This information is intended for use by health professionals

1. Name of the medicinal product

Bicalutamide 150 mg film-coated Tablets

2. Qualitative and quantitative composition

Each tablet contains 150 mg of bicalutamide.

Excipients with known effect: One tablet contains 181.32 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

White, round, biconvex film-coated tablet, with the inscription “BCM 150” in one side.

4. Clinical particulars
4.1 Therapeutic indications

Bicalutamide 150 mg tablets are 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 tablets are 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

Adult males including the elderly

One 150 mg tablet once a day.

The tablets should be swallowed whole with liquid.

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

Children and adolescents

Bicalutamide is contraindicated in children and adolescents.

Renal impairment

No dose adjustment is necessary for patients with renal impairment

Hepatic impairment

No dose 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).

4.3 Contraindications

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

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

• Co-administration of terfenadine, astemizole or cisapride with bicalutamide 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 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).

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.

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

In vitro studies have shown that the (R)-enantiomer of 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 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 administering bicalutamide to patients taking medicinal products that inhibit the oxidation processes in the liver, e.g. cimetidine and ketoconazole. 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 site. It is therefore recommended that prothrombin time is closely monitored if bicalutamide is started in patients who are already receiving coumarin anticoagulants.

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).

4.6 Fertility, pregnancy and lactation

This medicinal product is contraindicated in women and must not be given to pregnant and 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 dizziness or somnolence may occur (see section 4.8). 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).

System Organ Class

Frequency

Undesirable effect

Blood and the lymphatic system disorders

Common

Anaemia

Immune system disorders

Uncommon

Hypersensitivity

Angioedema

Urticaria

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Common

Decreased libido

Depression

Nervous system disorders

Common

Dizziness

Somnolence

Cardiac disorders

Not known

QT prolongation (see sections 4.4 and 4.5)

Vascular disorders

Common

Hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon

Interstitial lung disease1 (fatal outcomes have been reported)

Gastrointestinal disorders

Common

Abdominal pain

Constipation

Dyspepsia

Flatulence

Nausea

Hepato-biliary disorders

Common

Hepatotoxicity

Jaundice

Hypertransaminasaemia2

Rare

Hepatic failure3 (fatal outcomes have been reported)

Skin and subcutaneous tissue disorders

Very common

Rash

Common

Alopecia

Hirsutism/hair growth

Dry skin4

Pruritis

Renal and urinary disorders

Common

Haematuria

Reproductive system and breast disorders

Very common

Gynaecomastia and breast tenderness5

Common

Erectile dysfunction

General disorders and administration site conditions

Very common

Asthenia

Common

Chest pain

Oedema

Investigations

Common

Weight increased

1 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.

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

3 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.

4 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.

5 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.

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

No case of overdose has been reported. There is no specific antidote; treatment should be symptomatic. Dialysis is unlikely to 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, anti-androgens.

ATC code: L02BB03

Bicalutamide is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to the 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 the “anti-androgen withdrawal syndrome” in a sub-set of patients.

Bicalutamide 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 3 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 to 1.09). 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 1 Proportion of locally advanced disease patients with disease progression over time by therapy sub-group

Analysis population

Treatment arm

Events (%) at 3 years

Events (%) at 5 years

Events (%) at 7 years

Events (%) at 10 years

Watchful waiting

(n = 657)

Bicalutamide 150 mg

19.7

36.3

52.1

73.2

placebo

39.8

59.7

70.7

79.1

Radiotherapy

(n = 305)

Bicalutamide 150 mg

13.9

33.0

42.1

62.7

placebo

30.7

49.4

58.6

72.2

Radical prostatectomy

(n = 1719)

Bicalutamide 150 mg

7.5

14.4

19.8

29.9

placebo

11.7

19.4

23.2

30.9

Table 2 Overall survival in locally advanced disease by therapy sub-group

Analysis population

Treatment arm

Events (%) at 3 years

Events (%) at 5 years

Events (%) at 7 years

Events (%) at 10 years

Watchful waiting

(n = 657)

Bicalutamide 150 mg

14.2

29.4

42.2

65.0

placebo

17.2

36.4

53.7

67.5

Radiotherapy

(n = 305)

Bicalutamide 150 mg

8.2

20.9

30.0

48.5

placebo

12.6

23.1

38.1

53.3

Radical prostatectomy

(n = 1719)

Bicalutamide 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 150mg 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 two studies with 480 previously untreated patients with non-metastatic (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 (HR = 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 clinical studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, bicalutamide 150mg was demonstrated to be less effective than castration in survival time (HR = 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

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.

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 22μg/ml are observed during daily administration of bicalutamide 150mg. 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 in patients with severe hepatic impairment.

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

In clinical study, the mean concentration of (R)-enantiomer in semen of men receiving bicalutamide 150 mg was 4.9µg/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3µg/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 (Leydig cells, thyroid, liver) observed 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 the species examined.

Full reversal of the testicular atrophy was 24 weeks after a 12-month repeated dose toxicity study in rats, although the function reversion was evident in reproduction studies of 7 weeks, after the end of an 11 week dosing. A period of subfertility or infertility should be assumed in man.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Lactose monohydrate

Povidone K-29/32

Crospovidone (type A)

Sodium lauryl sulphate

Magnesium stearate

Film-coating

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Macrogol 4000

6.2 Incompatibilities

Not applicable.

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

20, 28, 30, 50, 84, 98 and 100 film-coated tablets in blister packs (PVC/PE/PVDC/ALU).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as:

Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

or

Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8. Marketing authorisation number(s)

PL 17780/0341

9. Date of first authorisation/renewal of the authorisation

21 November 2008

10. Date of revision of the text

11 June 2015