FLUTAMIDE

1 Pediatrics Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 2 Geriatrics Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

3 Pharmacokinetics. 2 CONTRAINDICATIONS FLUTAMIDE (flutamide) is contraindicated in:  Patients who are hypersensitive to flutamide or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, See

1 Adverse Reaction Overview The most frequently reported adverse reactions to flutamide monotherapy are gynecomastia and/or breast tenderness, sometimes accompanied by galactorrhe a. These reactions disappear upon discontinuation of treatment or reduction in dosage.

The incidence of gynecomastia is reduced greatly when flutamide is administered concomitantly with a LHRH agonist. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide in combination with a LHRH agonist are listed in the table below.

For comparison, adverse experiences seen with a LHRH agonist and placebo are also listed in the following table. Table 2 - Adverse reactions with an incidence of ≥ 5% Flutamide + LHRH-agonist (n=294) Placebo + LHRH-agonist (n=285) % All % All Hot Flashes 61 57 Loss of Libido 36 31 Impotence 33 29 Diarrhea 12 4 Nausea/Vomiting 11 10 Gynecomastia 9 11 Other 7 9 Other GI 6 4 PrFLUTAMIDE (flutamide) Page 11 of 27 As shown in the table, for both treatment groups, the most frequently occurring adv erse experiences (hot flashes, loss of libido, impotence) were those known to be associated with low serum androgen levels and known to occur with LHRH-agonists alone.

The only notable difference between these treatment groups was the higher incidence of diarrhea in the flutamide + LHRH-agonist group (12%; severe in 5%) as compared to the placebo + LHRH-agonist group (4%; were severe in less than 1%).

In addition, the following adverse reactions were reported during treatment with flutamide + LHRH-agonist. No causal relatedness of these reactions to drug treatment has been made, and some of the adverse experiences reported are those that commonly occur in elderly patients.

Cardiovascular System:

Hypertension in 1% of patients. Rarely thrombophlebitis, pulmonary embolism, myocardial infarction.

Central Nervous System:

CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients. Rarely insomnia, tiredness, headache, dizziness, weakness, malaise, blurred vision and decreased libido have been reported.

Endocrine System:

Gynecomastia in 9% of patients. Rarely breast tenderness sometimes accompanied by galactorrhea.

Gastrointestinal System:

Nausea/vomiting occurred in 11%; diarrhea 12%, anorexia 4%, and other gastro-intestinal disorders occurred in 6% of patients. Increased appetite, indigestion and constipation have also been reported.

Hematopoietic System:

Anemia occurred in 6% of patients, leukopenia 3%, thrombocytopenia 1%.

Liver and Biliary System:

Clinically evident hepatitis and jaundice occurred in <1% of patients.

Skin:

Irritation at the injection site and rash occurred in 3% of patients. Photosensitivity reactions have been reported in five patients.

Other:

Pruritus, ecchymosis, herpes zoster, thirst, lymphedema, lupus-like syndrome, hematuria, reduced sperm counts have been reported rarely in long-term treatment. Edema occurred in 4% of patients; neuromuscular, genitourinary symptoms occurred in 2% of patients.

Interstitial lung disease occurred in <1% of patients. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings Laboratory Values: Reported abnormal laboratory test results include elevated SGOT (AST), SGPT (ALT); elevated blood urea nitrogen (BUN) and bilirubin levels; less frequently, elevated serum creatinine levels and elevated gamma-glutamyl transferase levels have been reported.

5 Post-Market Adverse Reactions In addition, the following adverse experiences have been reported during world -wide marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions- including erythema, ulcerations, bullous eruptions, and epidermal necrolysis - and change in urine colour to an amber or yellow-green appearance, which can be attributed to flutamide and/or its metabolites.

Also observed were cholestatic jaundice, hepatic encephalopathy and hepatic necrosis. The hepatic conditions were usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide.

Cardiac failure, sudden cardiac deaths have been reported. Hyperglycemia and aggravated diabetes mellitus have been reported very rarely. Two reports of malignant male breast neoplasms in patients being dosed with flutamide have been reported.

One involved aggravation of a pre-existing nodule which was first detected three to four months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma.

The other report involved gynecomastia and a nodule noted two and six months respectively, after initiation of flutamide monotherapy for treatment of advanced prostatic carcinoma. Nine months after the initiation of therapy, the nodule was excised and diagnosed as a moderately differentiated invasive ductal tumor staged T4N0M0, G3, no metastases had advanced.

General Gynecomastia occurred in 9% of patients receiving flutamide together with medical castration. Physicians must familiarize themselves with the proper use of LHRH before combination medication is contemplated. Carcinogenesis and Mutagenesis After long-term administration in rats, flutamide produced testicular interstitial cell adenomas and dose-related increases in mammary gland adenomas or carcinomas.

The relevance of these findings to humans is unknown. It should be noted that few cases of malignant breast neoplasms have been reported in male patients receiving flutamide; causality has not been established (see 16 NON-CLINICAL TOXICOLOGY).

 Antiandrogen Withdrawal Syndrome In some patients with metastatic prostate cancer, antiandrogens (steroidal or non-steroidal), may promote, rather than inhibit, the growth of prostate cancer. A decrease in PSA and/or clinical improvement following the discontinuation of antiandrogens have 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.

Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients oral tablet 250 mg carnauba wax, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake 16%, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide.

PrFLUTAMIDE (flutamide) Page 7 of 27 Cardiovascular FLUTAMIDE is indicated for use in combination with an LHRH analogue or orchiectomy. Based on evidence from the published literature, combined androgen blockade with an antiandrogen plus LHRH analogue increases risk of cardiovascular disease (heart attack, cardiac failure, sudden cardiac death) and adversely affects independent cardiovascular risk factors (serum lipoproteins, insulin sensitivity and obesity).

Physicians should carefully consider whether the benefits of combined androgen blockade outweigh the potential cardiovascular ris k. Assessment of cardiovascular risk factors, monitoring for signs and symptoms suggestive of development of cardiovascular disease, and management according to local clinical practice and guidelines should be considered.

Since flutamide tends to elevate plasma testosterone and estradiol levels, fluid retention may occur. Accordingly, flutamide should be used with caution in those patients with cardiac disease.  Effect on QT/QTc interval FLUTAMIDE is indicated for use in combination with an LHRH analogue or orchiectomy.

The potential for QT/QTc prolongation has not been studied with FLUTAMIDE. Combined androgen blockade studies with other anti-androgen plus LHRH analogue or surgical castration have been associated with the potential to prolong QT/QTc interval on ECG.

g. g. g. 2 Drug Interactions Overview). Endocrine and Metabolism A reduction in glucose tolerance and/or glycated hemoglobin (HbAlc) has been observed in males receiving combined androgen blockade. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes.

Consideration should therefore be given to monitoring blood glucose and/or glycated hemoglobin (HbAlc) in patients receiving FLUTAMIDE in combination with LHRH analogues. Hematologic Anemia is a known physiologic consequence of testosterone suppression.

Assessment of anemia risk and management according to local clinical practice and guidelines should be considered. Hepatic/Biliary/Pancreatic  Hepatic Injury There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide.

Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy, and death related to acute hepatic PrFLUTAMIDE (flutamide) Page 8 of 27 failure. The hepatic injury was reversible after prompt discontinuation of therapy in some patients.

Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide. Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal.

Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. , nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness.

If at any time a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow- up of liver function tests until resolution. Treatment with flutamide should not be initiated in patients with serum transaminase levels exceeding 2 to 3 times the upper limit of normal.

Since transaminase abnormalities, cholestatic jaundice, hepatic necrosis, and hepatic encephalopathy have been reported with the use of flutamide, periodic liver function tests must be performed in all patients. , pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained “flu - like” symptoms).

If […]

FLUTAMIDE (flutamide) is contraindicated in:  Patients who are hypersensitive to flutamide or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, See 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

 Patients with severe hepatic impairment. FLUTAMIDE has not been studied in women and is not indicated for this population, particularly for nonserious or nonthreatening conditions.