Bicalutamide

Bicalutamide is a non-steroidal antiandrogen with no other endocrine activity. It binds to androgen receptors without activating gene expression, so it inhibits androgen stimulation, and this inhibition makes the prostate tumour regress. It is a racemate whose antiandrogen activity lies almost entirely in the (R)-enantiomer.

Mechanism of Action

• Receptor blockade: bicalutamide competes with androgens for the androgen receptor and so blocks the action of androgens of adrenal and testicular origin, which stimulate the growth of normal and malignant prostate tissue. It has no affinity for progestogen, oestrogen or glucocorticoid receptors.
• Withdrawal syndrome: in some patients, stopping treatment can lead to an antiandrogen withdrawal syndrome.
• With LHRH analogues: in a large controlled study (median follow-up 95 weeks), bicalutamide 50 mg plus an LHRH analogue and flutamide plus an LHRH analogue did not differ in time to treatment failure.
• At 150 mg: in a pooled analysis of three placebo-controlled trials in 8,113 men with localised or locally advanced non-metastatic prostate cancer, objective disease progression after a median follow-up of 7.4 years occurred in 27.4% on bicalutamide 150 mg and 30.7% on placebo. The risk reduction was clearest in patients at highest risk of progression.

Pharmacokinetics

• Absorption: well absorbed after oral dosing; food has no clinically significant effect on bioavailability.
• Distribution: highly protein-bound (96% for the racemate, above 99% for the (R)-enantiomer).
• Metabolism: extensive, by oxidation and glucuronidation. The inactive (S)-enantiomer is cleared mainly by glucuronidation; the active (R)-enantiomer is mostly oxidised and then glucuronidated.
• Elimination: metabolites leave via the kidneys and bile in roughly equal amounts. The (S)-enantiomer is cleared quickly; the (R)-enantiomer has a plasma elimination half-life of about 1 week, so daily 50 mg dosing causes about 10-fold accumulation.
• Steady state: (R)-enantiomer concentrations are about 9 μg/mL on 50 mg daily and 22 μg/mL on 150 mg daily, and it makes up 99% of the circulating enantiomers.
• Special populations: (R)-enantiomer kinetics are not affected by age, renal impairment or mild to moderate hepatic impairment; elimination is slower in severe hepatic impairment.
• Semen: on 150 mg, the mean (R)-bicalutamide concentration in semen was 4.9 μg/mL. The amount that could pass to a woman during intercourse is small (about 0.3 μg/kg) and lower than the level needed to cause changes in the offspring of laboratory animals.

• Advanced prostate cancer: treatment of advanced prostate cancer in combination with LHRH analogues or surgical castration.
• Locally advanced prostate cancer: in patients with locally advanced prostate cancer at high risk of disease progression, either alone or as an adjuvant to radical prostatectomy or radiotherapy.

• Women, and children and adolescents under 18 years.
• Hypersensitivity to bicalutamide or to any of the excipients.
• Concomitant use of terfenadine, astemizole or cisapride.

The SmPC lists reactions separately for 150 mg a day (used alone) and 50 mg a day (used with an LHRH analogue or castration). The most frequent are gynaecomastia and breast tenderness at both doses, asthenia, and hot flushes with 50 mg.

Very common (≥1/10): gynaecomastia and breast tenderness, asthenia (both doses); rash (150 mg); anaemia, dizziness, abdominal pain, constipation, nausea, hot flush, haematuria and oedema (50 mg).

Common (≥1/100 to <1/10): weight increase, decreased appetite, somnolence, dyspepsia, flatulence, alopecia, hair regrowth or hirsutism, dry skin, pruritus, chest pain, hepatotoxicity, jaundice, raised transaminases, erectile dysfunction, decreased libido and depression (both doses); anaemia, dizziness, abdominal pain, constipation, nausea, haematuria, hot flush and oedema (150 mg); rash, myocardial infarction (fatal cases reported) and cardiac failure (50 mg).

Uncommon (≥1/1,000 to <1/100): interstitial lung disease (fatal cases reported); hypersensitivity, angioedema, urticaria.

Rare (≥1/10,000 to <1/1,000): hepatic failure (fatal cases reported); photosensitivity reaction.

Not known: QT prolongation.

Most men on 150 mg alone develop gynaecomastia or breast pain, severe in up to 5%, and it may not resolve after stopping, especially after long treatment; with 50 mg it can be reduced by concomitant castration. The heart events at 50 mg come from a pharmacoepidemiological study of LHRH agonists and antiandrogens, where the risk appeared higher with 50 mg plus an LHRH agonist and there was no evidence of increased risk with 150 mg alone. Liver changes are rarely severe and are often transient, resolving or improving on continued treatment or after stopping. Increases in prothrombin time and INR have been reported with coumarin anticoagulants.

• LHRH analogues: no evidence of a pharmacodynamic or pharmacokinetic interaction.
• Coumarin anticoagulants (warfarin): bicalutamide can displace warfarin from protein-binding sites, and an increased anticoagulant effect has been reported, in some cases with a risk of bleeding. Prothrombin time and INR should be monitored closely and an anticoagulant dose adjustment considered.
• Terfenadine, astemizole, cisapride: contraindicated. In a study, exposure to a sensitive CYP3A4 substrate rose by up to 80% after 28 days of bicalutamide, which could matter for medicines with a narrow therapeutic index.
• Ciclosporin and calcium channel blockers: use caution; dose reduction may be needed, particularly if the effect or side effects increase. For ciclosporin, plasma concentrations and clinical status should be monitored closely when bicalutamide is started or stopped.
• Medicines that inhibit oxidation, such as cimetidine and ketoconazole: use caution, since in theory bicalutamide levels and side effects could rise.
• QT-prolonging medicines: use with bicalutamide should be assessed carefully, because androgen deprivation can also prolong the QT interval. The SmPC names class IA antiarrhythmics (quinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics.
• Enzyme effects: R-bicalutamide inhibits CYP3A4 in vitro, with smaller effects on CYP2C9, 2C19 and 2D6; clinical studies suggest the size of the inhibition is unlikely to be clinically important.
• Food: no clinically significant effect; take it at the same time each day.

Bicalutamide is taken by mouth once daily by adult men, including the elderly. The tablets are swallowed whole with a little water.

Recommended Dose

• Advanced prostate cancer: one 50 mg tablet once daily, together with an LHRH analogue or surgical castration. Bicalutamide is started 3 days before the LHRH analogue or at the same time as surgical castration.
• Locally advanced prostate cancer: 150 mg once daily (three 50 mg tablets, or one tablet of the separate 150 mg presentation), for at least 2 years or until the disease progresses.

Treatment Review

Stopping 150 mg treatment should be considered in patients with objective disease progression together with a raised PSA.

Special Populations

• Elderly: same dose as other adults.
• Renal impairment: no dose adjustment. There is no experience in severe impairment (creatinine clearance below 30 mL/min), so use caution.
• Hepatic impairment: no adjustment in mild impairment. Accumulation may increase in moderate to severe impairment, so use caution.
• Children and adolescents under 18 years, and women: contraindicated.

Liver Function

Bicalutamide is extensively metabolised in the liver, and elimination may be slower in severe hepatic impairment, so use caution in moderate to severe impairment. Severe liver changes and hepatic failure have rarely been observed, and deaths have been reported; treatment should be stopped if they occur. Periodic liver function tests should be considered, since most changes are expected in the first 6 months.

Lung Disease

Interstitial lung disease has been observed uncommonly, with deaths reported. Treatment should be stopped if it occurs.

Blood Glucose

Reduced glucose tolerance has been seen in men treated with LHRH agonists, which can appear as diabetes or as loss of glycaemic control in existing diabetes. Monitoring blood glucose should be considered when bicalutamide is combined with LHRH agonists.

Heart and QT Interval

Cardiac function should be monitored periodically in patients with heart disease taking 150 mg. Androgen deprivation therapy may prolong the QT interval, although no causal link with Casodex has been established. In patients with a history of QT prolongation or risk factors for it, and in those taking medicines that might prolong QT, the benefit and risk, including the risk of torsade de pointes, should be assessed before starting.

Anticoagulants and Enzyme Interactions

The anticoagulant effect of coumarins can be potentiated, with higher prothrombin time and INR and, in some cases, a bleeding risk, so close monitoring and dose adjustment of the anticoagulant are advised. Bicalutamide inhibits CYP3A4, so caution is needed with medicines mainly metabolised by this enzyme.

Sperm and Contraception

Androgen therapy can cause morphological changes in sperm. The effect of bicalutamide on sperm morphology has not been assessed and no such changes have been reported with Casodex, but patients and their partners should use adequate contraception during treatment and for the period after it that the SmPC specifies.

Pregnancy, Breastfeeding and Fertility

• Pregnancy and breastfeeding: bicalutamide is contraindicated in women and must not be given during pregnancy or breastfeeding.
• Fertility: a reversible reduction in male fertility was seen in animal studies. In men, a period of reduced fertility or infertility should be assumed.

Lactose and Sodium

Each tablet contains 61 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Casodex may affect the ability to drive or use machines. Somnolence can occur occasionally, and affected patients should take care.

Do not store Casodex tablets above 30 °C. They are supplied in PVC/aluminium blisters of 30 tablets.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Bicalutamide is taken at home, so it is supplied to the patient or to the treating clinic on prescription.