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AG-BICALUTAMIDE is a brand name for Bicalutamide, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: AND CLINICAL USE....................................................................................3 CONTRAINDICATIONS..........................................................................................................3 W A R N I N G S A N D P R E C A U T I O N S…
Verbatim from this product's HC label. Tap a section to expand.
Recommended Dose and Dosage Adjustment Bicalutamide 50mg Tablets in metastatic disease: 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.
Dosing Considerations in Special Populations 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 WARNINGS AND PRECAUTIONS). OVERDOSAGE A single dose of AG-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 2000 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 AG-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.
For management of a suspected overdose, contact your regional Poison Control Centre. ACTION AND CLINICAL PHARMACOLOGY Pharmacodynamics AG-Bicalutamide (bicalutamide) 50mg Tablets are a non-steroidal 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 tumours. 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 faeces (43%) over a 9 day collection period.
Adverse Drug Reaction Overview Bicalutamide in Metastatic Patients In patients with advanced prostate cancer, treated in the multicentre, double-blind controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analogue, the most frequent adverse experiences were hot flushes (53%), asthenia (22%), constipation (22%), nausea (14%), peripheral edema (13%), haematuria (12%), abdominal pain (11%), dizziness (10%), gynaecomastia (9%), rash (9%), chest pain (8%), impotence (7%), flatulence (7%), dyspepsia (7%), anorexia (6%), breast tenderness (6%), weight gain (5%), depression (4%), dry skin (4%), alopecia (4%), pruritis (3%), somnolence (3%), decreased libido (2%), hirsuitism (2%), and hypersensitivity reactions (including angioneurotic edema and urticaria) (1%).
Adverse event reports of abnormal liver function test results occurred in 7% of patients. These changes were frequently transient and rarely severe, resolving or improving with continued therapy or following cessation of therapy. Hepatic failure (see WARNINGS AND PRECAUTIONS) and interstitial lung disease have been observed in post-marketed data.
Bicalutamide in general has been well tolerated with few withdrawals due to adverse events. 7%). After a 160 week follow-up, there were 213/401 deaths in the bicalutamide-LHRH arm and 235/407 deaths in the flutamide-LHRH arm of the trial.
There were 30 vs. 18 deaths due to adverse events in the two arms respectively and in both arms, the most common causes of death due to adverse events were attributed to the cardiovascular system (see ‘Cardiovascular’ under the ‘Clinical Trial Adverse Drug Reactions’ sub-section below).
Clinical Trial Adverse Drug Reactions The following adverse experiences were reported within the same clinical trial with an incidence of ≥ 5%, regardless of causality. Page 7 of 30 Table 1 Incidence Of Adverse Events (≥ 5% In Either Treatment Group) Regardless Of Causality Treatment Group Number of Patients (%) Adverse Event Bicalutamide Plus LHRH Analogue (n=401) Flutamide Plus LHRH Analogue (n=407) Hot Flushes 211 (53) 217 (53) Pain (General) 142 (35) 127 (31) Back Pain 102 (25) 105 (26) Asthenia 89 (22) 87 (21) Constipation 87 (22) 69 (17) Pelvic Pain 85 (21) 70 (17) Infection 71 (18) 57 (14) Nausea 56 (14) 54 (13) Peripheral Edema 53 (13) 42 (10) Anemiaa 51 (13) 60 (15) Dyspnea 51 (13) 32 (8) Diarrhea 49 (12) 107 (26) Nocturia 49 (12) 55 (14) Hematuria 48 (12) 26 (6) Abdominal Pain 46 (11) 46 (11) Dizziness 41 (10) 35 (9) Bone Pain 37 (9) 43 (11) Gynaecomastia 36 (9) 30 (8) Rash 35 (9) 30 (7) Urinary Tract Infection 35 (9) 36 (9) Chest Pain 34 (8) 34 (8) Hypertension 34 (8) 29 (7) Cough Increased 33 (8) 24 (6) Pharyngitis 32 (8) 23 (6) Paresthesia 31 (8) 40 (10) Increased Liver Enzyme Testb 30 (7) 46 (11) Weight Loss 30 (7) 39 (10) Headache 29 (7) 27 (7) Flu Syndrome 28 (7) 20 (5) Myasthenia 27 (7) 19 (5) Page 8 of 30 Treatment Group Number of Patients (%) Adverse Event Bicalutamide Plus LHRH Analogue (n=401) Flutamide Plus LHRH Analogue (n=407) Insomnia 27 (7) 39 (10) Impotence 27 (7) 35 (9) Flatulence 26 (7) 22 (5) Hyperglycemia 26 (7) 27 (7) Dyspepsia 26 (7) 23 (6) Anorexia 25 (6) 29 (7) Sweating 25 (6) 20 (5) Bronchitis 24 (6) 11 (3) Breast Pain (tenderness) 23 (6) 15 (4) Urinary Frequency 23 (6) 29 (7) Alkaline Phosphatase Increased 22 (5) 24 (6) Weight Gain 22 (5) 18 (4) Arthritis 21 (5) 29 (7) Anxiety 20 (5) 9 (2) Urinary Retention 20 (5) 14 (3) Urinary Impaired 19 (5) 15 (4) Pneumonia 18 (4) 19 (5) Pathological Fracture 17 (4) 32 (8) Depression 16 (4) 33 (8) Vomiting 16 (4) 28 (7) Rhinitis 15 (4) 22 (5) Urinary Incontinence 15 (4) 32 (8) a Anemia includes hypochromic anemia and iron deficiency anemia.
• AG-Bicalutamide should only be administered under the supervision of a physician experienced with the treatment of prostate cancer and the use of anti- androgens. • AG-Bicalutamide 150mg/day dose should not be used (see WARNINGS & PRECAUTIONS, General).
• AG-Bicalutamide may rarely be associated with hepatic failure (see WARNINGS & PRECAUTIONS, Hepatic). General During treatment with bicalutamide, somnolence has been reported and those patients who experience this symptom should observe caution when driving or using machines.
Localized Prostate Cancer patients AG-Bicalutamide (bicalutamide) 150 mg Tablets is NOT to be administered. 4 year median follow-up, the use of bicalutamide 150 mg as immediate therapy for the treatment of localized prostate cancer in patients otherwise undergoing watchful waiting is associated with increased mortality.
Health Canada previously assessed bicalutamide 150 mg versus castration in the locally advanced patient population and found level 1 scientific evidence (one of the 2 randomized clinical trials) of increased mortality in bicalutamide 150 mg treated patients.
Patients taking AG-Bicalutamide 50 mg per day for the treatment of metastatic prostate cancer are not affected by this new information. Anti-androgen Withdrawal Syndrome In some patients with metastatic prostate cancer, anti-androgens (steroidal and non-steroidal), may promote, rather than inhibit, the growth of prostate cancer.
A decrease in PSA and/or clinical improvement following discontinuation of antiandrogens has been reported. It is recommended that patients prescribed an antiandrogen, who have PSA progression, should have the antiandrogen discontinued immediately and be monitored for 6 - 8 weeks for a withdrawal response prior to any decision to proceed with other prostate cancer therapy.
Gynaecomastia, Breast Pain Gynaecomastia has been reported in patients receiving bicalutamide. For metastatic (M1) patients receiving bicalutamide, concomitant surgical or medical castration may reduce the effects of gynaecomastia. Hepatic AG-Bicalutamide is extensively metabolized in the liver.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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 Page 12 of 30 bicalutamide.
At steady state, the active (R)-enantiomer accounts for 99% of the circulating plasma bicalutamide concentration. 6%). On daily administration, the (R)-enantiomer accumulates about 10-fold in plasma, consistent with an elimination half-life of approximately one week.
The (S)- enantiomer is very rapidly cleared relative to the (R)-enantiomer. Bicalutamide is extensively metabolized via both oxidation and glucuronidation with approximately equal renal and biliary elimination of the metabolites.
Special Populations and Conditions Pediatrics:
The pharmacokinetics of the (R)-enantiomer are unaffected by age.
Geriatrics:
The pharmacokinetics of the (R)-enantiomer are unaffected by age.
Hepatic Insufficiency:
The pharmacokinetics of the (R)-enantiomer are unaffected by mild to moderate hepatic impairment. Patients with severe hepatic impairment eliminate the (R)- enantiomer from plasma more slowly.
Renal Insufficiency:
The pharmacokinetics of the (R)-enantiomer are unaffected by renal impairment. STORAGE AND STABILITY Store between 15 - 30°C. DOSAGE FORMS, COMPOSITION AND PACKAGING AG-Bicalutamide is white to off white, round, biconvex, film coated tablets debossed with ‘B50’ on one side and plain on other side.
In addition to the active ingredient bicalutamide, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose E 5, polyethylene glycol, povidone K-30, sodium starch glycolate and titanium dioxide.
Available in blister strips of 15 tablets, 30 tablets per package. 37 Structural Formula: Physiochemical Properties: Bicalutamide is a fine white to off white powder which is practically insoluble in water at 37°C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.
The pKa is approximately 12. AG-Bicalutamide is a racemate with their antiandrogen activity being predominately exhibited by the (R)-enantiomer of bicalutamide. ) conducted in healthy adult male subjects under fasting conditions. Data from 40 subjects who completed the study are presented below.
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b Abnormal liver function tests reported as adverse events. In addition, the following adverse experiences were reported by investigators within the same clinical trial (as possible adverse drug reactions in the opinion of investigating clinicians) with a frequency of less than 5%, during treatment with bicalutamide 50 mg plus an LHRH analogue.
No causal relationship of these experiences to drug treatment has been made.
Page 9 of 30 Cardiovascular:
In the pivotal trial of 813 patients comparing bicalutamide 50 mg once daily with Flutamide 250 mg three times a day, each in combination with an LHRH analogue, an imbalance of deaths related to cardiovascular adverse events was noted (bicalutamide-LHRH therapy: 18 deaths; Flutamide-LHRH therapy: 9 deaths) however, there is difficulty in interpreting this imbalance as the exposure was longer on the bicalutamide- LHRH arm by a mean of 13 weeks.
Other cardiovascular-related experiences reported include angina pectoris, congestive heart failure, myocardial infarction, heart arrest, coronary artery disorder, syncope, atrial fibrillation, cerebrovascular accident, deep thrombophlebitis, arrhythmia, bradycardia, cerebral ischemia, hemorrhage.
Central Nervous System: hypertonia, confusion, somnolence, decreased libido, neuropathy, nervousness Endocrine System: diabetes mellitus Gastrointestinal: melena, rectal hemorrhage, dry mouth, dysphagia, gastrointestinal disorder, periodontal abscess, gastrointestinal carcinoma, rectal disorder, intestinal obstruction, gastritis Hematological: ecchymosis, thrombocytopenia Immune System Disorders: hypersensitivity reactions, including angioneurotic oedema and urticaria Metabolic & Nutritional: edema, BUN increased, creatinine increased, dehydration, gout, hypercholesteremia, hypoglycemia, hypercalcemia Musculoskeletal: leg cramps, bone disorders, myalgia Respiratory System: lung disorder, asthma, epistaxis, sinusitis, pleural effusion, voice alteration Skin & Appendages: dry skin, alopecia, pruritus, herpes zoster, skin carcinoma, skin disorder, […]
Data suggests that the elimination of bicalutamide may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of bicalutamide. Therefore, AG-Bicalutamide should be used with Page 5 of 30 caution in patients with moderate to severe hepatic impairment.
Severe hepatic changes and hepatic failure have been observed rarely with bicalutamide. AG- Bicalutamide therapy should be discontinued if changes are severe.
Special Populations Pregnant and Nursing Women:
AG-Bicalutamide is contraindicated in females. AG- Bicalutamide 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).
Pediatrics:
The safety and effectiveness of bicalutamide (non-steroidal antiandrogen) in children has not been established. Monitoring and Laboratory Tests Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring patients' response.
Since transaminase abnormalities and jaundice, rarely severe, 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 AG-Bicalutamide may elevate plasma testosterone and estradiol levels, fluid retention could occur. Accordingly, AG-Bicalutamide should be used with caution in those patients with cardiac disease.
A reduction in glucose tolerance has been observed in males receiving bicalutamide in combination with 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 AG-Bicalutamide in combination with LHRH agonists.
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