CASODEX Film-coated tablets Ref.[6511] Active ingredients: Bicalutamide

Initiation of treatment should be under the direct supervision of a specialist.

Bicalutamide is extensively metabolised in the liver. Data suggest that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of bicalutamide. Therefore, Casodex 150 mg should be used with caution in patients with moderate to severe hepatic impairment.

Periodic liver function testing should be considered due to the possibility of hepatic changes. The majority of changes are expected to occur within the first 6 months of Casodex therapy.

Severe hepatic changes and hepatic failure have been observed rarely with Casodex 150 mg, and fatal outcomes have been reported (see section 4.8). Casodex 150 mg therapy should be discontinued if changes are severe.

For patients who have an objective progression of disease together with elevated PSA, cessation of Casodex therapy should be considered.

Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4), as such, caution should be exercised when co-administered with drugs metabolised predominantly by CYP 3A4 (see sections 4.3 and 4.5).

In rare cases, photosensitivity reactions have been reported for patients taking Casodex 150 mg. Patients should be advised to avoid direct exposure to excessive sunlight or UV-light while on Casodex 150 mg and the use of sunscreens may be considered. In cases where the photosensitivity reaction is more persistent and/or severe, an appropriate symptomatic treatment should be initiated.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Casodex.

Antiandrogen therapy may cause morphological changes in spermatozoa. Although the effect of bicalutamide on sperm morphology has not been evaluated and no such changes have been reported for patients who received Casodex, patients and/or their partners should follow adequate contraception during and for 130 days after Casodex therapy.

Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant Casodex therapy, which may result in increased Prothrombin Time (PT) and International Normalised Ratio (INR). Some cases have been associated with risk of bleeding. Close monitoring of PT/INR is advised and anticoagulant dose adjustment should be considered (see sections 4.5 and 4.8).

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4, with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Although clinical studies using antipyrine as a marker of cytochrome P450 (CYP) activity showed no evidence of a drug interaction potential with Casodex, mean midazolam exposure (AUC) was increased by up to 80% after co-administration of Casodex for 28 days. For drugs with a narrow therapeutic index such an increase could be of relevance. As such, concomitant use of terfenadine, astemizole and cisapride is contraindicated (see section 4.3) and caution should be exercised with the co-administration of Casodex with compounds such as ciclosporin and calcium channel blockers. Dosage reduction may be required for these drugs particularly if there is evidence of enhanced or adverse drug effect. For ciclosporin, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of Casodex therapy.

Caution should be exercised when prescribing Casodex with other drugs which may inhibit drug oxidation e.g. cimetidine and ketoconazole. In theory, this could result in increased plasma concentrations of bicalutamide which theoretically could lead to an increase in side effects.

In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. There have been reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with Casodex. It is therefore recommended that if Casodex 150 mg is administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustments of anticoagulant dose considered (see sections 4.4 and 4.8).

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Casodex with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

Bicalutamide is contraindicated in females and must not be given to pregnant women.

Breast-feeding

Bicalutamide is contraindicated during breast-feeding.

Fertility

Reversible impairment of male fertility has been observed in animal studies (see section 5.3). A period of subfertility or infertility should be assumed in man.

Casodex is unlikely to impair the ability of patients to drive or operate machinery. However, it should be noted that occasionally somnolence may occur. Any affected patients should exercise caution.

In this section, undesirable effects are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000); not known (cannot be estimated from the available data).

Table 1. Frequency of Adverse Reactions:

Blood and the lymphatic system disorders

Common: Anaemia

Immune system disorders

Uncommon: Hypersensitivity, angioedema and urticaria

Metabolism and nutrition disorders

Common: Decreased appetite

Psychiatric disorders

Common: Decreased libido, Depression

Nervous system disorders

Common: Dizziness, Somnolence

Cardiac disorders

Not known: QT prolongation (see sections 4.4 and 4.5)

Vascular disorders

Common: Hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon: Interstitial lung diseasee (fatal outcomes have been reported).

Gastrointestinal disorders

Common: Abdominal pain, Constipation, Dyspepsia, Flatulence, Nausea

Hepato-biliary disorders

Common: Hepatotoxicity, jaundice, hypertransaminasaemiaa

Rare: Hepatic failured (fatal outcomes have been reported).

Skin and subcutaneous tissue disorders

Very common: Rash

Common: Alopecia, Hirsutism/hair re-growth, Dry skinc, Pruritus

Rare: Photosensitivity reaction

Renal and urinary disorders

Common: Haematuria

Reproductive system and breast disorders

Very common: Gynaecomastia and breast tendernessb

Common: Erectile dysfunction

General disorders and administration site conditions

Very common: Asthenia

Common: Chest pain, Oedema

Investigations

Common: Weight increased

^a Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
^b The majority of patients receiving Casodex 150 mg as monotherapy experience gynaecomastia and/or breast pain. In studies these symptoms were considered to be severe in up to 5% of the patients. Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.
^c Due to the coding conventions used in the EPC studies, adverse events of ‘dry skin’ were coded under the COSTART term of ‘rash’. No separate frequency descriptor can therefore be determined for the 150 mg Casodex dose however the same frequency as the 50 mg dose is assumed.
^d Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of hepatic failure in patients receiving treatment in the open-label Casodex arm of the 150 mg EPC studies.
^e Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of interstitial pneumonia in the randomised treatment period of the 150 mg EPC studies.

Increased PT/INR: Accounts of coumarin anticoagulants interacting with Casodex have been reported in post-marketing surveillance (see sections 4.4 and 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.

Not applicable.