CASODEX®
Zeneca
Bicalutamide
Nonsteroidal Antiandrogen
Action And Clinical Pharmacology: Bicalutamide is a nonsteroidal antiandrogen, devoid of other endocrine activity. Bicalutamide competitively inhibits the action of androgens by binding to cytosol androgen receptors in target tissue. This inhibition results in regression of prostatic tumors. Bicalutamide is a racemate and the (R)-enantiomer is primarily responsible for the antiandrogenic activity of bicalutamide.
Pharmacokinetics : The absorption, distribution, metabolism and excretion of bicalutamide has been investigated after administration of a single 50 mg oral dose to volunteers. The results indicated that the dose was extensively absorbed and was excreted almost equally in urine (36%) and feces (43%) over a 9-day collection period. There is no evidence of any clinically significant effect of food on bioavailability. Steady state plasma concentrations of the (R)-enantiomer of approximately 9 µg/mL are observed during daily administration of 50 mg doses of bicalutamide. At steady state, the active (R)-enantiomer accounts for 99% of the circulating plasma bicalutamide concentration. Bicalutamide is highly protein bound (96%). On daily administration, the (R)-enantiomer accumulates about 10-fold in plasma, consistent with an elimination half-life of approximately 1 week. The (S)-enantiomer is very rapidly cleared relative to the (R)-enantiomer. At the 50 mg/day dose, the pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. Patients with severe hepatic impairment eliminate the (R)-enantiomer from plasma more slowly. Bicalutamide is extensively metabolized via both oxidation and glucuronidation with approximately equal renal and biliary elimination of the metabolites.
Clinical Experience: In a large multicentre, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) 3 times a day, each in combination with LHRH analogues (either goserelin acetate implant or leuprolide acetate depot). At a median follow-up of 49 weeks, bicalutamide-LHRH analogue therapy was associated with a statistically significant (p=0.005) improvement in time to treatment failure. With a longer follow-up (median 95 weeks), improvement in time to treatment failure was no longer statistically significant (p=0.10). At the same timepoint, 130 (32%) patients treated with bicalutamide-LHRH analogue therapy and 145 (35%) patients treated with flutamide-LHRH analogue therapy had died.
Subjective responses, (including scores for pain, analgesic use and Eastern Oncology Cooperative Group (ECOG) performance status) assessed in patients with symptoms at entry were seen in 95 (52%) patients treated with bicalutamide and in 88 (54%) patients treated with flutamide, each in combination therapy with LHRH analogues. This small difference was not statistically significant between bicalutamide 50 mg combination therapy and flutamide combination therapy.
Indications And Clinical Uses: For use in combination therapy with either an LHRH analogue or surgical castration in the treatment of metastatic (Stage D2) prostate cancer.
Contra-Indications: In patients with hypersensitivity to the drug or any of its components.
Bicalutamide is contraindicated in females. The safety and effectiveness in women has not been studied.
Bicalutamide is contraindicated in children. The safety and effectiveness of bicalutamide in children has not been studied.
Precautions: Children: The safety and effectiveness of bicalutamide in children has not been established.
Pregnancy and Lactation: Bicalutamide is contraindicated in females. The drug may cause fetal harm when administered to pregnant women. The male offspring of rats (but not rabbits) receiving doses of 10 mg/kg/day and above, were observed to have reduced anogenital distance and hypospadias in reproductive toxicology studies. These pharmacological effects have been observed with other antiandrogens. No other teratogenic effects were observed in rabbits (receiving doses up to 200 mg/kg/day) or rats (receiving doses up to 250 mg/kg/day).
Patients with Hepatic Impairment: Bicalutamide is extensively metabolized in the liver. Data suggests that bicalutamide’s elimination may be slower in subjects with severe hepatic impairment and this could lead to some accumulation of bicalutamide. Therefore, bicalutamide should be used with caution in patients with moderate to severe hepatic impairment.
Gynecomastia has been reported in patients receiving bicalutamide which may be reduced by concomitant castration.
Drug Interactions: Clinical studies with bicalutamide have not demonstrated any drug/drug interactions with LHRH analogues. Bicalutamide does not appear to interact with commonly prescribed drugs. There is no evidence of hepatic enzyme induction in patients receiving a daily dose of 150 mg. In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is recommended that if bicalutamide is started in patients who are already receiving coumarin anticoagulants prothrombin time should be closely monitored and adjustment of the anticoagulant dose may be necessary.
Laboratory Tests: Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring patients’ responses.
Since transaminase abnormalities and, rarely, jaundice have been reported with the use of bicalutamide, periodic liver function tests should be considered. If clinically indicated, discontinuation of therapy should be considered. Abnormalities are usually reversible upon discontinuation.
Since bicalutamide may elevate plasma testosterone and estradiol levels, fluid retention could occur. Accordingly, bicalutamide should be used with caution in those patients with cardiac disease.
Information for the Patient: Patients should be informed that therapy with bicalutamide should be started at the same time as treatment with an LHRH analogue or surgical castration, and that patients should not interrupt or stop taking these medications without consulting their physician.
Adverse Reactions: Bicalutamide, in general has been well tolerated with few withdrawals due to adverse events. The pharmacological action of bicalutamide may give rise to certain expected effects. These include hot flashes, pruritus, dry skin and in addition, breast tenderness and gynecomastia which may be reduced by concomitant castration. Bicalutamide may also be associated with the occurrence of diarrhea, nausea, vomiting and asthenia. In patients with advanced prostate cancer, treated with bicalutamide in combination with an LHRH analogue, the most frequent adverse experience was hot flashes (49%).
Diarrhea was the adverse event most frequently leading to treatment withdrawal with 6% of patients treated with flutamide-LHRH analogue and 0.5% of patients treated with bicalutamide-LHRH analogue withdrawing.
In the multicentre, double-blind controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg 3 times a day, each in combination with an LHRH analogue, the following adverse experiences with an incidence of more than 5%, regardless of causality have been reported.
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 bicalutamide 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: heart failure.
Gastrointestinal: anorexia, dry mouth, dyspepsia, constipation, flatulence.
CNS: dizziness, insomnia, somnolence, decreased libido.
Respiratory: dyspnea.
Urogenital: impotence, nocturia.
Hematological: anemia.
Skin and Appendages: alopecia, rash, sweating, hirsutism.
Metabolic and Nutritional: hyperglycemia, edema, weight gain, weight loss, diabetes mellitus.
Whole Body: abdominal pain, chest pain, headache, pain, pelvic pain, chills.
Abnormal Laboratory Test Values: Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, creatinine and decreased hemoglobin and white cell count have been reported in both bicalutamide-LHRH analogue treated and flutamide-LHRH analogue treated patients. Increased liver enzyme tests and decreases in hemoglobin were reported less frequently with bicalutamide-LHRH analogue therapy. Other changes were reported with similar incidence in both treatment groups.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: A single dose of bicalutamide that results in symptoms of an overdose considered to be life-threatening has not been established. In animal studies, bicalutamide demonstrated a low potential acute toxicity. The LD50 in mice and rats was greater than 2 000 mg/kg. Long-term clinical trials have been conducted with doses up to 200 mg of bicalutamide daily and these doses have been well tolerated.
There is no specific antidote; treatment of an overdose should be symptomatic.
In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that in this patient population multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Dosage And Administration: The recommended dose for bicalutamide therapy in combination with an LHRH analogue or surgical castration is one 50 mg tablet once daily with or without food. Bicalutamide treatment should be started at the same time as treatment with an LHRH analogue or after surgical castration.
Renal or Hepatic Impairment: No dosage adjustment is necessary for patients with renal or mild hepatic impairment. Increased accumulation may occur in patients with moderate to severe hepatic impairment (see Precautions).
Availability And Storage: Each white, film-coated tablet, intagliated with CDX50 on one side and a logo on the other side, contains: bicalutamide 50 mg. Nonmedicinal ingredients: lactose, magnesium stearate, methylhydroxypropylcellulose, polyethylene glycol, polyvidone, sodium starch glycolate and titanium dioxide. Blisters of 30. Store between 15 and 30°C.
CASODEX® Zeneca Bicalutamide Nonsteroidal Antiandrogen
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