Bicalutamide 50mg Film-Coated Tablets.

Document: spc-doc_PL 04569-1003 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 50mg bicalutamide.

Excipient with known effect:

Each 50 mg tablet contains 69.26 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

White round, bi-convex, film-coated tablet with ‘BIC 50’ on one side and ‘G’ on the

other.

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 older people: one tablet (50mg) once a day.

Treatment with Bicalutamide tablets should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration.

Paediatric population

Bicalutamide is contraindicated in children (see section 4.3).

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).

Method of administration For oral use.

4.3 Contraindications

Bicalutamide is contraindicated in females (see section 4.6) and children.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

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.

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 preexisting 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

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).

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 contra-indicated (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 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 tablets 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 Pregnancy and lactation

Bicalutamide is contraindicated in females (see section 4.3) 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

Bicalutamide in general, has been well tolerated with few withdrawals due to adverse events.

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
Immune system disorders	Uncommon	Hypersensitivity, angioedema, and urticaria
Metabolism and nutrition disorders	Common	Decreased appetite
Psychiatric disorders	Common	Decreased libido, depression
Nervous System Disorders	Very common Common	Dizziness Somnolence
Cardiac disorders	Common	Myocardial infarction (fatal outcomes have been reported)¹, cardiac failure¹
	Not known	QT prolongation (see sections 4.4 and 4.5)
Vascular disorders	Very common	Hot flush
Respiratory, thoracic and mediastinal disorders	Uncommon	Interstitial lung disease², (fatal outcomes have been reported)
Gastrointestinal disorders	Very common Common	Abdominal pain, constipation, nausea Dyspepsia, flatulence

Hepato-biliary disorders	Common Rare	Hepatotoxicity, jaundice, hypertransaminasaemia³ Hepatic failure⁴ (fatal outcomes have been reported.
Skin and	Common	Alopecia, hirsutism/ hair re-growth, dry skin,
subcutaneous tissue disorders		prurituis, rash
Renal and	Very	Haematuria
urinary disorders	common
Reproductive	Very	Gynaecomastia and breast tenderness⁵
system and breast disorders	common
	Common	Erectile dysfunction
General	Very	Asthenia, oedema
disorders and	common
administration site conditions	Common	Chest pain
Investigations	Common	Weight gain

1 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 bicalutamide150 mg was used as a monotherapy to treat prostate cancer.

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 interstitial pneumonia in the randomised treatment period of the 150 mg EPC studies

3 Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy (see section 4.4)

4 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. Periodic liver function testing should be considered (see section 4.4)

5 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.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There is no human experience of overdosage. 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: Antiandrogens, ATC code: L02BB03 Mechanism of action

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 tablets 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

Absorption:

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

Distribution:

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 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.

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.

Biotransformation:

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

Elimination:

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

In a clinical study the mean concentration of R-bicalutamide in semen of men receiving bicalutamide 150 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.

5.3 Preclinical safety data

Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals. Target organ changes, including tumour induction, in animals, are related to these activities. None of the findings in the preclinical testing is considered to have relevance to the treatment of advanced prostate cancer patients.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core

Lactose monohydrate Povidone K-29/32 Sodium starch glycolate Magnesium stearate

Film Coating

Lactose monohydrate Hypromellose 15cp (E464) Titanium dioxide (E171) Triacetin

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

PVdC coated PVC blister strips with aluminium foil lidding. Pack sizes 28, 30, 40, 90 and 100.

Polypropylene tablet container with polyethylene lid (Securitamers). Pack sizes 28, 30, 100, 500 and 1000.

Al/Al blisters. Pack sizes 28, 30, 40, 90 and 100.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 04569/1003

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/01/2007

DATE OF REVISION OF THE TEXT

05/02/2015