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 film coated tablet contains 50 mg bicalutamide.
Excipient(s): Each tablet contains 62.7 mg of lactose monohydrate For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
White, round, biconvex film-coated tablets, with diameter of 6.5 mm.
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
Adult males including the elderly: one film coated tablet tablet (50mg) daily with or without food.
Route: Oral
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.
Children and adolescents: Bicalutamide 50 mg is not-indicated in children and adolescents.
Renal impairment: no dosage adjustment is necessary for patients with renal impairment. There is no experience with the use of bicalutamide in patients with severe renal impairment (creatinine clearance < 30 ml/mi.)
Hepatic impairment: no dosage 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 50 mg is contra-indicated in females and children (see section 4.6). Hypersensitivity to the active substance or any of the excipients, listed in section 6.1. Co-administration of terfenadine, astemizole or cisapride with Bicalutamide 50 mg 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 and subsequently patients should be kept under regular surveillance.
Bicalutamide is extensively metabolised in the liver. Research results 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.
Severe hepatic changes have been observed rarely with Bicalutamide (see Section 4.8). Bicalutamide therapy should be discontinued if changes are severe.
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.
As there is no experience with the use of Bicalutamide in patients with severe renal impairment (creatinine clearance < 30 ml/min), Bicalutamide should only be used with caution in these patients.
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).
Periodical monitoring of cardiac function is advisable in patients with heart disease.
Bicalutamide 50 mg contains lactose. 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
No pharmacological or pharmacokinetic interactions have been demonstrated between Bicalutamide and LHRH analogues.
In vitro studies have shown that the R-enantiomer of 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 administering Bicalutamide to patients taking medicinal products that inhibit the oxidation processes in the liver, e.g. cimetidine and ketoconazole. 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 prothrombin time is closely monitored if Bicalutamide is started in patients who are already receiving coumarin anticoagulants.
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) anti arrhythmic 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
This medicinal product is contraindicated in women and must not be given to pregnant and nursing mothers.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, it should be noted that occasionally dizziness or somnolence may occur(see section 4.8). 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).
|
System Organ Class |
Frequency |
Undesirable effect |
|
Blood and lymphatic system disorders |
Very common |
Anaemia |
|
Immune system disorders |
Uncommon |
Hypersensitivity, angioeodema and 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)4, cardiac failure4 |
|
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 disease5 (fatal outcomes have been reported) |
|
Gastrointestinal disorders |
Very common |
Abdominal pain, Constipation, Nausea |
|
Common |
Dyspepsia, Flatulence | |
|
Hepato-biliary disorders |
Common |
Hepatotoxicity, jaundice, Hypertransaminasaemia1 |
|
Rare |
2 Hepatic failure (fatal outcomes have been reported). | |
|
Skin and subcutaneous tissue disorders |
Common |
Alopecia, Hirsuitism/hair re-growth Dry skin, Pruritis, Rash |
|
Rare |
Photosensitivity reaction | |
|
Renal and urinary disorders |
Very common |
Haematuria |
|
Reproductive system and breast disorders |
Very common |
Gynaecomastia and breast tenderness1 |
|
Common |
Erectile dysfunction | |
|
General disorders and administration site conditions |
Very common |
Asthenia, Oedema |
|
Common |
Chest pain | |
|
Investigations |
Common |
Weight increased |
'Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
2Listed 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.
4Observed 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 evident when bicalutamide 150 mg was used as a monotherapy to treat prostate cancer.
5Listed 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.
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
No case of overdose has been reported. Since bicalutamide belongs to the anilide compounds there is a theoretical risk of the development of methaemoglobinaemia. Methaemoglobinaemia has been observed in animals after an overdose. Accordingly, a patient with an acute intoxication can be cyanotic. 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, antiandrogens, ATC code: L02BB03.
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 antiandrogenic activity being almost exclusively in the (R)-enantiomer.
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.
Biotransformation
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)-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 9pg/ml are observed during daily administration of 50mg doses of bicalutamide. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
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.
Distribution
Bicalutamide is highly protein bound (racemate to 96%, R-enantiomer >
99%
) and extensively metabolised (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
Elimination
In a clinical study the mean concentration of (R)-bicalutamide in semen of men receiving bicalutmide 150mg was 4.9pg/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3pg/kg. This is below that required to induce changes in offspring of laboratory animals.
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. Target organs changes in animals are clearly related to the primary and secondary pharmacological action of bicalutamide. These comprise involution of androgen-dependent tissues; thyroid follicular adenomas, hepatic and Leydig cell hyperplasias and neoplasias or cancer; disturbance of male offspring sexual differentiation; reversible impairment of fertility in males. This enzyme induction observed in animals has not been found in humans. Genotoxicity studies did not reveal any mutagenic potential of bicalutamide. All adverse effects observed in animal studies are considered to have no relevance to the treatment of patients with advanced prostate cancer.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Povidone K- 25
Sodium starch glycolate Type A Magnesium Stearate
Film-Coating:
Opadry OY-S-9622 consisting of: Hypromellose 5 cp (E464) Titanium dioxide (E171) Propylene Glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
Special precautions for storage
6.4
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC/Aluminium blisters 28 tablets contained in a carton.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Relonchem Limited 27 Old Gloucester Street London WC1 3XX
8. MARKETING AUTHORISATION NUMBER(S)
PL 20395/0076
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/10/2008
10 DATE OF REVISION OF THE TEXT
20/10/2016
May be reduced by concomitant castration.