Document: spc-doc_PL 40378-0134 change

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Bicalutamide 50mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each film-coated tablet contains 50mg bicalutamide.

Excipients include lactose monohydrate (see section 4.4).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

White to off-white, circular, biconvex film-coated tablet, with B50on one side and plain on the 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 contraindicated in females and children (see section 4.6).

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

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

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 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.

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).

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

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 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. 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 contraindicated 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 (>1/1,000 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

Frequency Organ System--\	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)
Blood and lymphatic system disorders	Anaemia
Immune system disorders			Hypersensitivit y reactions, angioedema and urticaria
Metabolism and nutrition disorders		Decreased appetite
Psychiatric disorder		Decreased libido Depression
Nervous system disorders	Dizziness	Somnolence
Cardiac disorders		Myocardial infarction (fatal outcomes have been reported)4, Cardiac failure4
Vascular disorders	Hot flush
Respiratory, thoracic and mediastinal disorders			Interstitial lung disease. Fatal outcomes have been reported.
Gastrointestinal disorders	Abdominal pain Constipation Nausea	Dyspepsia Flatulence
Hepato-biliary disorders		Hepatotoxicity, jaundice, raised transaminases1		Hepatic failure2. Fatal outcomes have been reported.
Skin and		Alopecia

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 very rarely in patients treated with bicalutamide, but a causal relationship has not been established with certainty. Periodic liver function testing should be considered (see also section 4.4).

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 50mg was used in combination with LHRH agonists but no increase in risk was evident when Bicalutamide 150mg was used as a monotherapy to treat prostate cancer.

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

Pharmacodynamic properties

Pharmacotherapeutic group: Anti-androgens ATC code: L02BB03

Bicalutamide is a non-steroidal antiandrogen, 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 50mg 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 Bicalutamide 150mg was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and 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.

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Lactose monohydrate Maize Starch Crospovidone Povidone

Sodium lauryl sulphate Colloidal anhydrous silica Magnesium Stearate Film Coating:

Hydroxy propyl methyl cellulose Titanium dioxide (E171) Polyethylene glycol 400

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4    Special precautions for    storage

Store below 30°C.

6.5 Nature and contents of container

PVC/Aluminium foil blister packs packed in cartons containing 14 or 28 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

APTIL Pharma Limited 9th Floor, CP House 97 - 107 Uxbridge Road Ealing, London W5 5TL

8    MARKETING AUTHORISATION NUMBER(S)

PL 40378/0134

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/10/2012

10    DATE OF REVISION OF THE TEXT

11/10/2012