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 bicalutamide.

Excipients with known effect:

Each tablet contains 396 mg 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 '507'on one side and plain on the 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).

4.2 Posology and method of administration

Posology

Paediatric population

Bicalutamide is not indicated in children under the age of 18 years.

Adult males including the elderly

One film-coated tablet (150 mg) daily with or without food.

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

Route: oral

The tablets should be swallowed whole with liquid.

4.3 Contraindications

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

Bicalutamide is contra-indicated in children under the age of 18 years, and in females (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.

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-administering 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 150 mg. Patients should be advised to avoid direct exposure to excessive sunlight or UV-light while on bicalutamide 150 mg 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 ration including the potential for Torsade de pointes prior to initiating bicalutamide.

Antiandrogen therapy may cause morphological changes in spermatozoa. Although the effect of bicalutamide on sperm morphology has not been evaluated and no such changes have been reported for patients who received bicalutamide, patients and/or their partners should follow adequate contraception during and for 130 days after bicalutamide therapy.

Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant bicalutamide therapy, which may result in increased Prothrombin Time (PT) and International Normalised Ratio (INR). Some cases have been associated with risk of bleeding. Close monitoring of PT/INR is advised and anticoagulant dose adjustment should be considered (see sections 4.5 and 4.8).

4.5 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. There have been reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with bicalutamide. It is therefore recommended that if bicalutamide is administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustment of anticoagulant dose considered (see sections 4.4 and 4.8).

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

Pregnancy

Bicalutamide is contraindicated in females (see section 4.3) and should not be used during pregnancy.

Breastfeeding

Bicalutamide is contraindicated in females (see section 4.3) and should not be used during breast-feeding.

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

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 disease5 (fatal outcomes have been reported)

Gastrointestinal disorders

Common

Abdominal pain, constipation, dyspepsia, flatulence, nausea

Hepatobiliary disorders

Common

Rare

Hepatotoxicity, jaundice, hypertransaminasemia1

Hepatic failure3 (fatal outcomes have been reported)

Skin and subcutaneous tissue disorders

Very common

Common

Rare

Rash

Alopecia, hirsuitism/hair re-growth, dry skin3, pruritis

Photosensitivity reaction

Renal and urinary disorders

Common

Haematuria

Reproductive system and breast disorders

Very common

Common

Gynaecomastia and breast tenderness2

Erectile dysfunction

General disorders and administration site conditions

Very common

Common

Asthenia

Chest pain, oedema

Investigations

Common

Weight increased

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

2. 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.

3. 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.

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 150 mg EPC studies.

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 randomized treatment period of the 150 mg EPC studies.

Increased PT/INR: Accounts of coumarin anticoagulants interacting with bicalutamide have been reported in post-marketing surveillance (see sections 4.4 and 4.5).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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-androgen, ATC code L02 B B03.

Mechanism of action

Bicalutamide is a non-steroidal anti-androgen, 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.

Clinical efficacy and safety

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 summarized in the following tables:

Table 2 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 3 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

17.0%

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 localized 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 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 (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.

Paediatric population

No studies have been conducted in paediatric patients (see sections 4.3 and 4.6).

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 metabolized (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 (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.

On daily administration of bicalutamide 150 mg, 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 22 microgram/ml are observed during daily administration of bicalutamide 150 mg. 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 150 mg bicalutamide was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and 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. Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all species examined. Reversal of testicular atrophy occurred 4 months after the completion of dosing in a 6-month rat study (at doses of approximately 0.6 times human therapeutic concentrations at the recommended dose of 150 mg). No recovery was observed at 24 weeks after the completion of dosing in a 12-month rat study (at doses of approximately 0.9 times human concentrations at the recommended human dose of 150 mg). Following 12 months of repeated dosing in dogs (at doses of approximately 3 times human therapeutic concentrations at the recommended human dose of 150 mg), the incidence of testicular atrophy was the same in dosed and control dogs after a 6-month recovery period. In a fertility study (at doses of approximately 0.6 times human therapeutic concentrations at the recommended human dose of 150 mg), male rats had an increased time to successful mating immediately after 11 weeks of dosing; reversal was observed after 7 weeks off-dose.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Lactose monohydrate

Magnesium stearate

Sodium starch glycolate Type A

Povidone.

Tablet coating

Opadry II White (33F28627) containing:

Hypromellose 6CP (E464)

Titanium dioxide (E171)

Lactose monohydrate

Macrogol 3000.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 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/Aluminium foil blister in pack sizes of 28, 30 and 84 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

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

7. Marketing authorisation holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing authorisation number(s)

PL 31750/0007

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 03/08/2010

Date of latest renewal: 21/06/2015

10. Date of revision of the text

08/05/2018