This information is intended for use by health professionals

1. Name of the medicinal product

Bicalutamide 50 mg film-coated Tablets

2. Qualitative and quantitative composition

Each tablet contains 50 mg of bicalutamide.

Excipients with known effect: One tablet contains 60.44 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

White, round, biconvex film-coated tablet, with the inscription “BCM 50” in one side.

4. Clinical particulars
4.1 Therapeutic indications

Treatment of advanced prostate cancer in combination with Luteinising Hormone-Releasing Hormone (LHRH) analogue therapy or surgical castration.

4.2 Posology and method of administration

Adult males including the elderly

One 50 mg tablet once a day.

The tablets should be swallowed whole with liquid.

Treatment with bicalutamide should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration.

Children and adolescents

Bicalutamide is contraindicated in children and adolescents.

Renal impairment

No dose adjustment is necessary for patients with renal impairment.

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment. Increased accumulation may occur in patients with moderate to severe hepatic impairment (see section 4.4).

4.3 Contraindications

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

• Bicalutamide is contraindicated in women and children (see section 4.6).

• Co-administration of terfenadine, astemizole or cisapride with bicalutamide is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Initiation of treatment should be under the direct supervision of a specialist and subsequently patients should be kept under regular surveillance.

Bicalutamide is extensively metabolised in the liver. Data suggests 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.

Severe hepatic changes and hepatic failure has been observed rarely with bicalutamide and fatal outcomes have been reported (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe.

Periodic liver function testing should be considered in order to find out about possible hepatic changes. The majority of changes are expected to occur within the first 6 months of bicalutamide therapy.

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.

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

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 QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating bicalutamide.

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

4.5 Interaction with other medicinal products and other forms of interaction

No pharmacological or pharmacokinetic interactions have been demonstrated between bicalutamide and LHRH analogues.

In vitro studies have shown that the (R)-enantiomer of 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 administering bicalutamide to patients taking medicinal products that inhibit the oxidation processes in the liver, e.g. cimetidine and ketoconazole. 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 site. It is therefore recommended that prothrombin time is closely monitored if bicalutamide is started in patients who are already receiving coumarin anticoagulants.

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, antipyschotics, etc. should be carefully evaluated (see section 4.4).

4.6 Fertility, pregnancy and lactation

This medicinal product is contraindicated in women and must not be given to pregnant and nursing mothers.

4.7 Effects on ability to drive and use machines

Bicalutamide is unlikely to impair the ability of patients to drive or operate machinery. However, it should be noted that occasionally dizziness or somnolence may occur (see section 4.8). Any affected patients should exercise caution.

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).

System Organ Class

Frequency

Undesirable effect

Blood and lymphatic system disorders

Very common

Anaemia

Immune system disorders

Uncommon

Hypersensitivity

Angioeodema

Urticaria

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Common

Decreased libido

Depression

Nervous system disorders

Very common

Dizziness

Common

Somnolence

Cardiac disorders

Common

Myocardial infarction (fatal outcomes have been reported)1

Cardiac failure1

Not known

QT prolongation (see sections 4.4 and 4.5)

Vascular disorders

Very common

Hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon

Interstitial lung disease2

(fatal outcomes have been reported)

Gastrointestinal disorders

Very common

Abdominal pain

Constipation

Nausea

Common

Dyspepsia

Flatulence

Hepato-biliary disorders

Common

Hepatotoxicity

Jaundice

Hypertransaminasaemia3

Rare

Hepatic failure4

(fatal outcomes have been reported)

Skin and subcutaneous tissue disorders

Common

Alopecia

Hirsuitism/hair re-growth

Dry skin

Pruritis

Rash

Renal and urinary disorders

Very common

Haematuria

Reproductive system and breast disorders

Very common

Gynaecomastia and breast tenderness5

Common

Erectile dysfunction

General disorders and administration site conditions

Very common

Asthenia

Oedema

Common

Chest pain

Investigations

Common

Weight increased

1 Observed in a pharmaco-epidemiology study of LHRH agonists and anti-androgens used in the treatment of prostate cancer. The risk appeared to be increased when bicalutamide 50 mg was used in combination with LHRH agonists, but no increase in risk was evident when bicalutamide 150 mg was used as a monotherapy to treat prostate cancer.

2 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.

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

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 the 150 mg EPC studies.

5 May be reduced by concomitant castration.

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.

4.9 Overdose

No case of overdose has been reported. There is no specific antidote; treatment should be symptomatic. Dialysis is unlikely to 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hormone antagonists and related agents, anti- androgens.

ATC code: L02BB03.

Bicalutamide is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically, discontinuation of bicalutamide can result in the “anti-androgen withdrawal syndrome” in a subset of patients.

Bicalutamide is a racemate with its anti-androgenic activity being almost exclusively associated with the (R)-enantiomer

5.2 Pharmacokinetic properties

Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.

The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.

On daily administration of bicalutamide, the (R)-enantiomer accumulates about 10 fold in plasma as a consequence of its long half-life.

Steady state plasma concentrations of the (R)-enantiomer of approximately 9µg/ml are observed during daily administration of 50 mg doses of bicalutamide. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that the (R)-enantiomer is more slowly eliminated from plasma in patients with severe hepatic impairment.

Bicalutamide is highly protein bound (racemate 96%, (R)-enantiomer > 99%) and extensively metabolised (via oxidation and glucuronidation). Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.

In a clinical study the mean concentration of (R)-bicalutamide in semen of men receiving bicalutmide 150 mg was 4.9 µg/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3 µg/kg. This is below that required to induce changes in offspring of laboratory animals.

5.3 Preclinical safety data

Bicalutamide is a potent anti-androgen and a mixed function oxidase enzyme inducer in animals. Target organ changes, including tumour induction, in animals, are related to these activities. None of the findings in the preclinical testing is considered to have relevance to the treatment of advanced prostate cancer patients.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Lactose monohydrate

Povidone K-29/32

Crospovidone (type A)

Sodium lauryl sulphate

Magnesium stearate

Film-coating

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Macrogol 4000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

20, 28, 30, 50, 84, 98 and 100 film-coated tablets in blister packs (PVC/PE/PVDC/ALU).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as:

Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

or

Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8. Marketing authorisation number(s)

PL 17780/0340

9. Date of first authorisation/renewal of the authorisation

21 November 2008

10. Date of revision of the text

11/06/2015