Bicalutamide 50mg Film-coated Tablets

Each tablet contains 50 mg of bicalutamide.

Excipients: 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, with the inscription “BCM 50” in one side.

Treatment of advanced prostate cancer in combination with Luteinising Hormone-Releasing Hormone (LHRH) analogue therapy or surgical castration.

Adult males including the elderly

One 50 mg tablet once a day.

Route: oral

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.

Children and adolescents

Bicalutamide is not indicated in children and adolescents.

Renal impairment

No dose 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 < 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).

Hypersensitivity to bicalutamide or any of the excipients.

Bicalutamide is contraindicated in women and children.

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

Initiation of treatment should be under the direct supervision of a specialist and subsequently patients should be kept under regular surveillance.

Bicalutamide is metabolised in the liver. Research results suggest that bicalutamide's 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.

Severe hepatic changes and hepatic failure has been observed rarely with bicalutamide and fatal outcomes have been reported (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe.

Periodic liver function testing is warranted in order to find out about possible hepatic changes. The majority of changes are expected to occur within the first 6 months of bicalutamide therapy.

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

Periodical monitoring of cardiac function is advisable in patients with heart disease.

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).

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

No pharmacological or pharmacokinetic interactions have been demonstrated between bicalutamide and LHRH analogues.

In vitro studies have shown that the R-enantiomer of 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 administering bicalutamide to patients taking medicinal products that inhibit the oxidation processes in the liver, e.g. cimetidine and ketoconazole. 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 prothrombin time is closely monitored if bicalutamide is started in patients who are already receiving coumarin anticoagulants.

Not applicable, since this medicinal product is not used in women.

Fertility

Reversible impairment of male fertility has been observed in animal studies (see section 5.3). A period of subfertility or infertility should be assumed in man.

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.

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).

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 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.

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.

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 agents, anti- androgens

ATC code: L02BB03

Bicalutamide is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to the wild type or normal 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 the “anti-androgen withdrawal syndrome” in a subset of patients.

Bicalutamide is a racemate with its anti-androgenic activity being almost exclusively associated with 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, 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 9µg/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 the (R)-enantiomer is more slowly eliminated from plasma in patients with severe hepatic impairment.

Bicalutamide is highly protein bound (racemate 96%, enantiomer-(R) > 99%) 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 bicalutmide 150mg was 4.9µg/ml. the amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3µg/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. Target organ changes, including tumour induction (Leydig cells, thyroid, liver), observed in animals, are clearly related to the primary and secondary pharmacological action of bicalutamide. The enzymatic induction was not observed in man and none of these findings was considered to have relevance to the treatment of advanced prostate cancer patients. The atrophy of seminiferous tubules is a predictable class effect of anti-androgens and has been observed in all the examined species. The total reversion of the testicles atrophy occurred 24 weeks after a toxicity study of repeated dose of 12 months in rats, although the function reversion has been evident in the reproduction studies of 7 weeks, after the end of an administration period of 11 weeks. In the man a period of sub-fertility or infertility should be considered.

Genotoxicity studies did not reveal any mutagenic potential of bicalutamide.

Tablet core:

Lactose monohydrate

Povidone K-29/32

Crospovidone Type A

Sodium lauryl sulphate

Magnesium stearate

Film-coating:

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Macrogol 4000

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Store in the original package.

20, 28, 30, 50, 84, 98 and 100 film-coated tablets in blister packs (PVC/PE/PVDC/ALU).

Not all pack sizes may be marketed.

No special requirements.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as:

Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS or Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

PL 17780/0340

21 November 2008

09 September 2011