Document: spc-doc_PL 36390-0097 change

• spc-doc_PL 04854-0030
• spc-doc_PL 11204-0330
• spc-doc_PL 14048-0023
• spc-doc_PL 17907-0504
• spc-doc_PL 18909-0230
• spc-doc_PL 20117-0051
• spc-doc_PL 22983-0002
• spc-doc_PL 30306-0225
• spc-doc_PL 36390-0097
• spc-doc_PL 40378-0135

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bicalutamide 150 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg bicalutamide.

Excipients with known effects:

Each film-coated tablets contains 183mg 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 bevelled edge film-coated tablet debossed with 150 on one side and plain on other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Bicalutamide 150 mg is indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk for disease progression (see section 5.1).

Bicalutamide 150 mg is also indicated for the management of patients with locally advanced, non-metastatic prostate cancer for whom surgical castration or other medical intervention is not considered appropriate or acceptable.

4.2 Posology and method of administration

Posology

Adult males including older people

The dosage is one 150 mg tablet to be taken orally once a day.

Bicalutamide 150 mg should be taken continuously for at least 2 years or until disease progression.

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 150 mg 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 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.

For patients who have an objective progression of disease together with elevated PSA, cessation of Bicalutamide therapy should be considered.

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.

Interaction with other medicinal products and other forms of interaction

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 disorde rs			Hypersen sitivity reactions 5 angioede ma and urticaria
Metabolis m and nutrition disorders		De cre ase d app etit e
Psychiatric disorder		Decreased libido Depressio n
Nervou s system disorde rs		Dizziness Somnolen ce
Cardiac disorde rs						QT prolongatio n (see sections 4.4 and 4.5).

Vascular disorders		Hot flush
Respiratory, thor acic and medi astin al disor ders			Interstitial lung Disease e(fatal outcom es have been reporte d).
Gastroi ntestina l disorde rs		Abdomi nal pain Const ipatio n Dy spe psi a Fla tule nce Na use a
Hepat obiliar y disord ers		Hepatot oxicity, jaundice 5 hypertra nsamina saemiaa		Hepatic failured (fatal outcom es have been reporte d).
Skin and subcutaneo us tissue disorders	Rash	Alopecia Hirsuiti sm/hair regrowt h Dry skinc Pruritis		Photosensit ivity reaction
Renal and urinary disorders		Haematur ia
Reprodu ctive system and breast disorders	Gynaec omastia and breast tendern essb	Erect ile dysf uncti on

General disorders and administr ation site conditions	Asthenia	Chest pain Oedema
Investigatio ns		Weight increased

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

b.    The majority of patients receiving bicalutamide 150 mg as monotherapy experience gynaecomastia and/or breast pain. In studies these symptoms were considered to be severe in up to 5% of the patients. Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.

c.    Due to the coding conventions used in the EPC studies, adverse events of 'dry skin' were coded under the COSTART term of 'rash'. No separate frequency descriptor can therefore be determined for the 150 mg bicalutamide dose however the same frequency as the 50 mg dose is assumed.

d.    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.

e.    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 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 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non-metastatic prostate cancer in a combined analysis of three placebo controlled, double-blind studies in 8113 patients, where bicalutamide was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). At 9.7 years median follow up, 36.6% and 38.17% of all bicalutamide and placebo-treated patients, respectively, had experienced objective disease progression.

A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.

No overall survival difference was seen at 9.7 years median follow up with 31.4% mortality (HR= 1.01; 95% CI 0.94 to1.09). However, some trends were apparent in exploratory subgroup analyses.

Data on progression-free survival and overall survival over time based on Kaplan-Meier estimates for patients with locally advanced disease are summarised in the following tables:

Table 2: Proportion of locally advanced disease patients with disease progression over time by therapy sub-group__

Analysis	Treatment	Events (%)	Events (%)	Events (%)	Events (%)
population	Arm	at 3 years	at 5 years	at 7 years	at 10 years

Watchful waiting (n=657)	Bicalutamid e 150 mg	19.7%	36.3%	52.1%	73.2%
	Placebo	39.8%	59.7%	70.7%	79.1%
Radiotherap y(n=305)	Bicalutamid e 150 mg	13.9%	33.0%	42.1%	62.7%
	Placebo	30.7%	49.4%	58.6%	72.2%
Radical prostatectom y(n=1719)	Bicalutamid e 150 mg	7.5%	14.4%	19.8%	29.9%
	Placebo	11.7%	19.4%	23.2%	30.9%

Table 3: Overall survival in locally advanced disease by therapy subgroup

Analysis population	Treatment Arm	Events (%) at 3 years	Events (%) at 5 years	Events (%) at 7 years	Events (%) at 10 years
Watchful waiting (n=657)	Bicalutamid e 150 mg	14.2%	29.4%	42.2%	65.0%
	Placebo	17.0%	36.4%	53.7%	67.5%
Radiotherap y(n=305)	Bicalutamid e 150 mg	8.2%	20.9%	30.0%	48.5%
	Placebo	12.6%	23.1%	38.1%	53.3%
Radical prostatectom y(n=1719)	Bicalutamid e 150 mg	4.6%	10.0%	14.6%	22.4%
	Placebo	4.2%	8.7%	12.6%	20.2%

For patients with localised disease receiving bicalutamide alone, there was no significant difference in progression free survival. There was no significant difference in overall survival in patients with localised disease who received bicalutamide as adjuvant therapy, following radiotherapy (HR=0.98; 95% CI 0.80 to 1.20) or radical prostatectomy (HR=1.03; 95% CI 0.85 to 1.25). In patients with localised disease, who would otherwise have been managed by watchful waiting, there was also a trend toward decreased survival compared with placebo patients (HR=1.15; 95% CI 1.00 to 1.32). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in patients with localised disease.

In a separate programme, the efficacy of bicalutamide 150 mg for the treatment of patients with locally advanced non-metastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of 2 studies with 480 previously untreated patients with nonmetastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between bicalutamide and castration in survival (hazard ratio = 1.05 [CI 0.81 to 1.36]); however, equivalence of the two treatments could not be concluded statistically.

In a combined analysis of 2 studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, bicalutamide 150 mg was demonstrated to be less effective than castration in survival time (hazard ratio = 1.30 [CI 1.04 to 1.65]), with a numerical difference in estimated time to death of 42 days (6 weeks) over a median survival time of 2 years.

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 (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 (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 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.

6.3 Shelf life

2 years.

6.4    Special precautions for storage

Store below 25°C

6.5    Nature and contents of container

PVC/Aluminium foil blister packs comprising strips of 5, 10 and 14 tablets to give pack sizes of 10, 20, 30, 40, 50, 80, 90, 100, 200 or 14, 28, 56, 84, 140 and 280 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,