Bicalutamide Drug Information

• Bicalutamide tablets, USP 50 mg daily are indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D 2 metastatic carcinoma of the prostate. Bicalutamide tablets, USP 150 mg daily are not approved for use alone or with other treatments [see Clinical Studies (14.2)].
• Bicalutamide tablet 50 mg is an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D 2 metastatic carcinoma of the prostate. (1)
• Bicalutamide tablet 150 mg daily is not approved for use alone or with other treatments. (1)

Recommended Dose and Schedule

The recommended dose for bicalutamide tablets therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets be taken at the same time each day. Treatment with bicalutamide tablets should be started at the same time as treatment with an LHRH analog.

If a dose of bicalutamide tablets is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose.

Dosage Adjustment in Renal Impairment No dosage adjustment is necessary for patients

with renal impairment.

Dosage Adjustment in Hepatic Impairment No dosage adjustment is necessary for patients

with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide, no dosage adjustment is necessary.

Clinical Trials Experience

In patients with advanced prostate cancer treated with bicalutamide in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%). In the multi-center, 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 analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported. Table 1 Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality Body System Adverse Reaction Treatment Group Number of Patients (%) Bicalutamide Plus LHRH Analog (n=401) Flutamide Plus LHRH Analog (n=407) Body as a Whole Pain (General) 142 127 Back Pain 102 105 Asthenia 89 87 Pelvic Pain 85 70 Infection 71 57 Abdominal Pain 46 46 Chest Pain 34 34 Headache 29 27 Flu Syndrome 28 30 Cardiovascular Hot Flashes 211 217 Hypertension 34 29 Digestive Constipation 87 69 Nausea 62 58 Diarrhea 49 107 Increased Liver Enzyme Test 30 46 Dyspepsia 30 23 Flatulence 26 22 Anorexia 25 29 Vomiting 24 32 Hemic and Lymphatic Anemia 45 53 Metabolic and Nutritional Peripheral Edema 53 42 Weight Loss 30 39 Hyperglycemia 26 27 Alkaline Phosphatase Increased 22 24 Weight Gain 22 18 Musculoskeletal Bone Pain 37 43 Myasthenia 27 19 Arthritis 21 29 Pathological Fracture 17 32 Nervous System Dizziness 41 35 Paresthesia 31 40 Insomnia 27 39 Anxiety 20 9 Depression 16 33 Respiratory System Dyspnea 51 32 Cough Increased 33 24 Pharyngitis 32 23 Bronchitis 24 22 Pneumonia 18 19 Rhinitis 15 22 Skin and Appendages Rash 35 30 Sweating 25 20 Urogenital Nocturia 49 55 Hematuria 48 26 Urinary Tract Infection 35 36 Gynecomastia 36 30 Impotence 27 35 Breast Pain 23 15 Urinary Frequency 23 29 Urinary Retention 20 14 Urinary Impaired 19 15 Urinary Incontinence 15 32 Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality. Body as a Whole: Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope Digestive: Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma Metabolic and Nutritional: Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesteremia Musculoskeletal: Myalgia; Leg Cramps Nervous: Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness Respiratory: Lung Disorder; Asthma; Epistaxis; Sinusitis Skin and Appendages: Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder Special Senses: Cataract Specified Urogenital: Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder Abnormal Laboratory Test Values: Laboratory abnormalities including: elevated AST, ALT, bilirubin, BUN, and creatinine; and decreased hemoglobin and white cell count, have been reported in both bicalutamide-LHRH analog treated and flutamide-LHRH analog treated patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bicalutamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory disorders: Interstitial lung disease (some fatal) including interstitial pneumonitis and pulmonary fibrosis, most often at doses greater than 50 mg.

Hemorrhage: Increased PT/INR due to interaction between coumarin anticoagulants and bicalutamide. Serious bleeding reported. Skin and subcutaneous tissue disorders: Photosensitivity

• Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes. In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that with coadministration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5-fold (for C max ) and 1.9-fold (for AUC). Hence, caution should be exercised when bicalutamide is coadministered with CYP 3A4 substrates. In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. PT/INR should be closely monitored in patients concomitantly receiving coumarin anticoagulants and bicalutamide. Adjustment of the anticoagulant dose may be necessary [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
• R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when bicalutamide is coadministered with CYP 3A4 substrates. (7)
• PT/INR should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide. (7)

Pregnancy Risk Summary Bicalutamide is contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide is not indicated for use in females. There are no human data on the use of bicalutamide in pregnant women.

In animal reproduction studies, oral administration of bicalutamide to pregnant rats during organogenesis caused abnormal development of reproductive organs in male fetuses at exposures approximately 0.7 to 2 times the human exposure at the recommended dose (see Data). Data Animal Data In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above (approximately 0.7 to 2 times the human exposure at the recommended dose). In a pre- and post-natal development study, female rats were dosed from gestation day 7-16 and allowed to litter and rear their offspring to weaning. Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance. In a peri- and post-natal development study, female rats were dosed from gestation day 16 to lactation day 22 and allowed to litter and rear their offspring to weaning.

Survival and weights of offspring during lactation were reduced for litters from maternal rats receiving doses of 250 mg/kg/day (approximately 2 times the human exposure at the recommended dose). Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance, smaller secondary sex organs, cryptorchidism and hypospadias resulting in an inability to mate and impregnate their female partners. Female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above had reduced pregnancy rates.

SD, 95% CI (–1.2 to 1.0) p=0.88. Table 2 shows descriptive data

for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors. Table 2. Growth Rates Endpoint Analysis Population Pre-study Mean Change from pre-study to 12 months % patients with growth reduction Change compared to pre-study growth rate. Mean Median (Min, Max) Growth rate (cm/yr) All treated (n=13) 10.8 -1.6 -2.8 (-7.4, 8.4) 9/13 (69%) PT PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors. (n=6) 10.3 -0.2 -

Median calculated as midpoint of 3rd and 4th ranked observations. (-7.2, 8.4)

4/6 (67%) NPT NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole, or other aromatase inhibitors. (n=7) 11.2 -2.8 -2.8 (-7.4, 1.1) 5/7 (71%) Growth rate (SD units) All treated (n=13) 0.4 -0.1 -0.4 (-2.7, 3.5) 9/13 (69%) PT (n=6) -0.1 +0.7 -0.2 (-1.6, 3.5) 4/6 (67%) NPT (n=7) 0.8 -0.7 -0.4 (-2.7, 0.5) 5/7 (71%) Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification. There were no deaths, serious adverse events, or discontinuations due to adverse events during the study.

Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (>3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%), and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase (1/14, 7%), increased aspartate aminotransferase (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrozole by investigators. For the patient who developed elevated ALT and AST, the elevation was <3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.

• Bicalutamide is contraindicated in:
• Hypersensitivity Bicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported.
• Women Bicalutamide has no indication for women, and should not be used in this population.
• Pregnancy Bicalutamide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
• Hypersensitivity ( 4 )
• Women ( 4 )
• Pregnancy ( 4, 8.1 )

Long-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established. 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.