
Injection, buserelin (as acetate) 1 mg/mL. Net price 2 × 5.5-mL vial = £28.64
Nasal spray, buserelin (as acetate) 100 micrograms/metered spray. Net price treatment pack of 4 × 10-g bottle with spray pump = £101.87. Counselling, see above
GOSERELIN
Indications locally advanced prostate cancer as an alternative to surgical castration; adjuvant treatment to radiotherapy or radical prostatectomy in patients with high-risk localised or locally advanced prostate cancer; neoadjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer; metastatic prostate cancer; advanced breast cancer; oestrogen-receptor-positive early breast cancer (section 8.3.4.1); endometriosis, endometrial thinning, uterine fibroids, assisted reproduction (section 6.7.2)
Cautions see notes above; diabetes; hypertension; depression; risk of ureteric obstruction and spinal cord compression in men
Contra-indications undiagnosed vaginal bleeding
Pregnancy see Goserelin, section 6.7.2
Breast-feeding see Goserelin, section 6.7.2
Side-effects see notes above; also transient changes in blood pressure, heart failure, myocardial infarction; paraesthesia; rarely hypercalcaemia (in patients with metastatic breast cancer)
Dose
See under preparations below
Zoladex® (AstraZeneca) 
Implant, goserelin (as acetate) 3.6 mg in SafeSystem® syringe applicator, net price each = £65.00
Dose breast cancer and prostate cancer (see indications above) by subcutaneous injection into anterior abdominal wall, 3.6 mg every 28 days
Zoladex® LA (AstraZeneca) 
Implant, goserelin (as acetate) 10.8 mg in SafeSystem® syringe applicator, net price each = £235.00
Dose prostate cancer (see indications above), by subcutaneous injection into anterior abdominal wall, 10.8 mg every 12 weeks
HISTRELIN
Indications advanced prostate cancer
Cautions see notes above; monitor patients at high risk of metabolic disease (e.g. bone disease, worsening diabetes) or cardiovascular disease before and during treatment; risk of ureteric obstruction and spinal cord compression
Side-effects see notes above; also hepatic disorder, dyspnoea, depression, asthenia, elevated blood glucose-concentration, increased urinary frequency, hypertrichosis; less commonly hypercholesterolaemia, palpitation, ventricular extrasystole, haematoma, tremor, anaemia, renal failure, nephrolithiasis, hypercalcaemia
Dose
By subcutaneous implantation into upper arm, 1 implant (50 mg) every 12 months; remove after 12 months of treatment
Counselling Avoid wetting arm containing implant for 24 hours and avoid lifting heavy objects or strenuous physical activity for 7 days after implantation
LEUPRORELIN ACETATE
Indications locally advanced prostate cancer as an alternative to surgical castration; adjuvant treatment to radiotherapy or radical prostatectomy in patients with high-risk localised or locally advanced prostate cancer; metastatic prostate cancer; endometriosis, endometrial thinning, uterine fibroids (section 6.7.2)
Cautions see notes above and section 6.7.2; risk of ureteric obstruction and spinal cord compression in men
Side-effects see notes above and section 6.7.2; also fatigue, muscle weakness, depression, paraesthesia, hypertension, palpitation, alteration of glucose tolerance and of blood lipids; hypotension, jaundice, thrombocytopenia and leucopenia reported
Dose
See under preparations below
Prostap® SR DCS (Takeda) 
Injection, dual-chamber prefilled syringe containing powder for reconstitution, leuprorelin acetate and solvent, net price 3.75-mg prefilled syringe = £75.24
Dose prostate cancer (see indications), by subcutaneous or by intramuscular injection, 3.75 mg every month
TRIPTORELIN
Indications prostate cancer; endometriosis, precocious puberty, reduction in size of uterine fibroids; male hypersexuality with severe sexual deviation (section 6.7.2)
Cautions see notes above; risk of ureteric obstruction and spinal cord compression in men; risk factors for osteoporosis
Side-effects see notes above; also dry mouth, transient hypertension, paraesthesia, and increased dysuria
Dose
See under preparations below
Decapeptyl® SR (Ipsen) 
Injection (powder for suspension), triptorelin (as acetate), net price 3-mg vial (with diluent) = £69.00
Dose locally advanced non-metastatic prostate cancer as an alternative to surgical castration, metastatic prostate cancer, as an adjuvant treatment to radiotherapy in high-risk localised or locally advanced prostate cancer, as neoadjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer, as an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression, by intramuscular injection, 3 mg every 4 weeks
Note Each vial includes an overage to allow accurate administration of a 3-mg dose
Injection (powder for suspension), triptorelin (as acetate), net price 11.25-mg vial (with diluent) = £207.00
Dose locally advanced non-metastatic prostate cancer as an alternative to surgical castration, metastatic prostate cancer, as an adjuvant treatment to radiotherapy in high-risk localised or locally advanced prostate cancer, as neoadjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer, as an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression, by intramuscular injection, 11.25 mg every 3 months (see also notes above)
Note Each vial includes an overage to allow accurate administration of an 11.25-mg dose
Injection (powder for suspension), triptorelin (as pamoate), net price 22.5-mg vial (with diluent) = £414.00
Dose locally advanced non-metastatic prostate cancer as an alternative to surgical castration, metastatic prostate cancer, as an adjuvant treatment to radiotherapy in high-risk localised or locally advanced prostate cancer, as neoadjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer, as an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression, by intramuscular injection, 22.5 mg every 6 months (see also notes above)
Note Each vial includes an overage to allow accurate administration of a 22.5-mg dose
Gonapeptyl Depot® (Ferring) 
Injection (powder for suspension), triptorelin (as acetate), net price 3.75-mg prefilled syringe (with prefilled syringe of vehicle) = £81.69
Dose advanced prostate cancer, by subcutaneous or deep intramuscular injection, 3.75 mg every 4 weeks (see also notes above)
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