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
One tablet contains 50 mg of bicalutamide.
Excipients with known effect: Contains 64.4 mg lactose monohydrate. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White or almost white, round, biconvex film-coated tablet, with engraved sign “L” on one side and “RG” on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of advanced prostate cancer in combination with luteinizing hormonereleasing hormone (LHRH) analogue therapy or surgical castration.
4.2 Posology and method of administration
Posology
Adult males including the elderly One 50 mg tablet once a day.
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.
Paediatric population
Bicalutamide is not indicated in children and adolescents.
Renal impairment
No dose 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/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).
Method of administration Route: oral
The tablets should be swallowed whole with liquid.
4.3 Contraindications
Hypersensitivity to bicalutamide or any of the excipients listed in section 6.1.
Bicalutamide is contraindicated in women and children (see section 4.6).
Co-administration of terfenadine, astemizole or cisapride with bicalutamide is contraindicated (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. Dara suggest that its elimination may be slower in patients with severe hepatic impairment and that 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 rarely observed with bicalutamide and fatal outcomes have been reported (see section 4.8). Bicalutamide therapy should be discontinued if changes are severe.
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.
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.
Periodical monitoring of cardiac function is advisable in patients with heart disease.
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 preexisting 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).
The product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
There is no evidence of any pharmacological 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 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) 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 dizziness or somnolence may occur (see section 4.8). Any affected patients should exercise caution.
4.8 Undesirable effects
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 |
Undesirable effect |
|
Blood and Lymphatic system disorder |
Very common |
Anaemia |
|
Very rare |
Thromb ocytop eni a | |
|
Nervous System Disorders |
Very common |
Dizziness |
|
Common |
Somnolence, insomnia | |
|
Vascular disorders |
Very common |
Hot flush |
|
Gastrointestinal disorders |
Very common |
Abdominal pain, constipation, nausea |
|
Common |
Dyspepsia, flatulence, diarrhoea | |
|
Uncommon |
Dry mouth, | |
|
Rare |
Vomiting | |
|
Skin and subcutaneous tissue |
Common |
Alopecia, hirsutism/ hair re-growth, rash, dry skin, pruritus, sweating |
|
disorders | ||
|
Renal and urinary disorders |
Very common |
Haematuria |
|
Uncommon |
Nocturia | |
|
Reproductive system and breast disorders |
Very common |
Gynaecomastia and breast tendernessa impotence |
|
Common |
Erectile dysfunction | |
|
General disorders and administration site conditions |
Very common |
Asthenia, oedema |
|
Common |
Chest pain, general pain, pelvic pain, chills | |
|
Uncommon) |
Headache, pain in the back, neck pain | |
|
Metabolism and nutrition disorders |
Common |
Decreased appetite, diabetes mellitus |
|
Uncommon |
Hyperglycaemia, weight loss | |
|
Psychiatric disorders |
Common |
Decreased libido, depression |
|
Cardiac disorders |
Common |
Myocardial infarction (fatal outcomes have been reported)b , Cardiac failureb |
|
Very rare |
Angina, conduction defects including PR and QT interval prolongations, arrhythmias, and non specific ECG changes | |
|
Hepatobiliary disorders |
Common |
Hepatotoxicity, jaundice, hypertransaminasaemiac |
|
Rare |
Hepatic failured (fatal outcomes have been reported) | |
|
Investigations |
Common Not known |
Weight increased QT prolongation (see sections 4.4 and 4.5) |
|
Immune system disorders |
Uncommon |
Hypersensitivity, angioedema, and urticaria |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Interstitial lung diseasee (fatal outcomes have been reported), dyspnoea |
a. May be reduced by concomitant castration.
b. 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.
c. Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy (see section 4.4).
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. 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.
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: Hormone antagonists and related agents, anti-androgens ATC code: L02BB03.
Bicalutamide is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to the wild type or normal androgen receptor 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 the ‘antiandrogen withdrawal syndrome’ in a subset of patients.
Bicalutamide is a racemate with its anti-androgenic activity being almost exclusively associated with 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 150 mg, the (R)-enantiomer accumulates about 10fold in plasma as a consequence of its long half-life.
Steady state plasma concentrations of the (R)-enantiomer, of approximately 22 microgram/ml are observed during daily administration of bicalutamide 150 mg. At steady state, the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that the (R)-enantiomer is more slowly eliminated from plasma in patients with severe hepatic impairment.
Bicalutamide is highly protein bound (racemate to 96%, (R)-enantiomer 99%) and extensively metabolised (by oxidation and glucuronidation). Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
In clinical study the mean concentration of R-bicalutamide in semen of men receiving bicalutamide 150 mg was 4.9 pg/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 pg/kg. This is below that requirerd 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 the liver. Enzyme induction has not been observed in humans. 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. 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:
Silica, colloidal anhydrous,
Magnesium stearate,
Povidone K-30,
Sodium starch glycolate (Type A),
Lactose monohydrate.
Film-coating:
Opadry II 33G28523 White (Triacetin, Macrogol 3350, Lactose monohydrate, Titanium dioxide (E171), Hypromellose).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
10, 14, 20, 28, 30, 40, 50, 56, 80, 84, 90, 100, 140, 200, 280 film-coated tablets in blister packs (PVC/PVDC/ aluminium foil)
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Arrow Generics Limited Whiddon Valley,
Barnstaple,
Devon,
EX32 8NS United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 18909/0229
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 27/06/2008
10 DATE OF REVISION OF THE TEXT
25/02/2015