Casodex

Casodex

bicalutamide

Manufacturer:

AstraZeneca

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Bicalutamide.
Description
50 mg: Each tablet contains 50 mg bicalutamide (INN).
150 mg: Each tablet contains 150 mg bicalutamide (INN).
Excipients/Inactive Ingredients: 50 mg: Casodex includes the following excipients: Lactose Monohydrate; Magnesium Stearate; Hypromellose; Macrogol 300; Povidone; Sodium Starch Glycolate; Titanium Dioxide (E171).
150 mg: Casodex 150 mg includes the following excipients: Tablet core: Lactose Monohydrate, Magnesium Stearate, Povidone, Carboxymethyl amidon sodium.
Film coating material: Hypromellose, Macrogol 300, Titanium Dioxide.
Action
Antiandrogen. ATC code: L02BB03.
Pharmacology: Pharmacodynamics:
Bicalutamide (Casodex) is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to androgen receptors (50-mg)/the wild type or normal androgen (150-mg) receptor without activating gene expression, and thus androgen receptors (50 mg) inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically, discontinuation of Casodex can result in the 'antiandrogen withdrawal syndrome' in a subset of patients.
50-mg: Casodex is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.
150-mg: 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 Casodex was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation). At 7.4 years median follow up, 27.4% and 30.7% of all Casodex and placebo treated patients, respectively, had experienced objective disease progression.
A reduction in risk of objective disease progression was seen across most patients 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 7.4 years median follow up with 22.9% mortality (HR=0.99; 95% CI 0.91 to 1.09). However, some trends were apparent in exploratory subgroup analyses: The progression-free survival and overall survival data for patients with locally advanced disease are summarised in the following tables: (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

For patients with localised disease receiving bicalutamide alone, there was no significant difference in progression free survival. In these patients there was also a trend toward decreased survival compared with placebo patients (HR=1.16; 95% CI 0.99 to 1.37). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in this group of patients.
In a separate programme, the efficacy of 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 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, 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.
Bicalutamide is a racemate with its antiandrogen activity being almost exclusively in the R-enantiomer.
Pharmacokinetics: Bicalutamide (Casodex) 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 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 mcg/mL (50-mg) and 22 mcg/mL (150-mg) are observed during daily administration of 50 mg, 150 mg doses of Casodex. 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 for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.
Bicalutamide (Casodex) is highly protein bound [racemate 96%, R-bicalutamide 99.6% (50-mg) & >99% (150-mg) and extensively metabolised (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 Casodex 150 mg was 4.9 mcg/mL. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and by extrapolation possibly equates to approximately 0.3 mcg/kg. This is below that required to induce changes in offspring of laboratory animals.
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 (Leydig cells, thyroid, liver) in animals, are related to these activities. Enzyme induction has not been observed in man.
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 12-month rat study (at doses of approximately 7 or 3 times human therapeutic concentrations at the recommended human dose of 50 mg or 150 mg, respectively), the incidence of testicular atrophy was the same in dosed and control drugs after a 6 month recovery period. In a fertility study (at doses of approximately 1.5 or 0.6 times human therapeutic concentrations at the recommended human dose of 50 mg or 150 mg, respectively) male rats had an increased time to successful mating immediately after 11 weeks of dosing, reversal was observed after 7 weeks off-dose.
Indications/Uses
50-mg: Treatment of advanced prostate cancer in combination with luteinizing hormone-releasing hormone (LHRH) analogue therapy or surgical castration.
150-mg: Casodex 150 mg is indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk for disease progression (see Pharmacology: Pharmacodynamics under Actions).
Casodex 150 mg is also indicated for the management of patients with locally advanced, non-metastatic prostate cancer for whom surgical castration or other medical intervention is not considered appropriate or acceptable.
Dosage/Direction for Use
Adult males including the elderly: 50-mg: one tablet (50 mg) once a day. Treatment with Casodex should be started at the same time as treatment with an LHRH analogue or surgical castration.
150-mg: The dosage is one 150 mg tablet to be taken orally once a day.
Casodex 150 mg should be taken continuously for at least 2 years or until disease progression.
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).
50-mg: Children: Casodex is contraindicated in children.
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.
Contraindications
Casodex must not be given to any patient who has shown a hypersensitivity reaction to the active substance or to any of the excipients of this product.
Co-administration of terfenadine, astemizole or cisapride with Casodex is contraindicated (see Interactions).
Casodex is contraindicated in females and children (see Use in Pregnancy & Lactation).
Special Precautions
Bicalutamide (Casodex) 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, 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 Casodex therapy.
Severe hepatic changes and hepatic failure have been observed rarely with Casodex and fatal outcomes have been reported (see Adverse Reactions). 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).
Androgen deprivation therapy may prolong the QT interval, although a causal association has not been established with Casodex. In patients with a history of or who have risk factors for QT prolongation and in patients receiving concomitant medicinal products that may prolong the QT interval (see Interactions) physicians should assess the benefit risk ratio including the potential for Torsade de Pointes prior to initiating 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 Casodex, patients and/or their partners should follow adequate contraception during and for 130 days after Casodex therapy.
50-mg: Each tablet of Casodex contains 61 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
150-mg: For patients who have an objective progression of disease together with elevated PSA, cessation of Casodex therapy should be considered.
In rare cases, photosensitivity reactions have been reported for patients taking Casodex 150 mg. Patients should be advised to avoid direct exposure to excessive sunlight or UV-light while on Casodex 150 mg and the use of sunscreens may be considered. In cases where the photosensitivity reaction is more persistent and/or severe, an appropriate symptomatic treatment should be initiated.
Lactose sensitive patients should be aware that each Casodex 150 mg tablet contains 183 mg of lactose monohydrate.
Effects on ability to drive and use machines: 50-mg: 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.
150-mg: No effects on ability to drive and use machines have been observed during treatment with Casodex 150 mg.
Use In Pregnancy & Lactation
Pregnancy: Bicalutamide (Casodex) is contraindicated in females and must not be given to pregnant women.
Breast-feeding: 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
Increased PT/INR: Amounts of Coumarin anticoagulants interacting with Casodex have been reported in post-marketing surveillance (see Precautions and Interactions).
50-mg:
Casodex in general, has been well tolerated with few withdrawals due to adverse events. (See Table 3.)

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Rare cardiovascular effects such as angina, heart failure, conduction defects including PR and QT interval prolongations, arrhythmias and non-specific ECG changes have been observed.
Thrombocytopenia has been reported uncommonly.
In addition, the following adverse experiences were reported in clinical trials (as possible adverse drug reactions in the opinion of investigating clinicians, with a frequency of ≥1%) during treatment with Casodex plus an LHRH analogue. No causal relationship of these experiences to drug treatment has been made and some of the experiences reported are those that commonly occur in elderly patients: Cardiovascular system: heart failure.
Gastrointestinal system: anorexia, dry mouth, dyspepsia, constipation, flatulence.
Central nervous system: dizziness, insomnia, somnolence, decreased libido.
Respiratory system: dyspnoea.
Urogenital: impotence, nocturia.
Haematological: anaemia.
Skin and appendages: alopecia, rash, sweating, hirsutism.
Metabolic and nutritional: diabetes mellitus, hyperglycaemia, oedema, weight gain, weight loss.
Whole body: abdominal pain, chest pain, headache, pain, pelvic pain, chills.
150-mg: The frequencies of adverse events are ranked according to the following: Very common (≥10%); Common (≥1% and <10%); Uncommon (≥0.1% and <1%); Rare (≥0.01% and <0.1%). (See Table 4.)

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Rare cardiovascular effects such as angina, heart failure, conduction defects including PR and QT interval prolongations, arrhythmias and non-specific ECG changes have been observed.
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 Casodex, mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of 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 and caution should be exercised with the co-administration of Casodex 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 Casodex therapy.
Caution should be exercised when prescribing 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 Casodex can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is therefore recommended that if Casodex 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 Casodex with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de Pointes should be carefully evaluated (see Precautions).
50-mg: There is no evidence of any pharmacodynamic or pharmacokinetic interactions between Casodex and LHRH analogues.
Caution For Usage
Instructions for use, handling and disposal: No special precautions required.
Incompatibilities: 50-mg: None known.
150-mg: None applicable.
Storage
Do not store above 30°C.
ATC Classification
L02BB03 - bicalutamide ; Belongs to the class of anti-androgens. Used in treatment of neoplastic diseases.
Presentation/Packing
FC tab (white) 50 mg x 28's. 150 mg x 28's.
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