Bicalutamide 50mg Film-Coated Tablets.

Document: spc-doc_PL 36390-0096 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bicalutamide 50mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg bicalutamide.

Excipients with known effects:

Each film-coated tablets contains 61mg of lactose monohydrate For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White to off-white, circular, biconvex film-coated tablet debossed, with 50 on one side and plain on the other side.

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 (50 mg) 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.

Paediatric population:

Bicalutamide 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).

Method of administration

For oral use only.

4.3 Contraindications

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

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.

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).

In rare cases, photosensitivity reactions have been reported for patients taking bicalutamide. Patients should be advised to avoid direct exposure to excessive sunlight or UV-light while on bicalutamide and the use of sunscreens may be considered. In cases where the photosensitivity reaction is more persistent and/or severe, an appropriate symptomatic treatment should be initiated.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

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 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 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) anti arrhythmic 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.

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

Frequency Organ\ System	Very Common	Common	Uncomm on	Rare	Very rare	Not known
Blood and lymphati c system disorders	Anaemia
Immun e system disorder s			Hypersens itivity reactions, angioede ma and urticaria
Metabolis m and nutrition disorders		De cre ase d app etit e
Psy chia tric diso rder		Decreased libido Depression
Nervou s system disorder	Dizziness	Somnolenc e

s
Cardiac disorders		Myo card ial infarctio n (fatal outcome s have been reported )⁴, Cardiac failure⁴			QT prolongati on (see sections 4.4 and 4.5).
Vascular disorders	Hot flush
Respiratory, thora cic and medi astin al disor ders			Interstitial lung disease ⁵ (Fatal outcom es have been reported ).
Gastroi ntestina l disorder s	Abdomin al pain Constipa tion Nausea	Dyspepsia Flatulence
Hepat obiliar y disord ers		Hepatot oxicity, jaundice 5 hypertra nsamina saemia¹		Hepatic failure²( fatal outcome s have been reported ).
Skin and subcutaneo us tissue disorders		Alopecia Hirsuiti sm/hair regrowth Dry skin Pruritus Rash		Photosens itivity reaction
Renal and urinary disorders	Haematuri a
Reproductiv e	Gynaecom astia	Erec tile

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General

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Asthenia

Oedema

Chest pain

Investigatio

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 anti-androgens used in the treatment of prostate cancer. The risk appears 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 the Yellow Card Scheme. Website: 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: Anti-androgens 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

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 (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.

Biotranformation

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 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.

Elimination

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.

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 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 Maize Starch Crospovidone Povidone

Sodium lauryl sulphate Colloidal anhydrous silica Magnesium Stearate Film Coating:

Hydroxy propyl methyl cellulose Titanium dioxide (E171)

Polyethylene glycol 400

6.2 Incompatibilities

Not applicable.

Shelf life

6.3

2 years.

6.4 Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

PVC/Aluminium foil blister packs packed in cartons containing 14 or 28 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7 MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited,

Hillbrow House,

Hillbrow Road,

Esher,

Surrey,

KT10 9NW

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0096

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

22/02/2011

10 DATE OF REVISION OF THE TEXT

25/06/2015