The recommended dose for Bicalutamide (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 (Bicalutamide) tablets be taken at the same time each day. Treatment with Bicalutamide (Bicalutamide) tablets should be started at the same time as treatment with an LHRH analog.

Bicalutamide (Bicalutamide) 50 mg tablets for oral administration.

Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Bicalutamide (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 (Bicalutamide) patients in controlled clinical trials.

Serum transaminase levels should be measured prior to starting treatment with Bicalutamide (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 (Bicalutamide) should be immediately discontinued with close follow-up of liver function.

Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient’s response.

If PSA levels rise during Bicalutamide (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.

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.

In patients with advanced prostate cancer treated with Bicalutamide (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 (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.

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the Bicalutamide (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:
Cardiovascular:
Digestive:
Metabolic and Nutritional:
Musculoskeletal:
Nervous:
Respiratory:
Skin and Appendages:
Special Senses:
Urogenital:
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 (Bicalutamide) -LHRH analog treated and flutamide-LHRH analog treated patients.

The following adverse reactions have been identified during postapproval use of Bicalutamide (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 , and uncommon cases of interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, have been reported with Bicalutamide (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.

Clinical studies have not shown any drug interactions between Bicalutamide (Bicalutamide) and LHRH analogs (goserelin or leuprolide). There is no evidence that Bicalutamide (Bicalutamide) induces hepatic enzymes.

PREGNANCY CATEGORY X Based on its mechanism of action, Bicalutamide (Bicalutamide) may cause fetal harm when administered to a pregnant woman. Bicalutamide (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 (Bicalutamide) in pregnancy and Bicalutamide (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).

The safety and effectiveness of Bicalutamide (Bicalutamide) in pediatric patients have not been established.

Labeling describing pediatric clinical studies for Bicalutamide (Bicalutamide) is approved for AstraZeneca Pharmaceuticals LP’s Bicalutamide (Bicalutamide) tablet.  However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights, a description of those clinical studies is not approved for this Bicalutamide (Bicalutamide) labeling.

Bicalutamide (Bicalutamide) should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide (Bicalutamide) is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of Bicalutamide (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

No clinically significant difference in the pharmacokinetics of either enantiomer of Bicalutamide (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).

Long-term clinical trials have been conducted with dosages up to 200 mg of Bicalutamide (Bicalutamide) daily and these dosages have been well tolerated. A single dose of Bicalutamide (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 (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 (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.

Bicalutamide (Bicalutamide) tablets contain 50 mg of Bicalutamide (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:

Bicalutamide (Bicalutamide) has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide (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 (Bicalutamide) tablet is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of Bicalutamide (Bicalutamide) ; the S-enantiomer is essentially inactive.

The inactive ingredients of Bicalutamide (Bicalutamide) tablets are lactose monohydrate, sodium starch glycolate type A, povidone, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide.

Bicalutamide (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 (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 (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 (Bicalutamide) and an LHRH agonist, and who discontinue Bicalutamide (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.

Absorption
Bicalutamide (Bicalutamide) is well-absorbed following oral administration, although the absolute bioavailability is unknown. Co-administration of Bicalutamide (Bicalutamide) with food has no clinically significant effect on rate or extent of absorption.

Distribution
Bicalutamide (Bicalutamide) is highly protein-bound (96%)

Metabolism/Elimination
Bicalutamide (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 (Bicalutamide) in normal males and patients with prostate cancer are presented in Table 2.

In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive Bicalutamide (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).

In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with Bicalutamide (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.
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 (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.
Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

Bicalutamide (Bicalutamide) 150 mg is not approved for use either alone or with other treatments.
Two identical multicenter, randomized, open-label trials comparing Bicalutamide (Bicalutamide) 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.

Monotherapy — M1 Group

Bicalutamide (Bicalutamide) 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that Bicalutamide (Bicalutamide) treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the Bicalutamide (Bicalutamide) treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, MO) Group

Bicalutamide (Bicalutamide) 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the Bicalutamide (Bicalutamide) group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the Bicalutamide (Bicalutamide) group.

In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for Bicalutamide (Bicalutamide) 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing Bicalutamide (Bicalutamide) 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

Bicalutamide (Bicalutamide) 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the Bicalutamide (Bicalutamide) arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the Bicalutamide (Bicalutamide) treated patients versus 279 (32.9%) deaths in the placebo treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).

White to off white, circular, biconvex, film-coated tablets debossed with "485" on one side and plain on other side.

Bottles of 30's with Child Resistant Cap…………..…. NDC 41616-485-83

Bottles of 100's with Child Resistant Cap………….…..NDC 41616-485-88

Bottles of 100's with Non Child Resistant Cap…..…….NDC 41616-485-08

Bottles of 1000's with Non Child Resistant Cap……….NDC 41616-485-18

Patients should be informed that therapy with Bicalutamide (Bicalutamide) tablets and the LHRH analog should be started at the same time and that they should not interrupt or stop taking these medications without consulting their physician.

During treatment with Bicalutamide (Bicalutamide) tablets, somnolence has been reported, and those patients who experience this symptom should observe caution when driving or operating machines.

Patients should be informed that diabetes, or loss of glycemic control in patients with pre-existing diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given to monitoring blood glucose in patients receiving Bicalutamide (Bicalutamide) tablets in combination with LHRH agonists.

                                                                                

                                                                              

Read the Patient Information that comes with Bicalutamide (Bicalutamide) tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

Bicalutamide (Bicalutamide) tablets are prescription medicines called androgen receptor inhibitors, used in combination with lutenizing hormone-releasing hormone (LHRH) medicines to treat stage D metastatic prostate cancer. It is not known if Bicalutamide (Bicalutamide) tablets are safe and effective in children.

Do not take Bicalutamide (Bicalutamide) tablets if:

Before you take Bicalutamide (Bicalutamide) tablets, tell your healthcare provider about all your medical conditions including if you:

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Bicalutamide (Bicalutamide) tablets and other medicines may affect each other causing side effects. Bicalutamide (Bicalutamide) tablets may affect the way other medicines work, and other medicines may affect how Bicalutamide (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.

Driving and operating machinery. Do not drive, operate machinery, or do other dangerous activities until you know how Bicalutamide (Bicalutamide) tablets affect you.

Bicalutamide (Bicalutamide) tablets can cause serious side effects.

Get medical help right away, if you have:

The most common side effects of Bicalutamide (Bicalutamide) tablets include:

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 (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.

Store Bicalutamide (Bicalutamide) tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Keep Bicalutamide (Bicalutamide) tablets and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Bicalutamide (Bicalutamide) tablets for a condition for which it was not prescribed. Do not give Bicalutamide (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 (Bicalutamide) tablets. If you would like more information about Bicalutamide (Bicalutamide) tablets talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Bicalutamide (Bicalutamide) tablets that is written for health professionals. For more information call 1-800-818-4555.

Active ingredients include: Bicalutamide (Bicalutamide)

Inactive ingredients include: lactose monohydrate, sodium starch glycolate type A, povidone, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide

Distributed by: 1150 Elijah McCoy Drive, Detroit, MI 48202

Manufactured at: Survey No. 259/15, Dadra-396 191, (U.T. of D & NH), India.

ISS. 06/2009