PrSANDOZ BICALUTAMIDE
Sandoz Canada Inc. Date of Preparation: February 01, 2006 145 Jules-Leger Date of Revision: March 19, 2007 Boucherville, QC, Canada J4B 7K8 Control No: 108482
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 5 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 9 ACTION AND CLINICAL PHARMACOLOGY 9 STORAGE AND STABILITY 10 DOSAGE FORMS, COMPOSITION AND PACKAGING 10
PHARMACEUTICAL INFORMATION 11 CLINICAL TRIALS 12 PHARMACOLOGY 14 TOXICOLOGY 15 REFERENCES 23
PrSandoz Bicalutamide (Bicalutamide Tablets)
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | 50 mg | lactose monohydrate For a complete listing see DOSAGE FORMS , COMPOSITION AND PACKAGING section . |
Sandoz 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.
Patients with localized prostate cancer otherwise undergoing watchful waiting (see WARNINGS AND PRECAUTIONS). Patients with hypersensitivity to the drug or any of its components. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING in product monograph. Women: The safety and effectiveness of bicalutamide in women has not been studied. Children: The safety and effectiveness of bicalutamide in children has not been studied.
Evidence from a large ongoing clinical study demonstrates that at 5.4 year median follow-up (see CLINICAL TRIALS), the use of 150 mg of bicalutamide as immediate therapy for the treatment of localized prostate cancer in patients otherwise undergoing watchful waiting is associated with increased mortality. In the absence of factors suggesting high risk of disease progression, it is recommended that clinicians do not administer 150 mg of bicalutamide in patients with localized prostate cancer. Health Canada previously assessed 150 mg of bicalutamide 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 150 mg bicalutamide treated patients. Patients taking 150 mg of bicalutamide per day for the treatment of metastatic prostate cancer are not affected by this new information. In some patients with metastatic prostate cancer, antiandrogens (steroidal and nonsteroidal), 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.
: It is recommended that clinicians do not administer 150 mg of bicalutamide in patients with localized disease who would otherwise undergo watchful waiting.
: 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 increased accumulation of bicalutamide. Therefore, Sandoz Bicalutamide should be used with caution in patients with moderate to severe hepatic impairment.
Severe hepatic changes have been observed rarely with bicalutamide. Sandoz Bicalutamide therapy should be discontinued if changes are severe.
: Gynaecomastia has been reported in patients receiving bicalutamide. For metastatic (M1) patients receiving bicalutamide 50 mg, concomitant surgical or medical castration may reduce the effects of gynaecomastia.
Sandoz Bicalutamide is contraindicated in females. Sandoz Bicalutamide may cause foetal 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).
: It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk, precaution should be exercised.
: The safety and effectiveness of Sandoz Bicalutamide (nonsteroidal antiandrogen) in children has not been established.
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 oestradiol levels, fluid retention could occur. Accordingly, Sandoz Bicalutamide should be used with caution in those patients with cardiac disease.
Adverse Drug Reaction Overview
Bicalutamide in Metastatic PatientsTable 1
: Bicalutamide, in general, has been well tolerated with few withdrawals due to adverse events (see
).
Table 1: Frequency of Adverse Reactions
| Frequency | System Organ Class | Event | |||
| Very Common (>=10%) | Reproductive system and breast disorders | Breast tenderness a | |||
| Gynecomastia a | |||||
| General disorders | Hot flushes a | ||||
| Common (>=1% and <10%) | Gastrointestinal disorders | Diarrhea | |||
| Nausea | |||||
| Hepatobiliary disorders | Hepatic changes (elevated levels of transaminases, jaundice) b | ||||
| General disorders | Asthenia | ||||
| Pruritus | |||||
| Uncommon (>=0.1% and <1%) | Immune system disorders | Hypersensitivity reactions, including angioneurotic oedema and urticaria | |||
| Respiratory, disorders | thoracic | and | mediastinal | Interstitial lung disease | |
| Rare (>=0.01% and <0.1%) | Gastrointestinal disorders | Vomiting | |||
| Skin and subcutaneous tissue disorders | Dry skin | ||||
a
May be reduced by concomitant castration.
b.
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 (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.
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 (see Table 2).
Table 2: Incidence of Common 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) | |||
| Body as a Whole | ||||
| Hot Flushes | 196 | (49) | 202 | (50) |
| Pain (General) | 109 | (27) | 93 | (23) |
| Back Pain | 62 | (15) | 68 | (17) |
| Asthenia | 60 | (15) | 69 | (17) |
| Pelvic Pain | 52 | (13) | 46 | (11) |
| Infection | 41 | (10) | 35 | (9) |
| Abdominal Pain | 33 | (8) | 31 | (8) |
| Chest Pain | 24 | (6) | 20 | (5) |
| Headache | 17 | (4) | 20 | (5) |
| Flu Syndrome | 16 | (4) | 20 | (5) |
| Cardiovascular System | ||||
| Hypertension | 21 | (5) | 18 | (4) |
| Central Nervous System | ||||
| Dizziness | 30 | (7) | 27 | (7) |
| Paresthesia | 24 | (6) | 27 | (7) |
| Insomnia | 19 | (5) | 30 | (7) |
| Gastrointestinal System | ||||
| Constipation | 67 | (17) | 50 | (12) |
| Nausea | 44 | (11) | 45 | (11) |
| Diarrhea | 40 | (10) | 98 | (24) |
| Flatulence | 22 | (5) | 16 | (4) |
| Vomiting | 12 | (3) | 20 | (5) |
| Hematological System | ||||
| Anemia a | 29 | (7) | 35 | (9) |
| Hepatobiliary Disorders | ||||
| Increased Liver Enzyme Test b | 25 | (6) | 40 | (10) |
| Metabolic & Nutritional System | ||||
| Peripheral Edema | 34 | (8) | 28 | (7) |
| Weight Loss | 16 | (4) | 20 | (5) |
| Hyperglycemia | 20 | (5) | 16 | (4) |
| Musculoskeletal System | ||||
| Bone Pain | 18 | (4) | 26 | (6) |
| Respiratory System | ||||
| Dyspnea | 30 | (7) | 24 | (6) |
| Skin and Appendages System | ||||
| Rash | 25 | (6) | 20 | (5) |
| Sweating | 23 | (6) | 18 | (4) |
| Urogenital System | ||||
| Nocturia | 35 | (9) | 43 | (11) |
| Hematuria | 30 | (7) | 20 | (5) |
| Urinary Tract Infection | 26 | (6) | 24 | (6) |
| Impotence | 20 | (5) | 29 | (7) |
| Gynecomastia | 19 | (5) | 23 | (6) |
| Urinary Incontinence | 9 | (2) | 20 | (5) |
a
Anemia includes anemia, hypochromic- and iron deficiency anemia
b
Increased liver enzyme test includes increases in ALT, AST or both.
Other Clinical Trial Adverse Drug Reactions
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 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:
Body as a Whole:
abdominal pain, chest pain, headache, pain, pelvic pain, chills
Cardiovascular:
heart failure
Central Nervous System: Gastrointestinal: Hematological:
dizziness, insomnia, somnolence, decreased libido
anorexia, dry mouth, dyspepsia, constipation, flatulence
anemia
Metabolic & Nutritional:
hyperglycaemia, edema, weight gain, weight loss, diabetes mellitus
Respiratory:
dyspnea
Skin & Appendages:
alopecia, rash, sweating, hirsutism
Urogenital:
impotence, nocturia
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.
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 CYP3A4, with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Although in vitro studies have suggested the potential for CASODEX(r) 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).
The drugs listed below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated). Warfarin: In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is recommended that if Sandoz 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. Interaction with other drugs has not been established.
Interactions with food have not been established.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
Sandoz Bicalutamide 50 mg in metastatic disease: the recommended dose for Sandoz 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.
: 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
).
A single dose of Sandoz 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 Sandoz 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 Sandoz 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.
Sandoz Bicalutamide (bicalutamide) is a nonsteroidal antiandrogen, devoid of other endocin activity. Bicalutamide competitively inhibits the action of androgen by binding to cytosol androgen receptors in target tissue. This inhibition results in regression of prostatic tumours. Sandoz Bicalutamide is a racemate and the (R)-enantiomer is primarily responsible for the antiandrogen activity of Sandoz Bicalutamide.
The absorption, distribution, metabolism and excretion of bicalutamide have 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 mcg/mL is observed during daily administration of 50 mg doses bicalutamide, respectively. 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 to the (R)-enantiomer. 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.
Store between 15 and 30degC.
Sandoz Bicalutamide 50 mg tablets are white, or almost white, round, biconvex film-coated tablets, with a sign "B" on one side and "50" on the other side. Available in blister packs of 30 tablets, and in 30 and 1000 counts HDPE bottles. In addition to the active ingredient bicalutamide, each tablet contains the following inactive ingredients: lactose monohydrate, sodium starch glycolate, povidone, colloidal anhydrous silica, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, triacetin.