Summary of product characteristics

SUMMARY OF PRODUCT CHARACTERISTICS

 

1.         NAME OF THE MEDICINAL PRODUCT

BICALUTAMIDE GRINDEKS 50 mg film-coated tablets

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg bicalutamide.

Excipient: each tablet contains 60 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3.       PHARMACEUTICAL form

Film-coated tablet.

White, round, biconvex, film-coated tablet.

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 once a day. 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

BICALUTAMIDE GRINDEKS is contraindicated in children (see section 4.3).

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 < 30 ml/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).

4.3       Contraindications

Hypersensitivity to bicalutamide or to any of the excipients.

Bicalutamide is contraindicated in females and children.

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

4.4     Special warnings and precautions for use

Bicalutamide, the active substance of BICALUTAMIDE GRINDEKS 50 mg tablets, 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.

Severe hepatic changes have been observed rarely with bicalutamide (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe.

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.

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.

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.

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 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, the mean area under the concentration time curve (AUC) for midazolam was increased by up to 80 %, after co‑administration of bicalutamide for 28 days.

For drugs that are extensively metabolised in the liver and have a narrow therapeutic index (such as terfenadine, astemizole, cisapride and cyclosporine), the inhibition of CYP 3A4 by bicalutamide could be of relevance. Co-administration of bicalutamide with these drugs is contraindicated (see section 4.3).

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 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 warfarin from its protein binding sites. It is therefore recommended that if bicalutamide treatment is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

4.6     Pregnancy and lactation

Bicalutamide is contraindicated in females.

4.7     Effects on ability to drive and use machines

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.

4.8         Undesirable effects

Bicalutamide is generally well tolerated with a low rate of discontinuation of treatment due to adverse events. The pharmacological action of bicalutamide may give rise to certain expected undesirable effects, such as hot flushes, pruritus, as well as breast tenderness and gynaecomastia, which may be reduced by concomitant castration. Diarrhoea, nausea, vomiting, general asthenia and dry skin may also occur.

Changes in hepatic function (elevated transaminase levels, jaundice), sometimes severe, were observed when using bicalutamide. These changes were usually transient, resolving or improving with continued treatment or following discontinuation of therapy (see section 4.4).

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

Adverse reactions are presented according to the MedDRA system organ classes and MedDRA frequency convention:

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), including isolated reports.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common:

Nervous system disorders: Dizziness

Vascular disorders: Hot flush

Gastrointestinal disorders: Abdominal pain, constipation, nausea

Renal and urinary disorders: Haematuria

Reproductive system and breast disorders: Gynaecomastia and breast tenderness^a

General disorders and administration site conditions: Asthenia, chest pain, oedema

Common:

Cardiac disorders: Heart failure

Gastrointestinal disorders: Dryness of mouth, dyspepsia, flatulence

Hepatobiliary disorders: Hepatic changes (including elevated levels of transaminases, jaundice)/hepatobiliary disorders^b

Nervous system disorders: Insomnia, somnolence

Psychiatric disorders: Decreased libido, depression

Respiratory, thoracic and mediastinal disorders: Dyspnoea

Reproductive system and breast disorders: Impotence

Renal and urinary disorders: Nocturia

Blood and lymphatic system disorders: Anaemia

Skin and subcutaneous tissue disorders: Alopecia, hirsutism/hair re-growth, dry skin, pruritis, rash, sweating

Metabolism and nutrition disorders: Diabetes mellitus, hyperglycaemia, weight loss, anorexia

Investigations: Weight gain

General disorders and administration site conditions: Headache, pain, lower abdominal pain, chills

Uncommon:

Immune system disorders: Hypersensitivity reactions including angioneurotic oedema and urticaria

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease (ILD)

Rare:

Hepatobiliary disorders: Hepatic failure^c

___________________________________________________________________

^a   May be reduced by concomitant castration.

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

^c   Hepatic failure has occurred rarely in patients treated with bicalutamide, but a causal relationship has not been established iwht certainty. Periodic liver function testing should be considered (see also section 4.4)

4.9     Overdose

There is no human experience of overdose. 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 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: Hormone antagonists and related agents, anti-androgens,

ATC code: L02BB03

Bicalutamide is a non-steroidal anti-androgen without any other endocrine activity. It binds to androgen receptors without activating gene expression and thus inhibits androgen stimulation. Inhibition results in the regression of prostatic tumours. Treatment discontinuation may result in antiandrogen withdrawal syndrome in some patients.

Bicalutamide has low affinity for SHBG, although this is unlikely to be clinically significant.

BICALUTAMIDE GRINDEKS 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.

In long-term administration, peak plasma concentrations of bicalutamide (R)-enantiomer are tenfold greater than those measured following a single dose of bicalutamide 50 mg.

Steady state plasma concentrations of the (R)-enantiomer of approximately 9 microgram/ml are observed during daily administration of 50 mg doses of bicalutamide. Because of its long half-life, a steady state is generally reached within 1 month after initiation of treatment.

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 an anti-androgen and a mixed function oxidase enzyme inducer in animals. Enzyme induction has not been observed in man. Carcinogenicity studies in male mice showed an increase in hepatocellular neoplasms, including malignancies. An increased incidence of thyroid follicular adenomas and testicular Leydig cell tumours was observed in rats. Target organ changes, including tumour induction, in animals, are considered to be the result of these activities. Non-clinical data reveal no special hazard for patients with advanced prostate cancer.

6.       PHARMACEUTICAL PARTICULARS

6.1     List of excipients

Tablet core:

Lactose monohydrate

Povidone K-30

Sodium starch glycolate

Magnesium stearate

Tablet film:

Opadry White Y-1-7000, which contains:

Hypromellose

Titanium dioxide (E 171)

Macrogol 400

6.2       Incompatibilities

Not applicable.

6.3     Shelf life

3 years.

6.4     Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

6.5         Nature and contents of container

PVC/Al and PVC/PVDC/Al blisters

Pack sizes:

10, 14, 28, 30, 50, 60, 90, 100

Not all pack sizes may be marketed.

6.6     Special precautions for disposal and other handling

No special requirements.

7.       MARKETING AUTHORISATION HOLDER

Joint Stock Company GRINDEKS

53 Krustpils St., Riga, LV-1057, Latvia

Tel: +371 67083205

Fax: +371 67083505

E-mail: grindeks@grindeks.lv

8.       MARKETING AUTHORISATION NUMBER(S)

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.     DATE OF REVISION OF THE TEXT

02/2011