Bicalutamide 50 Mg Film-Coated Tablets

Document: spc-doc_PL 17907-0503 change

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 of bicalutamide as active ingredient. Excipient with known effect: Also 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

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

Posology

Adult males including the elderly: The dosage is one 50 mg tablet to be taken orally once a day.

Paediatric Population

Bicalutamide film-coated tablets 50 mg is contraindicated in children and adolescents.

Patients with 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).

Patients with 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).

Method of administration

For oral administration.

The tablet should be swallowed whole with a glass of water.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

Bicalutamide film-coated tablets 50 mg is contraindicated in females and children and adolescents (see section 4.6).

Co-administration of terfenadine, astemizole or cisapride with bicalutamide is contraindicated (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 suggest 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. Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating bicalutamide.

Important information regarding the ingredients of this medicine

This medicine 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) and caution should be exercised with the coadministration 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 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.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of bicalutamide with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults

4.6 Fertility, pregnancy and lactation

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

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.

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 the lymphatic system disorders	Very common	Anaemia
Immune system disorders	Uncommon	Hypersensitivity, angioedema and urticaria
Metabolism and nutrition disorders	Common	Decreased appetite
	Common	Diabetes mellitus
	Uncommon	Elevation of blood glucose
Psychiatric disorders	Common	Decreased libido
		Depression
Nervous system disorders	Very common	Dizziness
	Common	Somnolence
Cardiac disorders	Common	Myocardial infarction (fatal outcomes have been reported)⁴, Cardiac failure⁴

	Not known	QT prolongation (see sections 4.4 and 4.5).
Vascular disorders	Very common	Hot flush
Respiratory, thoracic	Uncommon	Interstitial lung disease^e
and mediastinal		(fatal outcomes have been
disorders		reported).
Gastrointestinal disorders	Very common	Abdominal pain Constipation Nausea
	Common	Dyspepsia Flatulence
Hepato-biliary	Common	Hepatotoxicity, jaundice,
disorders		hypertransaminasaemia¹
	Rare	Hepatic failure² (fatal outcomes have been reported).
Skin and subcutaneous tissue	Common	Alopecia
disorders		Hirsuitism/hair re-growth Dry skin Pruritis, rash
Renal and urinary disorders	Very common	Haematuria
Reproductive system	Very common	Gynaecomastia and breast
and breast disorders		tenderness³
	Common	Erectile dysfunction
General disorders and administration site	Very common	Asthenia
conditions		Oedema
	Common	Chest pain
Investigations	Common	Weight increased

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 anti-androgens 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 overdosage. Since bicalutamide belongs to the anilide compounds there is a theoretical risk of the development of methaemoglobinaemia. Methaemoglobinaemia has been observed in animals after 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, Antiandrogens, ATC code:L02 BB03

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

Bicalutamide is a racemate with its antiandrogen activity being almost exclusively in the R-enantiomer.

5.2 Pharmacokinetic properties

Absorption

Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.

Distribution

Bicalutamide is highly protein bound (racemate 96%, (R)-enantiomer >99%) and extensively metabolised (oxidation and glucuronidation); its metabolites are eliminated via the kidneys and bile in approximately equal proportions.

Biotransformation

The (S)-enantiomer is rapidly cleared relative to (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.

On daily administration of bicalutamide , the (R)-enantiomer accumulates about 10fold 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. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

Elimination

In a clinical study the mean concentration of R-bicalutamide in semen of men receiving bicalutamide150 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.

Special populations

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.

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 om humans.

Target organ changes, including tumour induction (Leydig cells, thyroid, liver) in animals, are related to these activities. Enzyme induction has not been observed in man and none of these findings is considered to have relevance to the treatment of patients with prostate cancer. Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all species examined. Full reversal of testicular atrophy was 24 weeks after a 12-month repeated dose toxicity study in rats, although functional reversal was evident in reproduction studies 7 weeks after the end of an 11 week dosing period. A period of subfertility or infertility should be assumed in man.

6.1 List of excipients

Lactose monohydrate Povidone K-25 Sodium starch glycolate Magnesium Stearate

Opadry OY (consists of hypromellose (5cP), titanium dioxide (E171), propylene glycol)

6.2 Incompatibilities

None

6.3 Shelf life

5 years

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/Al blister packs of 10, 14, 20, 28, 30, 40, 50, 56, 80, 84, 90, 100, 140, 200, and 280 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Bristol Laboratories Ltd,

Unit 3, Canalside,

Northbridge Road, Berkhamsted, Herts, HP4 1EG, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 17907/0503

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/08/2015

10 DATE OF REVISION OF THE TEXT

18/08/2015

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

Listed as an adverse drug reaction following review of post-marketed data.

Frequency has been determined from the incidence of reported adverse events of