Casodex/Casodex 150

Casodex/Casodex 150

bicalutamide

Manufacturer:

AstraZeneca

Distributor:

DKSH
Full Prescribing Info
Contents
Bicalutamide.
Action
Antiandrogen.
Pharmacology: Pharmacodynamics: Bicalutamide is a nonsteroidal 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 tumors results from this inhibition. Clinically, discontinuation of Casodex/Casodex 150 can result in the "antiandrogen withdrawal syndrome" in a subset of patients.
Casodex 150 was studied as a treatment for patients with localized (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) nonmetastatic prostate cancer in a combined analysis of 3 placebo-controlled double-blind studies in 8113 patients, where Casodex 150 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 150- and placebo-treated patients, respectively, had experienced objective disease progression.
In the subgroup of patients with locally advanced prostate cancer who did not receive treatment with radical prostatectomy or radiotherapy, immediate therapy with Casodex 150 significantly reduced the risk of objective disease progression [Hazard Ratio (HR)=0.6; 95% CI 0.49-0.73]. A statistically significant reduction in the risk of objective disease progression was also seen in the subgroup of patients with locally advanced disease who received Casodex as adjuvant to radical prostatectomy or radiotherapy (HR=0.69; 95% CI 0.58-0.82). There was no significant difference in progression in patients with localized disease.
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 postatectomy, 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 0.91-1.09). However, some trends were apparent in exploratory subgroup analyses of those patients receiving Casodex 150 as immediate therapy alone.
Patients with localized disease receiving Casodex 150 alone showed a trend toward decreased survival compared with placebo patients (HR=1.16; 95% CI 0.99-1.37). In view of this, the benefit-risk profile for the use of Casodex 150 is not considered favorable in this group of patients.
For patients with locally advanced disease receiving Casodex 150 alone, there was a trend toward improved survival with Casodex 150 compared to placebo (HR=0.81; 95% CI 0.66-1.01).
The progression-free survival and overall survival data for patients with locally advanced disease are summarized in the table. (See table.)

Click on icon to see table/diagram/image

In a separate programme, the efficacy of Casodex 150 for the treatment of patients with locally advanced nonmetastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of 2 studies with 480 previously untreated patients with nonmetastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between Casodex 150 and castration in survival [hazard ratio=1.05 (CI 0.81-1.36)]; however, equivalence of the 2 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 was demonstrated to be less effective than castration in survival time [hazard ratio=1.3 (CI 1.04-1.65)], 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 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/Casodex 150, 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 and 22 mcg/mL are observed during daily administration of Casodex and Casodex 150, respectively. At steady state, the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
The pharmacokinetics of the (R)-enantiomer is 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 is highly protein-bound (racemate 96%, (R)-enantiomer >99%) and extensively metabolized (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 was 4.9 mcg/mL. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 mcg/kg. This is below that required to induce changes in offspring of laboratory animals.
Toxicology: Preclinical Safety Data Relevant to the Prescriber: Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme-inducer in animals. Target organ changes, including tumor induction (Leydig cells, thyroid, liver) in animals, are related to these activities. Enzyme induction has not been observed in man and none of these findings is considered to have relevance to the treatment of advanced prostate cancer patients.
Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all species examined. Full reversal of testicular atrophy was 24 weeks after a 12-month repeated-dose toxicity study in rats, although functional reversal was evident in reproduction studies 7 weeks after the end of an 11-week dosing period. A period of subfertility or infertility should be assumed in man.
Indications/Uses
Casodex: Treatment of advanced prostate cancer in combination with LHRH analogue therapy or surgical castration.
Casodex 150: In patients with locally advanced prostate cancer (T3-T4, any N, MO; T1-T2, N+, MO), Casodex 150 is indicated as immediate therapy either alone or as adjuvant to treatment by radical prostatectomy or radiotherapy (see Pharmacology under Actions).
Also for the management of patients with locally advanced, nonmetastatic 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): 1 tab taken orally once a day.
Treatment with Casodex should be started at the same time as treatment with an LHRH analogue or surgical castration.
Casodex 150 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).
Overdosage
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.
Contraindications
Patients who have shown a hypersensitivity reaction to bicalutamide or any of the excipients of Casodex/Casodex 150.
Co-administration of terfenadine, astemizole or cisapride with Casodex/Casodex 150 is contraindicated (see Interactions).
Use pregnancy & lactation: Bicalutamide is contraindicated in females and must not be given to pregnant women or nursing mothers.
Use in children: Casodex/Casodex 150 is contraindicated in children.
Special Precautions
Bicalutamide is extensively metabolized 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. Therefore, Casodex/Casodex 150 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/Casodex 150 therapy.
Severe hepatic changes have been observed rarely with Casodex/Casodex 150 (see Adverse Reactions). Casodex/Casodex 150 therapy should be discontinued if changes are severe.
For patients who have an objective progression of disease together with elevated PSA, cessation of Casodex/Casodex 150 therapy should be considered.
Bicalutamide has been shown to inhibit cytochrome P-450 (CYP3A4), as such, caution should be exercised when co-administered with drugs metabolized predominantly by CYP3A4 (see Contraindications and Interactions).
Lactose-sensitive patients should be aware that each Casodex 150 tablet contains 183 mg of lactose monohydrate (see Contraindications).
Effects on the Ability to Drive or Operate Machinery: No effects on ability to drive and use machines have been observed during treatment with Casodex/Casodex 150.
Use In Pregnancy & Lactation
Bicalutamide is contraindicated in females and must not be given to pregnant women or nursing mothers.
Adverse Reactions
Casodex: Casodex in general, has been well tolerated with few withdrawals due to adverse events.
Frequency of Adverse Reactions:
Very Common (≥10%): Reproductive System and Breast Disorders: Breast tenderness1, Gynecomastia1.
General Disorders: Hot flushes1.
Common (≥1% and <10%): Gastrointestinal Disorders: Diarrhoea, nausea.
Hepatobiliary Disorders: Hepatic changes (elevated levels of transaminases, jaundice)2.
General Disorders: Asthenia, pruritus.
Uncommon (≥0.1% and <1%): Immune System Disorders: Hypersensitivity reactions, including angioneurotic edema and urticaria.
Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease.
Rare (≥0.01% and <0.1%): Gastrointestinal Disorders: Vomiting.
Skin and Subcutaneous Tissue Disorders: Dry skin.
Hepatobiliary Disorders: Hepatic failure3.
1May be reduced by concomitant castration. 2Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy (see Precautions). 3Hepatic failure has occurred very rarely in patients treated with Casodex, but a causal relationship has not been established with certainty. Periodic liver function testing should be considered (see Precautions).
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.
Hematological: Anaemia.
Skin and Appendages: Alopecia, rash, sweating, hirsutism.
Metabolic and Nutritional: Diabetes mellitus, hyperglycaemia, edema, weight gain, weight loss.
Whole Body: Abdominal pain, chest pain, headache, pain, pelvic pain, chills.
Casodex 150: The pharmacological action of bicalutamide may give rise to certain undesirable effects. These include the following:
Very Common (>10%): Gynecomastia, breast tenderness. The majority of patients receiving Casodex 150 as monotherapy experience gynecomastia and/or breast pain. In studies, these symptoms were considered to be severe in up to 5% of the patients. Gynecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.
Common or Frequent (≥1%): Hot flushes, pruritus, asthenia, alopecia, hair regrowth, dry skin, decreased libido, nausea, impotence and weight gain.
Uncommon or Infrequent (≥0.1% to <1%): Abdominal pain, depression, dyspepsia, hematuria and interstitial lung disease. Hypersensitivity reactions, including angioneurotic edema and urticaria.
Hepatic changes (elevated levels of transaminases, cholestasis and jaundice), which are rarely severe. The changes were frequently transient, resolving or improving with continued therapy or following cessation of therapy. Hepatic failure has occurred very rarely in patients treated with bicalutamide but a causal relationship has not been established with certainty. Periodic liver function testing should be considered. (See Precautions.)
Drug Interactions
There is no evidence of any pharmacodynamic or pharmacokinetic interactions between Casodex and LHRH analogues.
In vitro studies have shown that (R)-bicalutamide is an inhibitor of CYP3A4, with lesser inhibitory effects on CYP2C9, 2C19 and 2D6 activity. Although clinical studies using antipyrine as a marker of cytochrome P-450 (CYP) activity showed no evidence of a drug interaction potential with Casodex/Casodex 150, mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of Casodex/Casodex 150 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/Casodex 150 with compounds eg, 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/Casodex 150 therapy.
Caution should be exercised when prescribing Casodex/Casodex 150 with other drugs which may inhibit drug oxidation eg, 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. It is therefore recommended that if Casodex/Casodex 150 is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.
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
Casodex: FC tab 50 mg (white) x 28's.
Casodex 150: FC tab 150 mg (white) x 28's.
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