Bicalutamide 50 mg film-coated tablets

Each tablet contains 50 mg of bicalutamide.

Excipient: each tablet contains 60.44 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet.

White, round, biconvex film-coated tablet debossed with BCM 50 on one side.

Treatment of advanced prostate cancer in combination with luteinising hormone-releasing hormone (LHRH) analogue therapy or surgical castration.

Adult males, including elderly patients: the dosage is one 50 mg tablet to be taken orally once a day.

Children and adolescents

Bicalutamide is not indicated in children or adolescents.

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.

Renal impairment

No dose adjustment is necessary in patients with renal impairment. There is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4).

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment. The medicinal product may accumulate in patients with moderate to severe hepatic impairment (see section 4.4).

Bicalutamide is contraindicated in females and children.

Bicalutamide must not be given to any patient who has shown a hypersensitivity reaction to its use.

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

Initiation of treatment should be under the direct supervision of a specialist. [this may not apply to all EU member states]

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 (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.

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

In vitro studies have shown that Rbicalutamide 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 site. It is therefore recommended that if bicalutamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

Bicalutamide is contraindicated in females and must not be given to pregnant women or nursing mothers.

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.

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

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

^b Hepatic failure has occurred 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).

^c May be reduced by concomitant castration.

In addition, cardiac failure was reported in clinical trials (as a possible adverse drug reaction in the opinion of investigating clinicians, with a frequency of> 1 %) during treatment with bicalutamide plus an LHRH analogue. There is no evidence of a causal relationship with drug treatment.

There is no human experience of over dosage. 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.

Pharmacotherapeutic group: anti-androgens, ATC-code: L02BB03

Bicalutamide is a non-steroid anti-androgen; it has no additional endocrine activity. It is bound to androgen receptors without activating gene expression and thereby inhibits androgen stimulation. The result of this inhibition is regression of prostate tumours. From the clinical point of view interruption of therapy in some patients could result in manifestation of the anti-androgen withdrawal syndrome.

Bicalutamide is a racemate with an anti-androgen effect, which is present almost exclusively in its Renantiomer.

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

Senantiomer is rapidly cleared in comparison to the Renantiomer, which half-life of plasma elimination is approximately 1 week.

With regular daily administration of bicalutamide the concentration of the Renantiomer in plasma in comparison with Senantiomer is approximately ten-fold, which is caused by its lengthy elimination half-life.

The plasma concentrations of Renantiomer reach approximately 9 microgram/ml in the case of a daily dose of 50 mg of bicalutamide. From the total number of enantiomers present in plasma in the steady state there is 99 % of Renantiomer, which has a dominant share in the therapeutic effect.

Pharmacokinetics of Renantiomer are not affected by age, renal impairment or mild to moderate hepatic impairment. It has been shown that in patients with severe liver impairment the Renantiomer is eliminated slower from plasma.

Bicalutamide is highly protein bound (racemate 96 %, RBicalutamide 99.6 %) and is extensively metabolised (by oxidation and glucuronidation): its metabolites are eliminated via the kidneys and bile in approximately equal proportions. After excreting to bile, hydrolysis of glucuronides occurs. Metabolised bicalutamide is rarely present in urine.

Bicalutamide is a pure and potent androgen receptor antagonist in experimental animals and humans. The main secondary pharmacological action is induction of CYP 450 dependent mixed function oxidases in liver. Enzyme induction has not been observed in humans. Target organ changes in animals are clearly related to the primary and secondary pharmacological action of bicalutamide comprised of involution of androgen-dependent tissues; thyroid gland, hepatic and Leydig cell hyperplasias and neoplasias or cancer; disturbance of male offspring sexual differentiation; reversible impairment of fertility in males. Genotoxicity studies did not reveal any mutagenic potential of bicalutamide. All adverse effects observed in animal studies are considered to be species-specific, having no relevance for humans in the indicated clinical setting.

Tablet core:

lactose monohydrate

Povidone K-29/32

Crospovidone

Sodium laurilsulfate

Magnesium stearate

Coating:

Lactose monohydrate

Hypromellose

Titanium oxide (E171)

Macrogol 4000

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

PVC/PE/PVDC/Al blister, box.

The packaging contains 5, 7, 10, 14, 20, 28, 30, 50, 84, 90, 98, 100, 140, 200 or 280 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Synthon BV

Microweg 22

6545 CM Nijmegen

Netherlands

PL 14048/0022

16 /10/2007

12/2009