Document: spc-doc_PL 31774-0018 change

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• spc-doc_PL 20075-0074
• spc-doc_PL 20395-0076
• spc-doc_PL 25258-0089
• spc-doc_PL 30306-0515
• spc-doc_PL 31774-0018
• spc-doc_PL 36390-0096

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bicalutamide 50 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg bicalutamide.

Excipient(s): Each tablet contains 62.7 mg of lactose monohydrate For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Film-coated tablet

White, round, biconvex film-coated tablets, with diameter of 6.5 mm

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2 Posology and method of administration

Posology

Paediatric population

Bicalutamide is not-indicated in children and adolescents.

Method of administration

Adult males including the elderly: one film-coated tablet (50mg) daily with or without food.

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.

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. The medicinal product may accumulate in patients with moderate to severe hepatic impairment (see section 4.4).

4.3    Contraindications

Bicalutamide 50 mg is contra-indicated in female and children (see section 4.6). Bicalutamide must not be given to any patient who has shown a hypersensitivity reaction to the active substance or to any of the excipients listed in section 6.1.

Co-administration of terfenadine, astemizole or cisapride with Bicalutamide 50 mg is contra-indicated. (see section 4.5)

4.4    Special warnings and precautions for use

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

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

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

Bicalutamide 50 mg contains lactose. 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 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 contraindicated (see section 4.3) andcaution should be exercised with the coadministration 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 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 sites. It is therefore recommended that if Bicalutamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

4.6    Fertility, pregnancy and lactation

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

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

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

System Organ Class	Frequency	Event
Blood and lymphatic system disorders	Very common	Anaemia
	Very rare	Thromb ocytop eni a
Immune system disorders	Uncommon	Hypersensitivity, angioedema and urticaria
Metabolism and nutrition disorders	Common	Decreased appetite, diabetes mellitus
	Uncommon	Hyperglycaemia, weight loss
Psychiatric disorders	Common	Decreased libido, depression
Nervous system disorders	Very common	Dizziness
	Common	Somnolence, insomnia
Cardiac disorders	Common	Myocardial infarction (fatal outcomes have been reported)4, Cardiac failure4
	Very rare	Angina, conduction defects including PR and QR interval prolongation, arrhythmias and non specific ECG changes
Vascular disorders	Very common	Hot flush
Respiratory, thoracic and mediastinal disorders	Uncommon	Interstitial lung disease5 (fatal outcomes have been reported).
	Uncommon	Dyspnoea
Gastrointestinal disorders	Very common	Abdominal pain, constipation, nausea
	Common	Dyspepsia, flatulence, diarrhoea
	Uncommon	Dry mouth
	Rare	Vomiting
Hepato-biliary disorders	Common	Hepatotoxicity, jaundice, bilirubinemia, hepatomegaly, cholestasis and hypertransaminasaemia1
	Rare	Hepatic failure (fatal outcomes have been reported).
Skin and subcutaneous tissue disorders	Common	Alopecia , hirsutism/hair regrowth, dry skin, pruritus, rash, sweating
	Rare	Photosensitivity reaction
Renal and urinary disorders	Very common	Haematuria

	Uncommon	Nocturia
Reproductive system and breast disorders	Very common	Gynaecomastia and breast tenderness3
	Common	Erectile dysfunction, impotence
General disorders and administration site conditions	Very common	Asthenia, oedema
	Common	Chest pain, general pain, pelvic pain, chills
	Uncommon	Headache, pain in the back, neck pain
Investigations	Common	Weight increased

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

2.    Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of hepatic failure in patients receiving treatment in the open-label bicalutamide arm of the 150 mg EPC studies.

3.    May be reduced by concomitant castration.

4.    Observed in a pharmaco-epidemiology study of LHRH agonists and antiandrogens used in the treatment of prostate cancer. The risk appeared to be increased when bicalutamide 50 mg was used in combination with LHRH agonists, but no increase in risk was evident when bicalutamide 150 mg was used as a monotherapy to treat prostate cancer.

5.    Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of interstitial pneumonia in the randomised treatment period of the 150 mg EPC studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hormone antagonists and related agenty, antiadrogen, ATC code: L02BB03.

Bicalutamide 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 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.

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.

Following a long-term administration of bicalutamide, the peak concentration of the (R)-enantiomer in the plasma is about 10-fold, as compared to the levels measured after a single dose of 50mg of Bicalutamide.

A dosing scheme of 50mg Bicalutamide daily will result in a steady-state concentration of the R-enantioner of 9 pg/ml and as a consequence of its long half-life, steady state is reached after approximately 1 month of therapy.

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 to 96%, R-enantiomer > 99% ) 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 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 liver. Enzyme induction has not been observed I humans. Target organs 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 mutagenic 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Lactose monohydrate Povidone K- 25

Sodium starch glycolate (Type A)

Magnesium Stearate

Film-Coating:

Opadry OY-S-9622 consisting of:

Hypromellose 5 Cp (E464)

Titanium dioxide (E171)

Propylene Glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 Months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

PVC/PVDC/Aluminium blisters