Document: spc-doc_PL 40378-0032 change

• spc-doc_PL 20417-0010
• spc-doc_PL 40378-0032

---

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Bicalutamide 50mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 50mg bicalutamide For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

White, round, biconvex, 7mm diameter. Marked ‘B 50’ on one 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 50mg Tablets 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 contraindicated 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 50 mg Tablets must not be given to any patient who has a known hypersensitivity to Bicalutamide or to any of the excipients.

Bicalutamide is contraindicated in females 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

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 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). Therefore, caution should be exercised when Bicalutamide is co-administered with drugs metabolised predominantly by CYP 3A4 (see sections 4.3 and 4.5).

Lactose sensitive patients should be aware that each Bicalutamide 50 mg Tablet contains 57 mg of lactose monohydrate. 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

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 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 50 mg Tablets are 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 form the available data).

Table 1. Frequency of Adverse Reactions

System Organ Class	Frequency	Event
Blood and lymphatic system disorder	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) ', Cardiac failure 1
Vascular disorders	Very common	Hot flush
Respiratory, thoracic and mediastinal disorders	Uncommon	Interstitial lung disease 2 (fatal outcomes have been reported)
Gastrointestinal disorders	Very common	Abdominal pain, constipation, nausea
	Common	Dyspepsia, flatulence
Hepatobiliary disorders	Common	Hepatotoxicitiy, jaundice, hypertransaminasaemia 1
	Rare	Hepatic failure 2 (fatal outcomes have been reported)
Skin and subcutaneous tissue disorders	Common	Alopecia, hirsutism/hair re-growth, rash, dry skin, pruritus
Renal and urinary disorders	Very common	Haematuria
Reproductive system and breast disorders	Very common	Gynaecomastia and breast tenderness 3
	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 Casodex 50 mg was used in combination with LHRH agonists, but no increase in risk was evident when Casodex 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.

treatment with Bicalutamide plus an LHRH analogue. There is no evidence of a causal relationship with drug treatment.

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

Pharmacotherapeutic Group: Anti-androgensATC 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 anti-androgen withdrawal syndrome in a subset of patients.

Bicalutamide is a racemate with its anti-androgenic 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.

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

Bicalutamide 50mg Tablets include the following excipients: Tablet Core:

Lactose monohydrate Sodium starch glycolate (Type A)

Povidone K-30 Magnesium Stearate Film Coating Material:

Opadry II 85F 18422 white containing:

Polyethylene glycol Polyvinyl alcohol Talc E553b

Titanium dioxide E171

6.2 Incompatibilities

Not applicable

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/11/2008

DATE OF REVISION OF THE TEXT

20/09/2012

1

   Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy (see section 4.4 Special warnings and special precautions for use).

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 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.

In addition, cardiac failure was reported in clinical trials (as possible adverse drug reaction in the opinion of investigating clinicians, with a frequency of > 1%) during