Bicalutamide

BICALUTAMIDE- bicalutamide tablet, film coated
Dava Pharmaceuticals, Inc.

1. INDICATIONS AND USAGE

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 D2 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)].

2. DOSAGE AND ADMINISTRATION

The recommended dose for Bicalutamide Tablets, USP 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, USP be taken at the same time each day. Treatment with Bicalutamide Tablets, USP should be started at the same time as treatment with an LHRH analog.

2.1. Dosage Adjustment in Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

2.2. 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 [see Use in Specific Populations (8.6)].

3. DOSAGE FORMS & STRENGTHS

Bicalutamide Tablets, USP 50 mg Tablets for oral administration.

4. CONTRAINDICATIONS

4.1. Hypersensitivity

Bicalutamide Tablets, USP are 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 [see Adverse Reactions (6.2)].

4.2. Women

Bicalutamide Tablets, USP have no indication for women, and should not be used in this population.

4.3. Pregnancy

Bicalutamide Tablets, USP may cause fetal harm when administered to a pregnant woman. Bicalutamide Tablets, USP are contraindicated in women, including those who are or may become pregnant. There are no studies in pregnant women using Bicalutamide Tablets, USP. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1)].

5. WARNINGS AND PRECAUTIONS

5.1. Hepatitis

Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Bicalutamide Tablets, USP. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of Bicalutamide Tablets, USP patients in controlled clinical trials.

Serum transaminase levels should be measured prior to starting treatment with Bicalutamide Tablets, USP, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, Bicalutamide Tablets, USP should be immediately discontinued with close follow-up of liver function.

5.2. Gynecomastia and Breast Pain

In clinical trials with Bicalutamide Tablets, USP 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.

5.3. Glucose Tolerance

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. 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 in patients receiving Bicalutamide Tablets, USP in combination with LHRH agonists.

5.4. Laboratory Tests

Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient’s response. If PSA levels rise during Bicalutamide Tablets, USP therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.

6. ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1. Clinical Trials Experience

In patients with advanced prostate cancer treated with Bicalutamide Tablets, USP in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).

In the multicenter, double-blind, controlled clinical trial comparing Bicalutamide Tablets, USP 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 GroupNumber of Patients (%)
Bicalutamide Tablets, USPPlus LHRH Analog(n=401) FlutamidePlus LHRH Analog(n=407)
*
Increased liver enzyme test includes increases in AST, ALT or both.
Anemia includes anemia, hypochronic-and iron deficiency anemia.
Body as a Whole
Pain (General) 142 (35) 127 (31)
Back Pain 102 (25) 105 (26)
Asthenia 89 (22) 87 (21)
Pelvic Pain 85 (21) 70 (17)
Infection 71 (18) 57 (14)
Abdominal Pain 46 (11) 46 (11)
Chest Pain 34 (8) 34 (8)
Headache 29 (7) 27 (7)
Flu Syndrome 28 (7) 30 (7)
Cardiovascular
Hot Flashes 211 (53) 217 (53)
Hypertension 34 (8) 29 (7)
Digestive
Constipation 87 (22) 69 (17)
Nausea 62 (15) 58 (14)
Diarrhea 49 (12) 107 (26)
Increased Liver Enzyme Test * 30 (7) 46 (11)
Dyspepsia 30 (7) 23 (6)
Flatulence 26 (6) 22 (5)
Anorexia 25 (6) 29 (7)
Vomiting 24 (6) 32 (8)
Hemic and Lymphatic
Anemia 45 (11) 53 (13)
Metabolic and Nutritional
Peripheral Edema 53 (13) 42 (10)
Weight Loss 30 (7) 39 (10)
Hyperglycemia 26 (6) 27 (7)
Alkaline Phosphatase Increased 22 (5) 24 (6)
Weight Gain 22 (5) 18 (4)
Muscoloskeletal
Bone Pain 37 (9) 43 (11)
Myasthenia 27 (7) 19 (5)
Arthritis 21 (5) 29 (7)
Pathological Fracture 17 (4) 32 (8)
Nervous System
Dizziness 41 (10) 35 (9)
Paresthesia 31 (8) 40 (10)
Insomnia 27 (7) 39 (10)
Anxiety 20 (5) 9 (2)
Depression 16 (4) 33 (8)
Respiratory System
Dyspnea 51 (13) 32 (8)
Cough Increased 33 (8) 24 (6)
Pharyngitis 32 (8) 23 (6)
Bronchitis 24 (6) 22 (3)
Pneumonia 18 (4) 19 (5)
Rhinitis 15 (4) 22 (5)
Skin and Appendages
Rash 35 (9) 30 (7)
Sweating 25 (6) 20 (5)
Urogenital
Nocturia 49 (12) 55 (14)
Hematuria 48 (12) 26 (6)
Urinary Tract Infection 35 (9) 36 (9)
Gynecomastia 36 (9) 30 (7)
Impotence 27 (7) 35 (9)
Breast Pain 23 (6) 15 (4)
Urinary Frequency 23 (6) 29 (7)
Urinary Retention 20 (5) 14 (3)
Urinary Impaired 19 (5) 15 (4)
Urinary Incontinence 15 (4) 32 (8)

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the Bicalutamide Tablets, USP-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 Tablets, USP-LHRH analog treated and flutamide-LHRH analog treated patients.

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