Bicalutamide 50 mg film-coated tablets

Film-coated tablet White, round, biconvex film-coated tablets, with diameter of 6.5 mm.

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** ****Adult males including older people****: one film-coated tablet (50mg) 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. ****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). ****Paediatric population****: bicalutamide is contraindicated for use in children (see section 4.3). **Method of administration**: Oral use.4.3 Contraindications Bicalutamide 50 mg is contra-indicated in females and children (see section 4.6). 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 (CYP3A4), as such caution should be exercised when co-administered with drugs metabolised predominantly by CYP3A4 (see sections 4.3 and 4.5). **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. Antiandrogen therapy may cause morphological changes in spermatozoa. Although the effect of bicalutamide on sperm morphology has not been evaluated and no such changes have been reported for patients who received bicalutamide, patients and/or their partners should follow adequate contraception during and for 130 days after bicalutamide therapy. Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant bicalutamide therapy, which may result in increased Prothrombin Time (PT) and International Normalised Ratio (INR). Some cases have been associated with risk of bleeding. Close monitoring of PT/INR is advised and anticoagulant dose adjustment should be considered (see sections 4.5 and 4.8). **Excipients** Bicalutamide 50 mg contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.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 the 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 contra-indicated (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 sites. There have been reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with bicalutamide. It is therefore recommended that if bicalutamide is administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustments of anticoagulant dose considered (see sections 4.4 and 4.8). 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). **Paediatric population** Interaction studies have only been performed in adults.4.6 Fertility, pregnancy and lactation Pregnancy Bicalutamide is contraindicated in females and must not be given to pregnant women. Breast-feeding Bicalutamide is contraindicated during breast-feeding. Fertility Reversible impairment of male fertility has been observed in animal studies (see section 5.3). A period of subfertility or infertility should be assumed in man.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 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 | | Hepatobiliary disorders | Common | Hepatotoxicity, jaundice, hypertransaminasaemia1 | | Rare | Hepatic failure2 (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 | Gynaecomastia and breast tenderness3 | | Common | Erectile dysfunction | | General disorders and administration site conditions | Very common | Asthenia oedema | | Common | Chest pain | | Investigations | Common | Weight increased |

1. Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
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 hepatic failure in patients receiving treatment in the open-label bicalutamide arm of the 150 mg EPC studies.
3. May be reduced by concomitant castration.
4. 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.
5. 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. Increased PT/INR: Accounts of coumarin anticoagulants interacting with bicalutamide have been reported in post marketing surveillance (see sections 4.4. and 4.5). **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 or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose There is no human experience of overdosage. 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.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Hormone antagonists and related agents, antiandrogens, ATC code: L02BB03. **Mechanism of action** 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. **Distribution** Bicalutamide is highly protein bound (racemate to 96%, (R)-enantiomer > 99%) and extensively metabolised (oxidation and glucuronidation); its metabolites are eliminated via the kidneys and bile in approximately equal proportions. **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 9 microgram/ml are observed during daily administration of 50 mg doses of bicalutamide. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers. **Elimination** 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. **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.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. Atrophy of seminiferous tubules of the testes is a predicted class effect with antiandrogens and has been observed for all species examined. Reversal of testicular atrophy occurred 4 months after the completion of dosing in a 6-month rat study (at doses of approximately 1.5 times human therapeutic concentrations at the recommended dose of 50 mg). No recovery was observed at 24 weeks after the completion of dosing in a 12-month rat study (at doses of approximately 2 times human concentrations at the recommended human dose of 50 mg). Following 12-months of repeated dosing in dogs (at doses of approximately 7 times human therapeutic concentrations at the recommended human dose of 50 mg), the incidence of testicular atrophy was the same in dosed and control dogs after a 6 month recovery period. In a fertility study (at doses of approximately 1.5 times human therapeutic concentrations at the recommended human dose of 50 mg), male rats had an increased time to successful mating immediately after 11 weeks of dosing; reversal was observed after 7 weeks off-dose.

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 (E464) Titanium dioxide (E171) Propylene Glycol6.2 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/PVDC/Aluminium blisters 10, 14, 20, 28, 30, 40, 56, 60, 100 and 150 tablets contained in a carton.. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.