Bicalutamide 50 Mg 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 of bicalutamide.
Excipients with known effect: each tablet contains 60.44 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, debossed with BCM 50 on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of advanced prostate cancer in combination with luteinising hormonereleasing hormone (LHRH) analogue therapy or surgical castration.
4.2 Posology and method of administration
Posology
Adult males, including elderly patients: the dosage is one 50 mg tablet to be taken orally once a day.
Paediatric population
Bicalutamide is not indicated in children or adolescents. Method of administration
The tablets should be swallowed whole with liquid.
Treatment with Bicalutamide should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration.
Renal impairment
No dose adjustment is necessary in patients with renal impairment. There is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4).
Hepatic impairment
No dose adjustment is necessary for patients with mild hepatic impairment. The medicinal product may accumulate in patients with moderate to severe hepatic impairment (see section 4.4.).
4.3 Contraindications
Bicalutamide is contraindicated in females and children (see section 4.6).
Bicalutamide must not be given to any patient who has shown a 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 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 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.
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.
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).
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.
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 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 site. 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) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).
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 form the available data).
Table 1: frequency of adverse reactions
|
System Organ Class |
Frequency |
Bicalutamide 50mg (+ LHRH analogue) |
|
Blood and lymphatic system disorders |
Very common |
Anaemia |
|
Immune system disorders |
Uncommon |
Hypersensitivity, angioedema and urticaria |
|
Metabolism and nutrition disorders |
Common |
Decreased appetite |
|
Psychiatric disorders |
Common |
Decreased libido, Depression |
|
Nervous System Disorders |
Very common Common |
Dizziness Somnolence |
Cardiac disorders Unknown
QT prolongation (see
|
sections 4.4 and 4.5) | ||
|
Vascular |
Very |
Hot flush |
|
disorders |
common | |
|
Respiratory, |
Uncommon |
Interstitial lung diseaseb |
|
thoracic and |
(fatal outcomes have | |
|
mediastinal disorders |
been reported) | |
|
Gastrointestinal |
Very |
Abdominal pain, |
|
disorders |
common |
Constipation, Nausea |
|
Common |
Dyspepsia, Flatulence | |
|
Hepato-biliary |
Common |
Hepatotoxicity, |
|
disorders |
Jaundice, hypertransaminasaemiac, | |
|
Rare |
Hepatic failured, (fatal outcomes have been reported) | |
|
Skin and |
Common |
Alopecia, Hirsuitism/ |
|
subcutaneous |
hair re-growth, Dry skin, | |
|
tissue disorders |
Pruritis, Rash | |
|
Renal and urinary |
Very |
Haematuria |
|
disorders |
common | |
|
Reproductive |
Very |
Gynaecomastia and |
|
system and breast disorders |
common |
breast tendernesse |
|
Common |
Erectile dysfunction | |
|
General disorders |
Very |
Asthenia, Oedema |
|
and administration site conditions |
common | |
|
Common |
Chest pain | |
|
Investigations |
Common |
Weight increased |
a 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.
b 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.
c Hepatic changes are rarely severe and were frequently transient,
resolving or improving with continued therapy or following cessation of therapy.
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 May be reduced by concomitant castration.
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 over dosage. 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: L02 B B03
Bicalutamide is a non-steroid anti-androgen; it has no additional endocrine activity. It is bound to androgen receptors without activating gene expression and thereby inhibits androgen stimulation. The result of this inhibition is regression of prostate tumours. From the clinical point of view interruption of therapy in some patients could result in manifestation of the anti-androgen withdrawal syndrome.
Bicalutamide is a racemate with an anti-androgen effect, which is present almost exclusively in its R-enantiomer.
5.2 Pharmacokinetic properties
Bicalutamide is well absorbed after oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
S-enantiomer is rapidly cleared in comparison to the R-enantiomer, which half-life of plasmat elimination is approximately 1 week.
With regular daily administration of bicalutamide the concentration of the R-enantiomer in plasma in comparison with S-enantiomer is approximately tenfold, which is caused by its lengthy elimination half-life.
The plasma concentrations of R-enantiomer reach approximately 9 microgram/ml in the case of a daily dose of 50 mg of bicalutamide. From the total number of enantiomers present in plasma in the steady state there is 99% of R-enantiomer, which has a dominant share in the therapeutic effect.
Pharmacokinetics of R-enantiomer are not affected by age, renal impairment or mild to moderate hepatic impairment. It has been shown that in patients with severe liver impairment the R-enantiomer is eliminated slower from plasma.
Bicalutamide is highly protein bound (racemate 96%, R-Bicalutamide 99.6%) and is extensively metabolised (by oxidation and glucuronidation): its metabolites are eliminated via the kidneys and bile in approximately equal proportions. After excreting to bile, hydrolysis of glucuronides occurs.
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 liver. Enzyme induction has not been observed in humans. Target organ changes in animals are clearly related to the primary and secondary pharmacological action of bicalutamide comprised of involution of androgen-dependent tissues; thyroid gland, hepatic and Leydig cell hyperplasias and neoplasias or cancer; disturbance of male offspring sexual differentiation; reversible impairment of fertility in males. Genotoxicity studies did not reveal any mutagenic potential of bicalutamide. 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
Lactose monohydrate Crospovidone Povidone K-29/32 Magnesium stearate Sodium lauryl sulfate
Coating
Lactose monohydrate Hypromellose Macrogol 4000 Titanium dioxide (E171)
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
PVC/PE/PVDC/Al blister pack, box.
The packaging contains 5, 7, 10, 14, 20, 28, 30, 40, 50, 56, 80, 84, 90, 98, 100, 140, 200 or 280 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland
MARKETING AUTHORISATION NUMBER(S)
PL 30306/0224
9
10
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16/10/2007
DATE OF REVISION OF THE TEXT
18/01/2016