Bicalutamide 50mg Film-Coated Tablets.
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bicalutamide 50 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50 mg bicalutamide.
Excipient:
Each tablet contain 33.25 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 “93” on one side and “220” on the other
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of advanced prostatic carcinoma in combination with luteinising hormone-releasing hormone (LHRH) analogue or surgical castration
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 treatment should be started within 1 week prior to the administration of an LHRH analogue or at the same time as surgical castration.
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 section 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).
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.
This product contains 35 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
There is no evidence of any pharmacodynamic or pharmacokinetic interactions between bicalutamide and LHRH analogues.
In vitro studies suggest that R-bicalutamide is an inhibitor of CYP 3A4 and has a weaker 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. 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 Very 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 Very common: Dizziness
Common: Somnolence
Vascular disorders Very common: Hot flush
Respiratory, thoracic and mediastinal disorders
Uncommon: Interstitial lung diseasea (fatal outcomes have been reported) Gastrointestinal disorders
Very common: Abdominal pain, constipation, nausea Common: Dyspepsia, flatulence
Hepatobiliary disorders
Common: Hepatotoxicitiy, jaundice, hypertransaminasaemia b Rare: Hepatic failure (fatal outcomes have been reported)c
Skin and subcutaneous tissue disorders
Common: Alopecia, hirsutism/hair re-growth, dry skin, pruritis, rash
Renal and urinary disorders Very common: Haematuria
Reproductive system and breast disorders Very common: Gynaecomastia, breast tendernessd,
Common: Erectile dysfunction
General disorders and administration site conditions Very common: Asthenia, oedema Common: Chest pain
Cardiac disorders
Common: Myocardial infarctione (fatal outcomes have been reported), cardiac failuree
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 May be reduced by concomitant castration.
e Observed in a pharmaco-epidemiology study of LHRH agonists and anti-androgens used in the treatment of prostate cancer. The risk appeared 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.
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.
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 50mg, the plateau plasmatic concentrations of the (R)-enantiomer reach approximately 9pg/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, 50, 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 00289/0980
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/04/2008 / 27/10/2008
10 DATE OF REVISION OF THE TEXT
01/08/2014