Bicalutamide 150mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bicalutamide 150 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 150 mg bicalutamide.
Excipient:
Each tablet contains 99.75 mg lactose anhydrous For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film coated tablet Description:
white to off-white biconvex film-coated tablets, debossed with “BCL” on one side and plain on the other
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Bicalutamide 150mg 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).
4.2 Posology and method of administration
Adult men including elderly patients:
One tablet once daily at the same time each day (usually in the morning or in the evening).
The minimum duration of treatment is 2 years or until disease progression.
Renal impairment
No adjustment of the dose is needed in patients with impaired renal function.
Hepatic impairment
No adjustment of the dose is needed in patients with mild impairment of hepatic function.
Patients with moderate to severe hepatic impairment may experience increased accumulation of bicalutamide (see section 4.4).
Children and adolescents
Bicalutamide is contraindicated in children (see section 4.3).
4.3 Contraindications
Hypersensitivity to bicalutamide or to any of the excipients (see sections 4.4 and 6.1). Bicalutamide is contraindicated in females and children (see section 4.6). Concomitant administration of terfenadine, astemizole and cisapride (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. Available data suggest that the elimination may be slower in patients with severe hepatic impairment, which may lead to increased accumulation of the substance. Therefore, caution is needed if bicalutamide is administered to 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.
Bicalutamide has been shown to inhibit cytochrome P450 (CYP 3A4), as such caution should be exercised when co-administered with drugs metabolized predominantly by CYP 3A4 (see sections 4.3 and 4.5).
For patients who have an objective progression of disease together with elevated PSA, cessation of bicalutamide therapy should be considered.
This product contains 105 mg lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5. Interaction with other medicinal products and other forms of interaction
In vitro studies suggest that R-bicalutamide is an inhibitor of CYP 3A4 and has weaker inhibitory effects on the CYP 2C9, 2C19, and 2D6 activities.
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. Therefore, concomitant administration of terfenadine, astemizole and cisapride is contraindicated (see section 4.3) and caution is required when concomitantly prescribing ciclosporin and calcium channel blockers. Dosage reduction may be required for these products, particularly if there is evidence of enhanced or adverse effect. For ciclosporin, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of bicalutamide therapy.
Caution is required during concomitant administration of substances that might inhibit oxidation of bicalutamide, i.e. medicinal products containing ketoconazole or cimetidine. 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 protein binding sites. Therefore, frequent and regular monitoring of prothrombin time is recommended after starting the administration of bicalutamide to patients who concomitantly use coumarin anticoagulants.
4.6 Fertility, pregnancy and lactation
Bicalutamide is contraindicated in women; therefore it must not be administered either in pregnancy, or in lactation.
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, adverse events are defined as follows: very common (>1/10); common
(>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare
(<1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders Common: Anaemia
Immune system disorders
Uncommon: Hypersensitivity, angiooedema and urticaria
Metabolism and nutrition disorders Common: Decreased appetite
Psychiatric disorders
Common: Decreased libido, depression
Nervous system disorders Common: Dizziness, somnolence
Vascular disorders Common: Hot flush
Respiratory, thoracic and mediastinal disorders
Uncommon: Interstitial lung disease3 (fatal outcomes have been reported) Gastrointestinal disorders
Common: Abdominal pain, constipation, dyspepsia, flatulence, nausea Hepatobiliary disorders
Common: Hepatotoxicitiy, jaundice, hypertransaminasaemiab Rare: Hepatic failurec (fatal outcomes have been reported)
Skin and subcutaneous tissue disorders Very common: Rash
Common: Alopecia, hirsutism/hair re-growth, dry skind, pruritis
Renal and urinary disorders Common: Haematuria
Reproductive system and breast disorders Very common: Gynaecomastia, breast tendernesse Common: Erectile dysfunction
General disorders and administration site conditions Very common: Asthenia Common: Chest pain, oedema
Investigations:
Common: Weight increased
a 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.
b Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
c 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.
d 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.
e 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
There is no experience with overdose in humans. There is no specific antidote and 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 treatment including frequent monitoring of vital functions is indicated.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-androgens ATC code: L02BB03
Bicalutamide is a non-steroidal anti-androgen without any other endocrine activity. It binds to androgen receptors without activating gene expression and thus inhibits androgen stimulation. Inhibition results in the regression of prostatic tumours. Treatment discontinuation may result in anti-androgen withdrawal syndrome in some patients.
Bicalutamide is a racemate, the (R)-enantiomer of which has most of the antiandrogen activity.
Bicalutamide 150mg was studied as a treatment for patients with localized (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 8,113 patients, where the product was given as immediate hormone therapy or as adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation). At 7.4 years median followup, 27.4 % of all bicalutamide-treated patients and 30.7 % of all placebo-treated patients 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 7.4 years median follow-up with 22.9% mortality (HR = 0.99; 95% confidence interval 0.91 to 1.09). However some trends were apparent for patients in exploratory subgroup analyses.
Progression-free survival and overall survival data for patients with locally advanced disease are summarised in the following tables:
Table 1
Progression-free survival in locally advanced disease by therapy sub-group
|
Analysis population |
Events (%) in Bicalutamide patients |
Events (%) in placebo patients |
Hazard ratio (95% CI) |
|
Watchful waiting |
193/335 (57.6) |
222/322 (68.9) |
0.60 (0.49 to 0.73) |
|
Radiotherapy |
66/161 (41.0) |
86/144 (59.7) |
0.56 (0.40 to 0.78) |
|
Radical prostatectomy |
179/870 (20.6) |
213/849 (25.1) |
0.75 (0.61 to 0.91) |
Table 2
Overall survival in locally advanced disease by therapy sub-group
|
Analysis population |
Deaths (%) in Bicalutamide patients |
Deaths (%) in placebo patients |
Hazard ratio (95% CI) |
|
Watchful waiting |
164/335 (49.0) |
183/322 (56.8) |
0.81 (0.66 to 1.01) |
|
Radiotherapy |
49/161 (30.4) |
61/144 (42.4) |
0.65 (0.44 to 0.95) |
|
Radical prostatectomy |
137/870 (15.7) |
122/849 (14.4) |
1.09 (0.85 to 1.39) |
For patients with localised disease, receiving bicalutamide alone, there was no significant difference in progression free survival. In these patients there was also a trend toward decreased survival compared with placebo patients (HR=1.16, 95% CI 0.99 to 1.37). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in this group of patients.
The effectiveness of bicalutamide 150mg in the treatment of patients with locally advanced prostatic carcinoma without metastases, for whom primary treatment with hormones was indicated, was evaluated separately using the meta-analysis of two studies comprising 480 patients with prostatic carcinoma without metastases (M0) who had not been treated before. There was no significant difference in survival (HR=1.05 (CI=0.81-1.36), p=0.669) or in the interval until progression (HR=1.20 (CI 0.96-1.51), p=0.107) between the group treated with bicalutamide 150mg and the group treated with castration.
A general trend with respect to quality of life in favour of bicalutamide 150mg in comparison with castration was observed; the subgroups that provided these data showed significantly higher sexual appetence (p=0.029) and fitness (p=0.046).
Combined analysis of 2 clinical studies comprising 805 patients with metastatic prostatic carcinoma, who had not been treated before with expected mortality 43%, showed that the treatment with bicalutamide 150mg is less effective than castration as for the survival time (HR=1.30 [confidence interval 1.04 - 1.65]). The estimated difference is 42 days while the mean survival time is 2 years.
5.2 Pharmacokinetic properties
Bicalutamide is well-absorbed after oral administration. Food has not proved to affect significantly the extent of bioavailability of bicalutamide.
The (S)-enantiomer is rapidly excreted in comparison with the (R)-enantiomer. The plasmatic elimination half-life is approximately one week.
After regular daily administration, the plasmatic concentration of the (R)-enantiomer when compared to the (S)-enantiomer is approximately 10times higher due to its long elimination half-life.
After a daily dose of 150mg, the plateau plasmatic concentrations of the (R)-enantiomer reach approximately 22pg/ml. Of the total amount of plasmatic plateau enantiomers, 99% of the (R)-enantiomer is responsible for the therapeutic action.
Age, renal impairment or mild to moderate hepatic impairment do not affect the pharmacokinetics of (R)-enantiomer. It was demonstrated that plasmatic elimination of the (R)-enantiomer is slower in patients with severe hepatic impairment.
Bicalutamide binds to proteins: (racemate 96%, (R)-enantiomer more than 99%) and is extensively metabolised (via oxidation and glucuronidation): the metabolites are excreted equally via kidneys and bile.
5.3 Preclinical safety data
Bicalutamide is a pure and potent androgen receptor antagonist in experimental animals and humans. The main secondary pharmacological action is induction of CYP450-dependent mixed function oxidases in the liver. Target organ changes in animals are clearly related to the primary and secondary pharmacological action of bicalutamide, and comprise involution of androgen-dependent tissues, thyroid, hepatic and Leydig cell hyperplasias and neoplasias or cancer, disturbance of male offspring sexual differentiation and reversible impairment of fertility in males. Genotoxicity studies did not reveal any mutagenic potential. All adverse effects observed in animal studies are considered to be species-specific, having no relevance for humans in the indicated clinical setting.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Microcrystalline cellulose Povidone
Croscarmellose sodium Sodium laurilsulfate Lactose monohydrate Anhydrous colloidal silica Magnesium stearate
Coating:
Hypromellose Polydextrose Titanium dioxide Macrogol 4000
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package
6.5 Nature and contents of container
Transparent PVC/PVdC/Al blister, cardboard carton 20, 28, 30, 40, 56, 60, 84, 90, and 100 film coated tablets Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG
8 MARKETING AUTHORISATION NUMBER
PL 00289/0981
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/08/2008 / 27/10/2008
10
DATE OF REVISION OF THE TEXT
01/08/2014