HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use bicalutamide tablets safely and
`effectively. See full prescribing information for bicalutamide tablets.
`
`Bicalutamide Tablet for Oral use
`Initial U.S. Approval: 1995
`
`! Gynecomastia and breast pain have been reported during treatment with bicalutamide 150 mg
`when used as a single agent. (5.2)
`! Bicalutamide is used in combination with a 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. (5.3)
`! Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if
`PSA increases. (5.4)
`
`-------------------------------------------INDICATIONS AND USAGE------------------------------------------
`
`---------------------------------------------ADVERSE REACTIONS--------------------------------------------
`
`
`! 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
`metastatic carcinoma of the prostate.
`
`! Bicalutamide tablet 150 mg daily is not approved for use alone or with other treatments. (1)
`
`2
`
`----------------------------------------DOSAGE 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)
`
`--------------------------------------DOSAGE FORMS AND STRENGTHS-------------------------------------
`
`50 mg tablets (3)
`
`---------------------------------------------CONTRAINDICATIONS--------------------------------------------
`
`! Hypersensitivity (4.1)
`! Women (4.2)
`! Pregnancy (4.3 and 8.1)
`
`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 CARACO Pharmaceutical Laboratories Ltd. at
`1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`----------------------------------------------DRUG INTERACTIONS--------------------------------------------
`
`! R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when bicalutamide is
`co-administered with CYP 3A4 substrates. (7)
`! Prothrombin times should be closely monitored in patient already receiving coumarin
`anticoagulants who are started on bicalutamide.(7)
`
`------------------------------------------USE IN SPECIFIC POPULATIONS------------------------------------
`
`! Pediatric patients: Labeling describing pediatric clinical studies for bicalutamide is approved for
`
`
`bicalutamide
`tablet. However, due
`AstraZeneca Pharmaceuticals
`to AstraZeneca
`LP’s
`Pharmaceuticals LP’s marketing exclusivity rights, a description of those clinical studies is not
`approved for this bicalutamide labeling. (8.4)
`
`------------------------------------------WARNINGS AND PRECAUTIONS------------------------------------
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`! Severe hepatic changes and hepatic failure have been observed rarely. 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)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1. INDICATIONS AND USAGE
`2. DOSAGE AND ADMINISTRATION
`2.1. Dosage Adjustment in Renal Impairment
`2.2. Dosage Adjustment in Hepatic Impairment
`3. DOSAGE FORMS & STRENGTHS
`4. CONTRAINDICATIONS
`4.1
`Hypersensitivity
`4.2 Women
`4.3
`Pregnancy
`5. WARNINGS AND PRECAUTIONS
`5.1
`Hepatitis
`5.2
`Gynecomastia and Breast Pain
`5.3
`Glucose Tolerance
`5.4
`Laboratory Tests
`6. ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`7. DRUG INTERACTIONS
`8. USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`
`FULL PRESCRIBING INFORMATION
`
`1. INDICATIONS AND USAGE
`
`Bicalutamide tablets 50 mg daily are indicated for use in combination therapy with a luteinizing
`
`hormone-releasing hormone (LHRH) analog for the treatment of Stage D metastatic carcinoma of the
`
`prostate.
`
`2
`
`Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments [see
`
`Clinical Studies (14.2)].
`
`Revised: [06/2009]
`
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Hepatic Impairment
`8.6
`Renal Impairment
`8.7
`8.8 Women
`10. OVERDOSAGE
`11. DESCRIPTION
`12. CLINICAL PHARMACOLOGY
`12.1. Mechanism of Action
`12.3. Pharmacokinetics
`13. NONCLINICAL TOXICOLOGY
`13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
`14. CLINICAL STUDIES
`14.1. Bicalutamide 50 mg Daily in Combination with an LHRH-A
`14.2. Safety Data from Clinical Studies using Bicalutamide 150 mg
`16. HOW SUPPLIED/STORAGE AND HANDLING
`16.1. Storage and Handling
`17. PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`5.2. 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.
`
`
`5.3. 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 in combination with LHRH agonists.
`
`2. DOSAGE AND ADMINISTRATION
`
`5.4.
`
`Anorexia
`Vomiting
`Hemic and Lymphatic
`
`‡
`Anemia
`Metabolic and Nutritional
`Peripheral Edema
`Weight Loss
`Hyperglycemia
`Alkaline Phosphatase
`Increased
`Weight Gain
`Musculoskeletal
`Bone Pain
`Myasthenia
`Arthritis
`Pathological Fracture
`Nervous System
`Dizziness
`Paresthesia
`Insomnia
`Anxiety
`Depression
`Respiratory System
`Dyspnea
`Cough Increased
`Pharyngitis
`Bronchitis
`Pneumonia
`Rhinitis
`Skin and Appendages
`Rash
`Sweating
`Urogenital
`Nocturia
`Hematuria
`Urinary Tract Infection
`Gynecomastia
`Impotence
`Breast Pain
`Urinary Frequency
`Urinary Retention
`Urinary Impaired
`Urinary Incontinence
`
`25 (6)
`24 (6)
`
`45 (11)
`
`53 (13)
`30 (7)
`26 (6)
`
`22 (5)
`22 (5)
`
`37 (9)
`27 (7)
`21 (5)
`17 (4)
`
`41 (10)
`31 (8)
`27 (7)
`20 (5)
`16 (4)
`
`51 (13)
`33 (8)
`32 (8)
`24 (6)
`18 (4)
`15 (4)
`
`35 (9)
`25 (6)
`
`49 (12)
`48 (12)
`35 (9)
`36 (9)
`27 (7)
`23 (6)
`23 (6)
`20 (5)
`19 (5)
`15 (4)
`
`
`
`29 (7)
`32 (8)
`
`53 (13)
`
`42 (10)
`39 (10)
`27 (7)
`
`24 (6)
`18 (4)
`
`43 (11)
`19 (5)
`29 (7)
`32 (8)
`
`35 (9)
`40 (10)
`39 (10)
`9 (2)
`33 (8)
`
`32 (8)
`24 (6)
`23 (6)
`22 (3)
`19 (5)
`22 (5)
`
`30 (7)
`20 (5)
`
`55 (14)
`26 (6)
`36 (9)
`30 (7)
`35 (9)
`15 (4)
`29 (7)
`14 (3)
`15 (4)
`32 (8)
`
`Increased liver enzyme test includes increases in AST, ALT or both.
`†
`‡ Anemia includes anemia, hypochronic-and iron deficiency anemia.
`
`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
`
`
`No clinically significant difference in the pharmacokinetics of either enantiomer of
`bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to
`healthy controls. However, the half-life of the R-enantiomer was increased approximately
`76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with
`severe liver disease (n=4).
`
`8.7. Renal Impairment
`Renal impairment (as measured by creatinine clearance) had no significant effect on the
`elimination of total bicalutamide or the active R-enantiomer.
`
`8.8. Women
`Bicalutamide has not been studied in women.
`
`10.
`
`OVERDOSAGE
`
`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.
`
`11.
`
`DESCRIPTION
`
`Bicalutamide tablets contain 50 mg of bicalutamide USP, 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
`empirical formulas are:
`
`O
`
`OH
`NH C C
`
`F
`
`CH2 SO2
`CH3
`CF3
`
`C H N O F S
`
`18 14 2 4 4
`
`CN
`
`Bicalutamide has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide is a fine
`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 tablet is a racemate with its antiandrogenic activity being almost exclusively exhibited by
`the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.
`
`The inactive ingredients of bicalutamide tablets are lactose monohydrate, sodium starch glycolate
`type A, povidone, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide.
`
`
`
`12.
`
`CLINICAL PHARMACOLOGY
`
`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 luteinizing hormone releasing hormone (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.
`
`12.3. Pharmacokinetics
`Absorption
`Bicalutamide is well-absorbed following oral administration, although the absolute
`bioavailability is unknown. Co-administration of bicalutamide with food has no clinically
`significant effect on rate or extent of absorption.
`
`Distribution
`
`Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].
`
`Metabolism/Elimination
`Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized
`primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is
`predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the
`parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer
`is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about
`99% of total steady-state plasma levels.
`
`Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients
`with prostate cancer are presented in Table 2.
`
`Parameter
`
` Table 2
`
`Normal Males (n=30)
`Apparent Oral Clearance (L/hr)
`Single Dose Peak Concentration (mcg/mL)
`Single Dose Time to
`Peak Concentration (hours)
`Half-life (days)
`Patients with Prostate Cancer (n=40)
`C (mcg/mL)
`
`ss
`
`Mean
`
`0.320
`0.768
`
`31.3
`5.8
`
`8.939
`
`Standard
`Deviation
`
`0.103
`0.178
`
`14.6
`2.29
`
`3.504
`
`13.
`
`NONCLINICAL TOXICOLOGY
`
`13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
`Two-year oral carcinogenicity studies were conducted in both male and female rats and
`mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ
`effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely,
`testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-
`state plasma concentration with the 5 mg/kg/day dose is approximately 2/3 human
`therapeutic concentrations*) and uterine adenocarcinoma in female rats at 75 mg/kg/day
`(approximately 1 ½ times the human therapeutic concentrations*). There is no evidence of
`Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient
`population.
`
`A small increase in the incidence of hepatocellular carcinoma in male mice given
`75 mg/kg/day of bicalutamide (approximately 4 times human therapeutic concentrations*)
`and an increased incidence of benign thyroid follicular cell adenomas in rats given
`5 mg/kg/day (approximately 2/3 human therapeutic concentrations*) and above were
`recorded. These neoplastic changes were progressions of non-neoplastic changes related
`to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not
`been observed following bicalutamide administration in man. There were no tumorigenic
`effects suggestive of genotoxic carcinogenesis.
`
`
`
`A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene
`conversion, Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse
`micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that bicalutamide
`does not have genotoxic activity.
`
`Administration of bicalutamide may lead to inhibition of spermatogenesis. The long-term
`effects of bicalutamide on male fertility have not been studied.
`
`In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic
`concentrations*), the precoital interval and time to successful mating were increased in the
`first pairing but no effects on fertility following successful mating were seen. These effects
`were reversed by 7 weeks after the end of an 11- week period of dosing.
`
`No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and
`2 times human therapeutic concentrations, respectively*) or their female offspring were
`observed. Administration of bicalutamide to pregnant females resulted in feminization of the
`male offspring leading to hypospadias at all dose levels. Affected male offspring were also
`impotent.
`
`*Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.
`
`14.
`
`CLINICAL STUDIES
`
`14.1. Bicalutamide 50 mg Daily in Combination with an LHRH-A
`In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated
`advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily
`(404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination
`with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).
`
`Size: 350x430 mm
`
`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.
`
`
`
`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 multicenter, 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 (³ 5% in Either Treatment Group) Regardless of
`Causality
`
`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 postapproval 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.
`
`Uncommon cases of hypersensitivity reactions, including angioneurotic edema and
`urticaria [see Contraindications (4.1)], and uncommon cases of interstitial lung disease,
`including interstitial pneumonitis and pulmonary fibrosis, have been reported with
`bicalutamide.
`
`Reduction in glucose tolerance, manifesting as diabetes or a loss of glycemic control in
`those with pre-existing diabetes, has been reported during treatment with LHRH agonists.
`
`Body System
`Adverse Reaction
`
`Body as a Whole
`Pain (General)
`Back Pain
`Asthenia
`Pelvic Pain
`Infection
`Abdominal Pain
`Chest Pain
`Headache
`Flu Syndrome
`Cardiovascular
`Hot Flashes
`Hypertension
`Digestive
`Constipation
`Nausea
`Diarrhea
`
`†
`Increased Liver Enzyme Test
`Dyspepsia
`Flatulence
`
`
`Treatment Group
`Number of Patients (%)
`
`
`Flutamide Plus
`Bicalutamide Plus
`
`LHRH Analog
`LHRH Analog
`
`
`
`(n=407)
`(n=401)
`
`
`
`142 (35)
`102 (25)
`89 (22)
`85 (21)
`71(18)
`46 (11)
`34 (8)
`29 (7)
`28 (7)
`
`211 (53)
`34 (8)
`
`87 (22)
`62 (15)
`49 (12)
`
`30 (7)
`30 (7)
`26 (6)
`
`127 (31)
`105 (26)
`87 (21)
`70 (17)
`57 (14)
`46 (11)
`34 (8)
`27 (7)
`30 (7)
`
`217 (53)
`29 (7)
`
`69 (17)
`58 (14)
`107 (26)
`
`46 (11)
`23 (6)
`22 (5)
`
`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 ) and
`1.9 fold (for AUC). Hence, caution should be exercised when bicalutamide is co-administered with
`CYP 3A4 substrates.
`
`max
`
`
`In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants
`from binding sites. Prothrombin times should be closely monitored in patients already receiving
`coumarin anticoagulants who are started on bicalutamide and adjustment of the anticoagulant dose
`may be necessary.
`
`8. USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`PREGNANCY CATEGORY X [see Contraindications (4.3)]. Based on its mechanism of
`action, bicalutamide may cause fetal harm when administered to a pregnant woman.
`Bicalutamide is contraindicated in women, including those who are or may become
`pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while
`taking this drug, the patient should be apprised of the potential hazard to a fetus.
`
`While there are no human data on the use of bicalutamide in pregnancy and bicalutamide is
`not for use in women, it is important to know that maternal use of an androgen receptor
`inhibitor could affect development of the fetus.
`
`In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day
`(approximately 2/3 of clinical exposure at the recommended dose) and above, were
`observed to have reduced anogenital distance and hypospadias. These pharmacological
`effects have been observed with other antiandrogens. No other teratogenic effects were
`observed in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 of clinical
`exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day
`(approximately 2 times the clinical exposure at the recommended dose).
`
`8.3. Nursing Mothers
`Bicalutamide is not indicated for use in women.
`
`8.4. Pediatric Use
`The safety and effectiveness of bicalutamide in pediatric patients have not been established.
`
`Labeling describing pediatric clinical studies for bicalutamide is approved for AstraZeneca
`
`
`Pharmaceuticals
`bicalutamide tablet. However, due to AstraZeneca Pharmaceuticals
`LP’s
`
`marketing exclusivity rights, a description of those clinical studies is not approved for
`LP’s
`this bicalutamide labeling.
`
`8.5. Geriatric Use
`In two studies in patients given 50 or 150 mg daily, no significant relationship between age
`and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.
`
`8.6. Hepatic Impairment
`Bicalutamide should be used with caution in patients with moderate-to-severe hepatic
`impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects
`with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and
`could lead to further accumulation. Periodic liver function tests should be considered for
`hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].
`
`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.
`
`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 50 mg tablets for oral administration.
`
`4. CONTRAINDICATIONS
`
`4.1. 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 [see Adverse Reactions (6.2)].
`
`4.2. Women
`Bicalutamide has no indication for women, and should not be used in this population.
`
`
`4.3. Pregnancy
`Bicalutamide may cause fetal harm when administered to a pregnant woman. Bicalutamide
`is contraindicated in women, including those who are or may become pregnant. There are
`no studies in pregnant women using bicalutamide. 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. 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 patients in controlled clinical trials.
`
`Serum transaminase levels should be measured prior to starting treatment with
`bicalutamide, 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 should be immediately discontinued
`with close follow-up of liver function.
`
`Bicalutamide Tablets 50 mg
`
`
`
`
`
`
`
`Blank
`
`Folding
`350--4 zigzag--38.88 mm
`430--4 zigzag--35.83 mm
`
`350 mm
`
`

`

`Tell your healthcare provider about all the medicines you take, including prescription and non-
`prescription medicines, vitamins and herbal supplements. Bicalutamide tablets and other medicines
`may affect each other causing side effects. Bicalutamide tablets may affect the way other medicines
`work, and other medicines may affect how bicalutamide tablets work.
`
`!
`
`Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers
`when you get a new medicine.
`
`How should I take bicalutamide tablets?
`! Take bicalutamide tablets exactly as prescribed.
`! Take bicalutamide tablets at the same time everyday.
`! Your treatment with bicalutamide tablets should start at the same time as your treatment with the
`LHRH medicine
`If you miss a dose do not take an extra dose, take the next dose at your regular time. Do not take
`2 doses at the same time.
`! Bicalutamide tablets can be taken with or without food.
`If you take too many bicalutamide tablets, call your healthcare provider or Poison Control Center or
`!
`go to the nearest hospital emergency room right away.
`! Do not stop taking bicalutamide tablets unless your healthcare provider tells you.
`! Your healthcare provider may do blood tests while you take bicalutamide tablets
`! Your prostate cancer may get worse while taking bicalutamide tablets in combination with LHRH
`medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to
`determine if your disease is worse.
`
`What should I avoid while taking bicalutamide tablets?
`Driving and operating machinery. Do not drive, operate machinery, or do other dangerous activities until
`you know how bicalutamide tablets affect you.
`
`What are the possible side effects of bicalutamide tablets?
`Bicalutamide tablets can cause serious side effects.
`Get medical help right away, if you have:
`trouble breathing with or without a cough or fever. Some people who take bicalutamide tablets get an
`!
`inflammation in the lungs called interstitial lung disease.
`! An allergic reaction. Symptoms of an allergic reaction include: itching of the skin, hives (raised
`
`bumps), swelling of the face, lips, tongue, throat, or trouble swallowing.
`! Yellowing of the skin and eyes (jaundice), dark urine, right upper stomach pain, nausea, vomiting,
`tiredness, loss of appetite, chills, fever, whole body pain. These may be symptoms of liver damage.
`! Poor blood sugar control can happen in people who take bicalutamide tablets in combination with
`LHRH medicines.
`! enlargement of breast (gynecomastia) and breast pain
`
`The most common side effects of bicalutamide tablets include:
`! hot flashes, or short periods of feeling warm and sweating
`! whole body pain in your back, pelvis, stomach
`feeling weak
`!
`! constipation
`infection
`!
`! nausea
`! swelling in your ankles, legs or feet
`! diarrhea
`! blood in your urine
`! waking from sleep to urinate at night
`! a decrease in red blood cells (anemia)
`feeling dizzy
`!
`
`Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
`
`These are not all the possible side effects of bicalutamide tablets. For more information, ask your
`healthcare provider or pharmacist.
`
`Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-
`1088.
`
`HOW SHOULD I STORE BICALUTAMIDE TABLETS?
`Store bicalutamide tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C
`(59° and 86°F).
`
`
`
`
`Keep bicalutamide tablets and all medicines out of the reach of children.
`
`General information about the safe and effective use of bicalutamide tablets.
`Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet.
`Do not use bicalutamide tablets for a condition for which it was not prescribed. Do not give bicalutamide
`tablets to other people, even if they have the same symptoms that you have. It may harm them.
`
`This patient information leaflet summarizes the most important information about bicalutamide tablets.
`If you would like more information about bicalutamide tablets talk with your healthcare provider. You can
`ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for
`health professionals. For more information call 1-800-818-4555.
`
`What are the ingredients in bicalutamide tablets?
`
`Active ingredients include: bicalutamide
`Inactive ingredients include: lactose monohydrate, sodium starch glycolate type A, povidone,
`magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide
`
`Distributed by:
`Caraco Pharmaceutical Laboratories, Ltd.
`1150 Elijah McCoy Drive, Detroit, MI 48202
`
`PGPI0081B
`ISS. 06/2009
`
`
`
` Manufactured at:
`
` Sun Pharmaceutical Industries
`
`Survey No. 259/15,
`Dadra-396 191, (U.T. of D & NH), India.
`
`350 mm
`
`Size: 350x430 mm
`
`In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%)
`patients treated with bicalutamide-LHRH analog therapy and 235 (57.5%) patients treated
`with flutamide-LHRH analog therapy had died. There was no significant difference in
`survival between treatment groups (see Figure 1). The hazard ratio for time to death
`(survival) was 0.87 (95% confidence interval 0.72 to 1.05).
`
`Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups.
`
`Bicalutamide plus LHRH-A
`Flutamide plus LHRH-A
`
`0
`
`365
`
`730
`1095
`Days to death
`
`1460
`
`1825
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Proportion surviving
`
`
`
`There was no significant difference in time to objective tumor progression between
`treatment groups (see Figure 2). Objective tumor progression was defined as the
`appearance of any bone metastases or the worsening of any existing bone metastases on
`bone scan attributable to metastatic disease, or an increase by 25% or more of any existing
`measurable extraskeletal metastases. The hazard ratio for time to progression of
`bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95%
`confidence interval, 0.79 to 1.10).
`
`Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Bicalutamide plus LHRH-A
`Flutamide plus LHRH-A
`
`0
`
`365
`
`730
`1095
`Days to progression
`
`1460
`
`1825
`
`Proportion