Bicalutamide

1. INDICATIONS AND USAGE Bicalutamide tablets 50 mg daily is 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 150 mg daily is not approved for use alone or with other treatments [see Clinical Studies (14.2) ]. Bicalutamide tablets 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 tablets 150 mg daily is not approved for use alone or with other treatments. (1)

3. DOSAGE FORMS AND STRENGTHS Bicalutamide Tablets USP 50 mg for oral administration. 50 mg tablets (3)

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 )

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.

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 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

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 Reactions (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)

8. USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception. (8.3) Pediatric patients: Efficacy has not been demonstrated for the treatment of familial male-limited precocious puberty (testotoxicosis). (8.4) 8.1. Pregnancy Risk Summary Bicalutamide tablets are contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide tablets are not indicated for use in females. There are no human data on the use of bicalutamide tablets 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. 8.2. Lactation Risk Summary Bicalutamide tablets are is not indicated for use in pregnant women. There is no information available on the presence of bicalutamide in human milk, or on the effects on the breastfed infant or on milk production. Bicalutamide has been detected in rat milk. 8.3. Females and Males of Reproductive Potential Contraception Males Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology (13.1) ] . Based on findings in animal reproduction studies and its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the final dose of bicalutamide tablets [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1) ] . Infertility Males Based on animal studies, bicalutamide can lead to inhibition of spermatogenesis and may impair fertility in males of reproductive potential. The long-term effects of bicalutamide on male fertility have not been studied [see Nonclinical Toxicology (13.1) ] . 8.4. Pediatric Use The safety and effectiveness of bicalutamide tablets in pediatric patients have not been established. Bicalutamide orodispersible tablet was studied in combination with anastrozole orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age ≥2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12-month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean ± SD characteristics at baseline were as follows: chronological age: 3.9±1.9 years; bone age 8.8±2.5; bone age/chronological age ratio: 2.06±0.51; growth rate (cm/yr): 10.81±4.22; growth rate standard deviation score (SDS): 0.41±1.36. The starting bicalutamide dose was 12.5 mg. Bicalutamide was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5-15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved bicalutamide dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of <10 pmol/L (2.7 pg/mL). The following ascending doses were used for bicalutamide: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase, 1 patient was on 12.5 mg bicalutamide, 8 patients were on 50 mg bicalutamide, and 4 patients were on 100 mg bicalutamide; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8. The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the ≥6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During bicalutamide/anastrozole treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS decreased by 0.1 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 Analysis population Pre-study Mean Change from pre-study to 12 months % patients with growth reduction 1 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 2 (n=6) 10.3 -0.2 -2.6 3 (-7.2, 8.4) 4/6 (67%) NPT 4 (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 2 (n=6) -0.1 +0.7 -0.2 3 (-1.6, 3.5) 4/6 (67%) NPT 4 (n=7) 0.8 -0.7 -0.4 (-2.7, 0.5) 5/7 (71%) Change compared to pre study growth rate. PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors. Median calculated as midpoint of 3 rd and 4 th ranked observations. NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole, or other aromatase inhibitors. 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. […]

12.1. Mechanism of Action Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen. When bicalutamide is combined with LHRH analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted. In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.