bicalutamide 50 mg Tablets Non-Steroidal Antiandrogen Genpharm ULC 85 Advance Rd. Etobicoke, Ontario M8Z 2S6 Control Number 121900 Date of Revision:
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 11 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 13 DOSAGE FORMS, COMPOSITION AND PACKAGING 13
PHARMACEUTICAL INFORMATION 14 CLINICAL TRIALS 14 DETAILED PHARMACOLOGY 17 TOXICOLOGY 18 REFERENCES 30
bicalutamide
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet / 50 mg | Lactose monohydrate, magnesium stearate, povidone, sodium starch glycolate, hydroxypropyl methylcellulose, titanium dioxide, triacetin. |
Gen-Bicalutamide (bicalutamide) 50 mg is indicated for use in combination therapy with either an LHRH analogue or surgical castration in the treatment of metastatic (Stage D2) prostate cancer.
Pediatrics:
The safety and effectiveness of Gen-Bicalutamide in children has not been established.
Gen-Bicalutamide (bicalutamide) is contraindicated in the following: Patients who are hypersensitive to the drug or any of its components. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph. Patients with localized prostate cancer otherwise undergoing watchful waiting. (see WARNINGS AND PRECAUTIONS) Women: The safety and effectiveness of Gen-Bicalutamide in women has not been studied. Children: The safety and effectiveness of Gen-Bicalutamide in children has not been studied.
Gen-Bicalutamide should only be administered under the supervision of a physician
experienced with the treatment of prostate cancer and the use of anti-androgens.
Gen-Bicalutamide 150 mg/day dose should not be used (see WARNINGS &
PRECAUTIONS).
Gen-Bicalutamide may rarely be associated with hepatic failure.
General
It is recommended that Gen-Bicalutamide (bicalutamide) 150 mg is NOT administered to patients with localized disease who would otherwise undergo watchful waiting. Evidence from a large on-going clinical study demonstrates that at 5.4 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. It is recommended that clinicians do not administer bicalutamide 150 mg in patients with localized prostate cancer. 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 Gen-Bicalutamide 50 mg per day for the treatment of metastatic prostate cancer are not affected by this new information.
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 Gen-Bicalutamide 50 mg, concomitant surgical or medical castration may reduce the effects of gynaecomastia.
Hepatic
Bicalutamide is extensively metabolized in the liver. 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, Gen-Bicalutamide should be used with caution in patients with moderate to severe hepatic impairment. Severe hepatic changes and hepatic failure have been observed rarely with bicalutamide. Gen- Bicalutamide therapy should be discontinued if changes are severe.
Special Populations
Gen-Bicalutamide is contraindicated in females. Gen- 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).
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 bicalutamide may elevate plasma testosterone and estradiol levels, fluid retention could occur. Accordingly, Gen-Bicalutamide should be used with caution in those patients with cardiac disease.
Adverse Drug Reaction Overview
Bicalutamide in Metastatic Patients
Bicalutamide, in general has been well tolerated with few withdrawals due to adverse events.
Table 1 Frequency of Adverse Reactions
Frequency System Organ Class Event
Very Common (>= 10%) Reproductive system and breast disorders Breast tenderness1 Gynaecomastia1 General disorders Hot flushes Common (>= 1% and < 10%) Gastrointestinal disorders Diarrhea Nausea Hepato-biliary disorders Hepatic changes (elevated levels of transaminases, jaundice)2 General disorders Asthenia Pruritis Uncommon (>= 0.1% and <1%) Immune system disorders Hypersensitivity reactions, including angioneurotic oedema 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 Hepato-biliary disorders Hepatic failure
May be reduced by concomitant castration
Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
In patients with advanced prostate cancer, treated with bicalutamide 50 mg in combination with an LHRH analogue, the most frequent adverse experience was hot flushes (53%). 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.
Clinical Trial Adverse Drug Reactions
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 following adverse experiences with an incidence of more than 5%, regardless of causality have been reported.
Table 2 Incidence Of Adverse Events (>=5% In Either Treatment Group) Regardless Of Causality
| Adverse Event | Treatment Group Number of Patients (%) | |||
| Bicalutamide 50 mg 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) |
| Anemia a | 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) |
| Gynecomastia | 36 | (9) | 30 | (7) |
| 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 Test b | 30 | (7) | 46 | (11) |
| Dyspepsia | 30 | (7) | 23 | (6) |
| Weight Loss | 30 | (7) | 39 | (10) |
| Headache | 29 | (7) | 27 | (7) |
| Flu Syndrome | 28 | (7) | 30 | (7) |
| Myasthenia | 27 | (7) | 19 | (5) |
| Insomnia | 27 | (7) | 39 | (10) |
| Impotence | 27 | (7) | 35 | (9) |
| Flatulence | 26 | (6) | 22 | (5) |
| Hyperglycemia | 26 | (6) | 27 | (7) |
| Anorexia | 25 | (6) | 29 | (7) |
| Vomiting | 25 | (6) | 28 | (7) |
| Sweating | 25 | (6) | 20 | (5) |
| Adverse Event | Treatment Group Number of Patients (%) | |||
| Bicalutamide 50 mg Plus LHRH Analogue (n=401) | Flutamide Plus LHRH Analogue (n=407) | |||
| 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) |
| Rhinitis | 15 | (4) | 22 | (5) |
| Urinary Incontinence | 15 | (4) | 32 | (8) |
a
Anemia includes anemia, hypochromic anemia and iron deficiency anemia.
b
Increased liver enzyme test includes increases in AST, ALT or both.
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% but 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 and some of the experiences reported are those that commonly occur in elderly patients:
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 infarct, heart arrest, coronary artery disorder, syncope, atrial fibrillation, cerebrovascular accident, deep thrombophlebitis, arrhythmia, bradycardia, cerebral ischemia, hemorrhage.
Gastrointestinal:
melena, rectal hemorrhage, dry mouth, dysphagia,
gastrointestinal disorder, periodontal abscess, gastrointestinal carcinoma, rectal disorder, intestinal obstruction, gastritis.
Endocrine System:
diabetes mellitus
Central Nervous System:
hypertonia, confusion, somnolence, decreased libido, neuropathy,
nervousness
Respiratory System:
lung disorder, asthma, epistaxis, sinusitis, pleural effusion, voice
alteration
Urogenital:
dysuria, urinary urgency, hydronephrosis, urinary tract disorder,
bladder stenosis, kidney calculus, prostatic disorder, balanitis
Hematological:
ecchymosis, thrombocytopenia
Skin & Appendages:
dry skin, alopecia, pruritus, herpes zoster, skin carcinoma, skin
disorder, skin hypertrophy, hirsutism, skin ulcer
Musculoskeletal
leg cramps, bone disorders, myalgia
Metabolic & Nutritional:
edema, BUN increased, creatinine increased, dehydration, gout,
hypercholesteremia, hypoglycemia, hypercalcemia
Special Senses:
cataract, abnormal vision, conjunctivitis
Whole Body:
neoplasm, neck pain, fever, chills, sepsis, hernia, cyst, injection
site reaction, allergic reaction, neck rigidity, face edema
Abnormal Hematologic and Clinical Chemistry Findings
Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, creatinine and decreased haemoglobin 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 haemoglobin were reported less frequently with bicalutamide-LHRH analogue therapy. Other changes were reported with similar incidence in both treatment groups.
Drug-Drug Interactions
Clinical studies with bicalutamide have not demonstrated any drug/drug interactions with LHRH analogues.
In vitro studies have shown that the R-enantiomer is an inhibitor of CYP 3A4, with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Although in vitro studies have suggested the potential for bicalutamide to inhibit cytochrome 3A4, a number of clinical studies show the magnitude of any inhibition is unlikely to be of clinical significance for the majority of substances which are metabolised by cytochrome P450. Nevertheless, such an increase in AUC could be of clinical relevance for drugs with a narrow therapeutic index (e.g. cyclosporin).
In vitro
studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is recommended that if Gen-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.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Recommended Dose and Dosage Adjustment
The recommended dose for Gen-Bicalutamide therapy in combination with an LHRH analogue or surgical castration is one 50 mg tablet once daily with or without food. Gen-Bicalutamide treatment should be started at the same time as treatment with an LHRH analogue or after surgical castration.
Dosing Considerations in Special Populations
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).
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 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 Gen-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 drug overdose, contact your regional Poison Control Centre.
Pharmacodynamics
Bicalutamide is 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. There is no evidence of any clinically significant effect of food on bioavailability. Steady state plasma concentrations of the (R)-enantiomer of approximately 9 ug/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 (racemate 96%, R-enantiomer 99.6%). 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
The pharmacokinetics of the (R)-enantiomer are unaffected by age.
The pharmacokinetics of the (R)-enantiomer are unaffected by age.
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.
The pharmacokinetics of the (R)-enantiomer are unaffected by renal impairment.
Store between 15 - 30degC.
Gen-Bicalutamide 50 mg tablets are white round, biconvex, film coated tablets with "BC" over "50" on one side and "G" on the other side. In addition to the active ingredient bicalutamide, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, povidone, sodium starch glycolate, hydroxypropyl methylcellulose, titanium dioxide, triacetin. Available in blister strips of 10 tablets, 30 tablets per package, and bottles of 100 tablets.