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 bicalutamide.
Excipient with known effect:
Each tablet contains 132 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 ‘485’ on one side and plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of advanced prostate cancer in combination with Luteinizing hormone releasing hormone (LHRH) analogue therapy or surgical castration.
4.2 Posology and method of administration
Posology
Paediatric population
Bicalutamide is contraindicated in children under the age of 18 years. Adult males including the elderly
One film-coated tablet (50mg) daily with or without food.
Method of administration
Route: oral
The tablets should be swallowed whole with liquid.
Treatment with Bicalutamide 50 mg 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 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).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Bicalutamide is contraindicated 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 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 metabolized 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-administering 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 coadministration 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. 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).
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.
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 lymphatic system disorders |
Very 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 |
Very common |
Dizziness |
|
Common |
Somnolence | |
|
Cardiac disorders |
Common |
Myocardial infarction (fatal outcomes have been reported)1, cardiac failure1 |
|
Not Known |
QT prolongation (see sections 4.4 and 4.5) | |
|
Vascular disorders |
Very common |
Hot flush |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Interstitial lung disease (fatal outcomes have been reported) |
|
Gastrointestinal disorders |
Very common Common |
Abdominal pain, constipation, nausea Dyspepsia, flatulence |
|
Hepatobiliary disorders |
Common |
Hepatotoxicity, jaundice, hypertransaminasaemia3 |
|
Rare |
Hepatic failure4 (fatal outcomes have been reported) | |
|
Skin and subcutaneous tissue disorders |
Common |
Alopecia, hirsutism/hair re-growth, dry skin, pruritus, rash |
|
Rare |
Photosensitivity reaction | |
|
Renal and urinary disorders |
Very common |
Haematuria |
|
Reproductive system and breast disorders |
Very common Common |
Gynaecomastia and breast tenderness5 Erectile dysfunction |
|
General disorders and administration site conditions |
Very common |
Asthenia, oedema Chest pain |
|
System Organ Class |
Frequency |
Event |
|
Common | ||
|
Investigations |
Common |
Weight increased |
1. Observed in a pharmaco-epidemiology study of LHRH agonists and antiandrogens 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 evidence when Bicalutamide 150 mg was used as a monotherapy to treat prostate cancer.
2. 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.
3. Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
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 the 150 mg EPC studies.
5. 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 at: 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: Hormone antagonists and related agents, antiandrogen, ATC code L02 B B03.
Bicalutamide is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to 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 antiandrogen withdrawal syndrome in a subset of patients.
Bicalutamide is a racemate with its anti-androgenic 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)-enantiomeraccumulates about 10-fold in plasma as a consequence of its long half-life.
Steady state plasma concentrations of approximately 9 microgram/ml are observed during daily administration of 50 mg doses of bicalutamide. At steady state is the predominately active (R)-enantiomer accounts for 99% of the total circulation 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.
Bicalutamide is highly protein bound (racemate 96%, (R)-enantiomer >99%) and extensively metabolized (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
In a clinical study the mean concentration of R-bicalutamide in semen of men receiving bicalutamide 150 mg was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3 microgram/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, in animals, are related to these activities. None of the findings in the preclinical
testing is considered to have relevance to the treatment of advanced prostate cancer patients.
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.
MARKETING AUTHORISATION HOLDER
7
Sun Pharmaceutical Industries Europe B.V. Polarisavenue 87 2132 JH Hoofddorp The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 31750/0006
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/08/2010
10 DATE OF REVISION OF THE TEXT
30/08/2016