Helsinn Birex Therapeutics Ltd

Bicalinn^® 50 mg Film-coated Tablets

Each film-coated tablet contains 50 mg Bicalutamide.

Also contains 60.0mg of Lactose Monohydrate.

For a full list of excipients, see section 6.1.

Film-coated Tablet.

White, round, biconvex film-coated tablet.

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

Adult males including the elderly: One tablet (50 mg) once a day. Treatment with Bicalinn should be started at the same time as treatment with an LHRH analogue or surgical castration.

Children: Bicalinn 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 Special warnings and special precautions for use).

Bicalinn is contraindicated in females and children.

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

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

Bicalinn 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 Bicalinn. Therefore, Bicalinn 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.

Severe hepatic changes and hepatic failure have been observed rarely with Bicalinn (see section 4.8 Undesirable effects). Bicalinn therapy should be discontinued if changes are severe.

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 Bicalinn 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 in vitro studies have suggested the potential for Bicalinn to inhibit cytochrome 3A4, a number of clinical studies show the magnitude of any inhibition is unlikely to be of clinical significance.

In vitro studies have shown that Bicalinn can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is therefore recommended that if Bicalinn is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

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

Bicalinn is unlikely to impair the ability of patients to drive or operate machinery.

Bicalinn 50 mg is only used in combination with surgical or medical castration. The reported adverse drug profile of Bicalinn 50 mg therefore includes effects that may also be seen with castration therapy alone. The most common reactions reported reflect the pharmacological activity; with the majority (53%) of patients reporting hot flushes and lower proportions (approximately 10%) reporting gynaecomastia or breast tenderness.

Table 1 Frequency of Adverse Reactions

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). Periodic liver function testing should be considered.

In addition, the following adverse experiences were reported in clinical trials (as possible adverse drug reactions in the opinion of investigating clinicians, with a frequency of 1%) during treatment with Bicalinn plus an LHRH analogue. No causal relationship of these experiences to drug treatment has been made and some of the experiences reported are those that commonly occur in elderly patients:

There is no human experience of overdosage. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since Bicalinn is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.

Bicalinn 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 Bicalinn can result in antiandrogen withdrawal syndrome in a subset of patients.

Bicalinn is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.

Bicalinn 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 Bicalinn, the (R)-enantiomer accumulates bout 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 Bicalinn. 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.

Bicalinn 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 Bicalinn 150 mg 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.

Bicalinn is a potent antiandrogen. Expected pharmacological effects of antiandrogens seen in animal studies include the following: atrophy of the prostate and seminal vesicles, benign Leydig cell tumours (rats) and adrenal cortical hypertrophy. Bicalinn is a mixed function oxidase inducer in animals and thyroid hypertrophy and adenoma (rat) and hepatocellular carcinoma (male mice) are a consequence of this. Enzyme induction has not been observed in man. None of the findings in preclinical testing are considered to have relevance to the treatment of advanced prostate cancer patients.

Core

Lactose Monohydrate

Povidone K-30

Sodium Starch Glycollate (Type A)

Magnesium Stearate

Film coating

Opadry White Y-1-7000

Hypromellose

Macrogol 400

Titanium Dioxide (E171)

Not applicable.

5 years.

None

PVC blister/aluminium foil packs, 28 tablets.

Available in pack sizes: 10, 14, 28, 30, 50, 60, 90, 100 Film-Coated Tablets

Not all pack sizes may be marketed.

No special requirements.

Helsinn Birex Therapeutics Ltd

Damastown

Mulhuddart

Dublin15

PA 915/15/1

12^th September 2008

December 2009