BICALUTAMIDE: 4,061 Adverse Event Reports & Safety Profile

Bicalutamide Tablets, USP contain 50 mg of bicalutamide, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural and molecular formulas are: Bicalutamide, USP has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide is a white to off-white powder which is practically insoluble in water at 37°C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran. Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive. Each bicalutamide tablet, USP intended for oral administration contains 50 mg of bicalutamide. In addition each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide. The product meets USP Dissolution Test 2. Image

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 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)

AND ADMINISTRATION The recommended dose for bicalutamide tablets therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening). (2)

2.1 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.

2.2 Dosage Adjustment in Renal Impairment No dosage adjustment is necessary for patients with renal impairment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7)]</span>.

2.3 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6)]</span>.

4.

Contraindications

Bicalutamide tablets are contraindicated in:

• Hypersensitivity Bicalutamide tablets 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.
• Women Bicalutamide tablets have no indication for women, and should not be used in this population.
• Pregnancy Bicalutamide tablets 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 )

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. Adverse reactions that occurred in more than 10% of patients receiving bicalutamide plus an LHRH-A were: hot flashes, pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1.

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 (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)

Musculoskeletal 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-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. 6.2.

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. [see Warnings and Precautions (5.2) ] Skin and subcutaneous tissue disorders: Photosensitivity

5. WARNINGS AND PRECAUTIONS

• Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment and periodically thereafter, and for symptoms or signs suggestive of hepatic dysfunction. Use bicalutamide with caution in patients with hepatic impairment. (5.1)
• Hemorrhage with Concomitant Use of Coumarin Anticoagulant. Closely monitor the Prothrombin Time (PT) and International Normalized Ratio (INR), and adjust the anticoagulant dose as needed. (5.2)
• Gynecomastia and breast pain have been reported during treatment with bicalutamide 150 mg when used as a single agent. (5.3)
• Bicalutamide is used in combination with an LHRH agonist. LHRH agonists have been shown to cause a reduction in glucose tolerance in males. Consideration should be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists. (5.4)
• Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. (5.5) 5.1.

Hepatitis

Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported postmarketing in association with the use of bicalutamide tablets. 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 tablet patients in controlled clinical trials. Serum transaminase levels should be measured prior to starting treatment with bicalutamide tablets, 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 should be immediately discontinued with close follow-up of liver function. 5.2. Hemorrhage with Concomitant Use of Coumarin Anticoagulant In the postmarketing setting, there have been reports of excessive prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) days to weeks after the introduction of bicalutamide in patients who were previously stable on coumarin anticoagulants. Some patients had serious bleeding including intracranial, retroperitoneal, and gastrointestinal requiring blood transfusion and/or administration of vitamin K. Closely monitor the PT/INR, and adjust the anticoagulant dose as needed [see Drug Interactions (7) and Adverse Reactions (6.2) ]. 5.3. Gynecomastia and Breast Pain In clinical trials with bicalutamide 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. 5.4.

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 in combination with LHRH agonists. 5.5.

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 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.

7.

Drug Interactions

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 co-administration 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 co-administered 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 reaction (6.2) ]

• R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when bicalutamide is co-administered with CYP 3A4 substrates. ( 7 )
• PT/INR should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide. ( 7 )