4.1. Therapeutic indications

Bicalutamide 150 mg is indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk for disease progression (see section 5.1).

4.2. Posology and method of administration

Posology

Adult

The recommended dose is 150 mg once a day.

Duration of treatment

Bicalutamide 150 mg should be taken continuously for at least 2 years or until disease progression.

Special populations

Elderly and Renal impairment:

No dosage adjustment is necessary for these patients.

Hepatic impairment:

No dosage adjustment is necessary for patients with mild hepatic impairment.

Dosage adjustment could be necessary in patients with moderate and severe hepatic impairment (see section 4.4).

Paediatric population

Bicalutamide is contraindicated in children and adolescent (see section 4.3).

Method of administration

Oral use.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Females (see sections 4.2 and 4.6).

Children and adolescent (see section 4.2).

Co-administration of terfenadine, astemizole or cisapride (see section 4.5).

4.4. Special warnings and precautions for use

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, Bicalutamide should be used with caution in patients with moderate to severe hepatic impairment (see section 4.2).

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 Bicalutamide therapy.

Severe hepatic changes and hepatic failure have been observed rarely with Bicalutamide, and fatal outcomes have been reported (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe. For patients who experience objective disease progression along with elevated PSA levels, consideration should be given to discontinuing Bicalutamide therapy.

Bicalutamide has been shown to inhibit cytochrome P450 (CYP 3A4), as such, caution should be exercised when co-administering 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 Bicalutamide 150 mg. Patients should be advised to avoid direct exposure to excessive sunlight or UV-light while on Bicalutamide 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.

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, therefore the benefit risk ration including the potential for Torsade de pointes prior to initiating Bicalutamide should be assessed (see section 4.5).

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 Bicalutamide, a period of subfertility or infertility should be assumed in man (see section 4.6). Patients and their partners should follow adequate contraception during and for 130 days after Bicalutamide therapy (see section 4.6).

Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant Bicalutamide 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).

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 Bicalutamide, mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of Bicalutamide 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 Bicalutamide 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 Bicalutamide therapy.

Caution should be exercised when prescribing Bicalutamide 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 Bicalutamide. It is therefore recommended that if Bicalutamide is administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustment of anticoagulant dose considered (see sections 4.4 and 4.8).

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Bicalutamide 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Bicalutamide is contraindicated in females (see section 4.3)

Breastfeeding

Bicalutamide is contraindicated in females (see section 4.3)

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 (see section 4.4).

Contraception in women and men

Patients and their female partners should be carefully informed about the potential risks for impairment of human fertility and should use effective contraception measures during treatment with Bicalutamide and for 130 days following completion of treatment (see section 4.4).

4.7. Effects on ability to drive and use machines

Since somnolence may occur Bicalutamide may impair the ability to drive and use machines.

4.8. Undesirable effects

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

System Organ Class

Frequency

Event

Blood and the lymphatic system disorders

Common

Anaemia

Immune system disorders

Uncommon

Hypersensitivity, angioedema, 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 disease5 (fatal outcomes have been reported)

Gastrointestinal disorders

Common

Abdominal pain, constipation, dyspepsia, flatulence, nausea

Hepatobiliary disorders

Common

Rare

Hepatotoxicity, jaundice, hypertransaminasemia1

Hepatic failure4 (fatal outcomes have been reported)

Skin and subcutaneous tissue disorders

Very common

Common

Rare

Rash

Alopecia, hirsuitism/hair re-growth, dry skin3, pruritis

Photosensitivity reaction

Renal and urinary disorders

Common

Haematuria

Reproductive system and breast disorders

Very common

Common

Gynaecomastia and breast tenderness2

Erectile dysfunction

General disorders and administration site conditions

Very common

Common

Asthenia

Chest pain, oedema

Investigations

Common

Weight increased

1. Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.

2. The majority of patients receiving Bicalutamide 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.

3. 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 Bicalutamide dose however the same frequency as the 50 mg dose is assumed.

4. 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 Bicalutamide arm of 150 mg EPC studies.

5. 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 randomized treatment period of the 150 mg EPC studies.

Increased PT/INR: Accounts of coumarin anticoagulants interacting with Bicalutamide 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no human experience of overdosage. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since Bicalutamide is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.