Bicalutamide 50mg Film-coated Tablets

Each film-coated tablet contains 50 mg Bicalutamide.

Excipients:

Each tablet contains 56mg of Lactose monohydrate.

For a full list of excipients, see section 6.1

Film-coated tablet.

White to off white, round biconvex, film-coated tablet debossed 'B 50' on one side and plain on other side.

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

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

Treatment with Bicalutamide Tablets 50mg 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 not indicated in children and adolescents.

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

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).

Hypersensitivity to bicalutamide or to any of the excipients.

Use in females, children and adolescents is contraindicated.

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

Initiation of treatment should be under the direct supervision of a specialist.

As there is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30/min), bicalutamide should only be used with caution in these patients.

Bicalutamide is extensively metabolized 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.

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

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 (see Section 4.3) and caution should be exercised with the co-administration of Bicalutamide with compounds such as cyclosporin 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.

Bicalutamide Tablets 50mg are contra-indicated in females and must not be given to pregnant women or breast-feeding mothers.

No studies on the effects on the ability to drive and use machines have been performed. However, it should be noted that occasionally dizziness or somnolence may occur (see section 4.8). Any affected patients should exercise caution.

The frequencies of adverse events are ranked according to the following: very common (1/10); common (1/100, < 1/10); uncommon (1/1,000, < 1/100); rare (1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 1 Frequency of Adverse Reactions

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)

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. It has been reported in a pharmaco-epidemiology study of LHRH agonists and anti-androgens used in the treatment of prostate cancer. The risk appears to be increased when Bicalutamide was used in combination with LHRH agonists but no increase in risk was evident when Bicalutamide was used as a monotherapy to treat prostate cancer.

No case of overdose has been reported. Since bicalutamide belongs to the anilide compounds there is a theoretical risk of the development of methaemoglobinaemia. Methaemoglobinaemia has been observed in animals after an overdose. Accordingly, a patient with an acute intoxication can be cyanotic. 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.

Pharmacotherapeutic group: Hormone antagonists and related agent, non-steroidal antiandrogens, ATC code: LO2BB03.

Bicalutamide is 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 tumors 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.

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 Tablets 50mg, 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 Tablets. 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 bicalutamide in semen of men receiving Bicalutamide 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.

Bicalutamide is a pure and potent androgen receptor antagonist in experimental animals and humans. The main secondary pharmacological action is induction of CYP450 dependent mixed function oxidases in the 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. These comprise involution of androgen-dependent tissues; thyroid follicular adenomas, 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 mutagenis potential of bicalutamide. All adverse effects observed in animal studies are considered to have no relevance to the treatment of patients with advanced prostate cancer.

Core tablet:

Lactose monohydrate

Sodium starch glycolate (Type A)

Povidone K-30

Magnesium stearate

Coating:

Hypromellose E 5

Macrogol 400

Titanium dioxide E171

Not applicable

2 years

This medicinal product does not require any special storage conditions

Tablets are packed in PVC-PVdC/ aluminium blisters

Bicalutamide 50 mg film-coated Tablets are packed in blisters in pack of 14, 20, 28, 30, 60, 84, 90, 98 or 100 tablets

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Accord Healthcare Limited

Sage House, 319, Pinner Road

North Harrow

Middlesex HA 1 4 HF-UK

PL 20075/0074

21-Apr-2011

14-Jul-2011