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Bicalutamide 50mg Tablets

Document: spc-doc_PL 20417-0010 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bicalutamide 50 mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg bicalutamide.

Each tablet contains 61 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White round, biconvex film-coated tablet embossed ‘B50’ on one side and plain on other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of advanced prostate cancer in combination with LHRH analogue therapy or surgical castration.

4.2 Posology and method of administration

Adult males including the elderly: one tablet (50mg) once a day.

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: Bicalutamide is contra-indicated in children.

Renal impairment: no dosage adjustment is necessary for patients with renal impairment.

Hepatic impairment: no dosage 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

Bicalutamide is contra-indicated in females and children.

Bicalutamide must not be given to any patient who has shown a hypersensitivity reaction to its use or to any excipients of this product.

Co-administration of terfenadine, astemizole or cisapride with bicalutamide is contra-indicated.

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 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.

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 have been observed rarely with bicalutamide (see Section 4.8). Bicalutamide therapy should be discontinued if changes are severe.

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 agonist.

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.

Bicalutamide Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take these tablets.

4.5 Interaction with other medicinal products and other forms of interaction

There is no evidence of any pharmacodynamic or pharmacokinetic interactions between bicalutamide and LHRH analogues.

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 contra-indicated 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 cyclosporin, 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. It is therefore recommended that if bicalutamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

4.6 Fertility, pregnancy and lactation

Bicalutamide is contra-indicated in females and must not be given to pregnant women or 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 somnolence may occur. 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 (> 1/1000 to < 1/100); rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (can not be estimated from the available data).

Table 1 Frequency of Adverse Reactions

System Organ Class

Frequency

Event

Blood and lymphatic system disorders

Very 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

Very common

Dizziness

Common

Somnolence

Cardiac disorders

common

Myocardial infarction (fatal outcomes have been reported)4, Cardiac

failure4

Vascular disorders

Very common

Hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon

Interstitial lung disease5. Fatal outcomes have been reported.

Gastrointestinal

disorders

Very common

Abdominal pain

Constipation

nausea

Common

Dyspepsia

Flatulence

Hepato-biliary

disorders

Common

Heptatotoxicity, jaundice, raised transaminases (hypertansaminasaemia)

Rare

Hepatic failure . (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 tenderness3

Common

Erectile dysfunction

General disorders and administrative site conditions

Very common

Asthenia

Oedema

Common

Chest pain

Investigations

Common

Weight gain

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

2.    Hepatic failure has occurred rarely in patients treated with Bicalutamide, but a casual relationship has not been established with certainty. Periodic liver function testing should be considered (see also section 4.4). 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 Casodex arm of the 150 mg EPC studies

3.    May be reduced by concomitant castration.

4.    Observed in a pharmaco-epidemiology study of LHRH agonists and antiandrogens used in the treatment of prostate cancer. The risk appears 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.

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 randomised treatment period of the 150 mg EPC studies

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

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 antiandrogen withdrawal syndrome in a subset of patients.

Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively in 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 9 microgram/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 for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.

Bicalutamide is highly protein bound (racemate 96%, R-Bicalutamide 99.6%) 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 Bicaluamide 150 mg was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3 microgram/kg. This is below that required to induce changes in offspring of laboratory animals.

5.3 Preclinical safety data

Bicalutamide is a potent antiandrogen 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 Maize starch Povidone Crospovidone Colloidal anhydrous silica Sodium lauryl sulphate Magnesium stearate

Film coating material:

Titanium dioxide (E171)

Hypromellose Macrogol 400

6.2 Incompatibilities

None known

6.3 Shelf life

3 years.

6.4 Special precautions for storage

There are no special conditions for storage.

6.5 Nature and contents of container

PVC/aluminium foil blister packs in an outer cardboard carton containing 28 film-coated tablets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough Northamptonshire NN8 6GT UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20417/0010

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/07/2011

10 DATE OF REVISION OF THE TEXT

10/09/2014