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Indications/Uses
Treatment of advanced prostate cancer in combination with luteinizing-hormone releasing hormone (LHRH) analogue therapy or surgical castration.
Dosage/Direction for Use
Adult males including the elderly: one tablet (50 mg) once a day.
Treatment with Bicalutamide (CASODEX) should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration.
Special populations: 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 Precautions).
Paediatric population: Bicalutamide (CASODEX) is contraindicated for use in children (see Contraindications).
Treatment with Bicalutamide (CASODEX) should be started at least 3 days before commencing treatment with an LHRH analogue, or at the same time as surgical castration.
Special populations: 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 Precautions).
Paediatric population: Bicalutamide (CASODEX) is contraindicated for use in children (see Contraindications).
Overdosage
There is no human experience of overdosage. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since Bicalutamide (CASODEX) is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.
Administration
May be taken with or without food.
Contraindications
Bicalutamide (CASODEX) is contraindicated in females and children (see Use in Pregnancy & Lactation).
Hypersensitivity reaction to the active substance or to any of the excipients list in Description.
Co-administration of terfenadine, astemizole or cisapride with Bicalutamide (CASODEX) is contraindicated (see Interactions).
Hypersensitivity reaction to the active substance or to any of the excipients list in Description.
Co-administration of terfenadine, astemizole or cisapride with Bicalutamide (CASODEX) is contraindicated (see Interactions).
Special Precautions
Initiation of treatment should be under the direct supervision of a specialist.
Bicalutamide (CASODEX) is extensively metabolised in the liver. Data suggest that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of Bicalutamide (CASODEX). Therefore, Bicalutamide (CASODEX) 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 (CASODEX) therapy.
Severe hepatic changes and hepatic failure have been observed rarely with Bicalutamide (CASODEX), and fatal outcomes have been reported (see Adverse Reactions). Bicalutamide (CASODEX) therapy should be discontinued if changes are severe.
Bicalutamide (CASODEX) 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 Contraindications and Interactions).
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 Interactions) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Bicalutamide (CASODEX).
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 (CASODEX), patients and/or their partners should follow adequate contraception during and for 130 days after Bicalutamide (CASODEX) therapy.
Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant Bicalutamide (CASODEX) 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 Interactions and Adverse Reactions).
A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving Bicalutamide (CASODEX) in combination with LHRH agonists.
Effects on ability to drive and use machines: Bicalutamide (CASODEX) 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.
Bicalutamide (CASODEX) is extensively metabolised in the liver. Data suggest that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of Bicalutamide (CASODEX). Therefore, Bicalutamide (CASODEX) 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 (CASODEX) therapy.
Severe hepatic changes and hepatic failure have been observed rarely with Bicalutamide (CASODEX), and fatal outcomes have been reported (see Adverse Reactions). Bicalutamide (CASODEX) therapy should be discontinued if changes are severe.
Bicalutamide (CASODEX) 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 Contraindications and Interactions).
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 Interactions) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Bicalutamide (CASODEX).
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 (CASODEX), patients and/or their partners should follow adequate contraception during and for 130 days after Bicalutamide (CASODEX) therapy.
Potentiation of coumarin anticoagulant effects have been reported in patients receiving concomitant Bicalutamide (CASODEX) 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 Interactions and Adverse Reactions).
A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving Bicalutamide (CASODEX) in combination with LHRH agonists.
Effects on ability to drive and use machines: Bicalutamide (CASODEX) 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.
Use In Pregnancy & Lactation
Pregnancy: Bicalutamide (CASODEX) is contraindicated in females and must not be given to pregnant women.
Breast-feeding: Bicalutamide (CASODEX) is contraindicated during breast-feeding.
Fertility: Reversible impairment of male fertility has been observed in animal studies (see Pharmacology: Toxicology: Preclinical safety data under Actions). A period of subfertility or infertility should be assumed in man.
Breast-feeding: Bicalutamide (CASODEX) is contraindicated during breast-feeding.
Fertility: Reversible impairment of male fertility has been observed in animal studies (see Pharmacology: Toxicology: Preclinical safety data under Actions). A period of subfertility or infertility should be assumed in man.
Adverse Reactions
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). (See Table 3.)
Increased PT/INR: Accounts of coumarin anticoagulants interacting with Bicalutamide (CASODEX) have been reported in post-marketing surveillance (see Precautions and Interactions).
Drug Interactions
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 (CASODEX), mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of Bicalutamide (CASODEX) 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 Contraindications) and caution should be exercised with the co-administration of Bicalutamide (CASODEX) with compounds such as cyclosporin and calcium channel blockers. Dosage reduction may be required for these drugs particularly if there is evidence of enhanced or adverse drug effect. For cyclosporin, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of Bicalutamide (CASODEX) therapy.
Caution should be exercised when prescribing Bicalutamide (CASODEX) with other drugs which may inhibit drug oxidation e.g. cimetidine and ketoconazole. In theory, this could result in increased plasma concentrations of Bicalutamide (CASODEX) 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 (CASODEX). It is therefore recommended that if Bicalutamide (CASODEX) is administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustments of anticoagulant dose considered (see Precautions and Adverse Reactions).
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Bicalutamide (CASODEX) 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) antiarrythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see Precautions).
Paediatric population: Interaction studies have only been performed in adults.
There is no evidence of any pharmacodynamic or pharmacokinetic interactions between Bicalutamide (CASODEX) and LHRH analogues.
Although clinical studies using antipyrine as a marker of cytochrome P450 (CYP) activity showed no evidence of a drug interaction potential with Bicalutamide (CASODEX), mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of Bicalutamide (CASODEX) 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 Contraindications) and caution should be exercised with the co-administration of Bicalutamide (CASODEX) with compounds such as cyclosporin and calcium channel blockers. Dosage reduction may be required for these drugs particularly if there is evidence of enhanced or adverse drug effect. For cyclosporin, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of Bicalutamide (CASODEX) therapy.
Caution should be exercised when prescribing Bicalutamide (CASODEX) with other drugs which may inhibit drug oxidation e.g. cimetidine and ketoconazole. In theory, this could result in increased plasma concentrations of Bicalutamide (CASODEX) 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 (CASODEX). It is therefore recommended that if Bicalutamide (CASODEX) is administered in patients who are concomitantly receiving coumarin anticoagulants, PT/INR should be closely monitored and adjustments of anticoagulant dose considered (see Precautions and Adverse Reactions).
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Bicalutamide (CASODEX) 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) antiarrythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see Precautions).
Paediatric population: Interaction studies have only been performed in adults.
There is no evidence of any pharmacodynamic or pharmacokinetic interactions between Bicalutamide (CASODEX) and LHRH analogues.
Caution For Usage
Incompatibilities: Not applicable.
Instructions for use, handling and disposal: Not applicable.
Instructions for use, handling and disposal: Not applicable.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic group: Anti-androgens. ATC code: L02BB03.
Pharmacology: Pharmacodynamics: Mechanism of action: Bicalutamide (CASODEX) 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 (CASODEX) can result in antiandrogen withdrawal syndrome in a subset of patients.
Bicalutamide (CASODEX) is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.
Clinical efficacy and safety: Bicalutamide (CASODEX) 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non-metastatic prostate cancer in a combined analysis of three placebo controlled, double-blind studies in 8113 patients, where Bicalutamide (CASODEX) was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). At 9.7 years median follow up, 36.6% and 38.17% of all Bicalutamide (CASODEX) and placebo-treated patients, respectively, had experienced objective disease progression.
A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.
No overall survival difference was seen at 9.7 years median follow up with 31.4% mortality (HR=1.01; 95% CI 0.94 to 1.09). However, some trends were apparent in exploratory subgroup analyses.
Data on progression-free survival and overall survival over time based on Kaplan-Meier estimates for patients with locally advanced disease are summarised in the following tables: (See Tables 1 and 2).
Pharmacology: Pharmacodynamics: Mechanism of action: Bicalutamide (CASODEX) 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 (CASODEX) can result in antiandrogen withdrawal syndrome in a subset of patients.
Bicalutamide (CASODEX) is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.
Clinical efficacy and safety: Bicalutamide (CASODEX) 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non-metastatic prostate cancer in a combined analysis of three placebo controlled, double-blind studies in 8113 patients, where Bicalutamide (CASODEX) was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). At 9.7 years median follow up, 36.6% and 38.17% of all Bicalutamide (CASODEX) and placebo-treated patients, respectively, had experienced objective disease progression.
A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.
No overall survival difference was seen at 9.7 years median follow up with 31.4% mortality (HR=1.01; 95% CI 0.94 to 1.09). However, some trends were apparent in exploratory subgroup analyses.
Data on progression-free survival and overall survival over time based on Kaplan-Meier estimates for patients with locally advanced disease are summarised in the following tables: (See Tables 1 and 2).
For patients with localised disease receiving Bicalutamide (CASODEX) alone, there was no significant difference in progression free survival. There was no significant difference in overall survival in patients with localised disease who received Bicalutamide (CASODEX) as adjuvant therapy, following radiotherapy (HR=0.98; 95% CI 0.80 to 1.20) or radical prostatectomy (HR=1.03; 95% CI 0.85 to 1.25). In patients with localised disease, who would otherwise have been managed by watchful waiting, there was also a trend toward decreased survival compared with placebo patients (HR=1.15; 95% CI 1.00 to 1.32). In view of this, the benefit-risk profile for the use of Bicalutamide (CASODEX) is not considered favourable in patients with localised disease.
In a separate programme, the efficacy of Bicalutamide (CASODEX) 150 mg for the treatment of patients with locally advanced non-metastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of 2 studies with 480 previously untreated patients with non-metastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between Bicalutamide (CASODEX) and castration in survival (hazard ratio = 1.05 [CI 0.81 to 1.36]); however, equivalence of the two treatments could not be concluded statistically.
In a combined analysis of 2 studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, Bicalutamide (CASODEX) 150 mg was demonstrated to be less effective than castration in survival time (hazard ratio = 1.30 [CI 1.04 to 1.65]), with a numerical difference in estimated time to death of 42 days (6 weeks) over a median survival time of 2 years.
Paediatric population: No studies have been conducted in paediatric patients (see Contraindications and Use in Pregnancy & Lactation).
Pharmacokinetics: Absorption: Bicalutamide (CASODEX) is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
Distribution: Bicalutamide (CASODEX) is highly protein bound (racemate 96% (R)-enantiomer >99%) and extensively metabolised (via 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 (CASODEX), 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 (CASODEX). 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 (CASODEX) 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.
Toxicology: Preclinical safety data: Bicalutamide (CASODEX) 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.
In a separate programme, the efficacy of Bicalutamide (CASODEX) 150 mg for the treatment of patients with locally advanced non-metastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of 2 studies with 480 previously untreated patients with non-metastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between Bicalutamide (CASODEX) and castration in survival (hazard ratio = 1.05 [CI 0.81 to 1.36]); however, equivalence of the two treatments could not be concluded statistically.
In a combined analysis of 2 studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, Bicalutamide (CASODEX) 150 mg was demonstrated to be less effective than castration in survival time (hazard ratio = 1.30 [CI 1.04 to 1.65]), with a numerical difference in estimated time to death of 42 days (6 weeks) over a median survival time of 2 years.
Paediatric population: No studies have been conducted in paediatric patients (see Contraindications and Use in Pregnancy & Lactation).
Pharmacokinetics: Absorption: Bicalutamide (CASODEX) is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
Distribution: Bicalutamide (CASODEX) is highly protein bound (racemate 96% (R)-enantiomer >99%) and extensively metabolised (via 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 (CASODEX), 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 (CASODEX). 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 (CASODEX) 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.
Toxicology: Preclinical safety data: Bicalutamide (CASODEX) 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.
MedsGo Class
Cancer Hormone Therapy
Features
Dosage
50 mg
Ingredients
- Bicalutamide
Packaging
Tablet 1's
Generic Name
Bicalutamide
Registration Number
DR-XY26042
Classification
Prescription Drug (RX)
Product Questions
Questions
