NDC 63629-8308 Bicalutamide

Bicalutamide

NDC Product Code 63629-8308

NDC CODE: 63629-8308

Proprietary Name: Bicalutamide What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Bicalutamide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Bicalutamide is used to treat prostate cancer. This medication works by blocking the action of male hormones in the prostate, slowing the growth of cancer cells. This medication should not be used in women and children.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF WHITE)
Shape: ROUND (C48348)
Size(s):
7 MM
Imprint(s):
B50
Score: 1

NDC Code Structure

NDC 63629-8308-1

Package Description: 30 TABLET in 1 BOTTLE

NDC 63629-8308-2

Package Description: 100 TABLET in 1 BOTTLE

NDC Product Information

Bicalutamide with NDC 63629-8308 is a a human prescription drug product labeled by Bryant Ranch Prepack. The generic name of Bicalutamide is bicalutamide. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Bryant Ranch Prepack

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Bicalutamide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • BICALUTAMIDE 50 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • POVIDONE K30 (UNII: U725QWY32X)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Androgen Receptor Antagonists - [MoA] (Mechanism of Action)
  • Androgen Receptor Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Bryant Ranch Prepack
Labeler Code: 63629
FDA Application Number: ANDA078917 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 07-06-2009 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Bicalutamide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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)].

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 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











[see Use in Specific Populations











(8.7)]











.

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











[see Use in Specific Populations











(8.6)]











.

3. Dosage Forms And Strengths

Bicalutamide tablets, USP 50 mg for oral administration are white to off-white, round, biconvex, film coated tablets, debossed ‘B 50’ on one side and plain on other side.

Other

  • Bicalutamide is contraindicated in:HypersensitivityBicalutamide 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.WomenBicalutamide has no indication for women, and should not be used in this population. PregnancyBicalutamide can cause fetal harm when administered to a pregnant woman
  • [see
  • Use in Specific Populations (8.1)].

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. 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.

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.

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 CausalityBody System Adverse ReactionTreatment 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) Infection71(18) 57 (14)Abdominal Pain46 (11)46 (11)Chest Pain34 (8)34 (8)Headache29 (7)27 (7)Flu Syndrome28 (7)30 (7)CardiovascularHot Flashes211 (53)217 (53)Hypertension34 (8)29 (7)DigestiveConstipation87 (22)69 (17)Nausea62 (15)58 (14)Diarrhea49 (12)107 (26)Increased Liver Enzyme Test30 (7)46 (11)Dyspepsia30 (7)23 (6)Flatulence26 (6)22 (5)Anorexia25 (6)29 (7)Vomiting24 (6)32 (8)Hemic and LymphaticAnemia45 (11)53 (13)Metabolic and NutritionalPeripheral Edema53 (13)42 (10)Weight Loss30 (7)39 (10)Hyperglycemia26 (6)27 (7)Alkaline Phosphatase Increased22 (5)24 (6)Weight Gain22 (5)18 (4)MusculoskeletalBone Pain37 (9)43 (11)Myasthenia27 (7)19 (5)Arthritis21 (5)29 (7)Pathological Fracture17 (4)32 (8)Nervous SystemDizziness41 (10)35 (9)Paresthesia31 (8)40 (10)Insomnia27 (7)39 (10)Anxiety20 (5)9 (2)Depression16 (4)33 (8)Respiratory SystemDyspnea51 (13)32 (8)Cough Increased33 (8)24 (6)Pharyngitis32 (8)23 (6)Bronchitis24 (6)22 (3)Pneumonia18 (4)19 (5)Rhinitis15 (4)22 (5)Skin and AppendagesRash35 (9)30 (7)Sweating25 (6)20 (5)UrogenitalNocturia49 (12)55 (14)Hematuria48 (12)26 (6)Urinary Tract Infection35 (9)36 (9)Gynecomastia36 (9)30 (7)Impotence27 (7)35 (9)Breast Pain23 (6)15 (4)Urinary Frequency23 (6)29 (7)Urinary Retention20 (5)14 (3)Urinary Impaired19 (5)15 (4)Urinary Incontinence15 (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 reaction (6.2) ]

8.1. Pregnancy

Risk Summary Bicalutamide is contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide is not indicated for use in females. There are no human data on the use of bicalutamide 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).





DataAnimal DataIn an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to15, 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 to 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 SummaryBicalutamide 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 MalesAntiandrogen 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





[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 tablets on male fertility have not been studied.




[see


Nonclinical Toxicology (13.1)]



.

8.4. Pediatric Use

The safety and effectiveness of bicalutamide 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 to 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 RatesEndpointAnalysis populationPre-study MeanChange from pre-study to 12 months% patients with growth reduction











Change compared to pre-study growth rate.MeanMedian(Min, Max)Growth rate (cm/yr)All treated (n=13)10.8-1.6-2.8(-7.4, 8.4)9/13 (69%)PT











PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors. (n=6)











10.3-0.2-2.6











Median calculated as midpoint of 3rd and 4th ranked observations.(-7.2, 8.4)4/6 (67%)NPT











NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole, or other aromatase inhibitors. (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











(n=6)











-0.1+0.7-0.2











(-1.6, 3.5)4/6 (67%)NPT











(n=7)











0.8-0.7-0.4(-2.7, 0.5)5/7 (71%)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. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (>3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%), and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrozole by investigators. For the patient who developed elevated ALT and AST,
the elevation was <3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.

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)].











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.

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, 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 empirical formulas are: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 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, USP are lactose monohydrate, magnesium stearate, hypromellose E5, polyethylene glycol 400, povidone K 30, sodium starch glycolate, and titanium dioxide. Bicalutamide tablets, USP 50 mg meets USP Dissolution Test 2.

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.

12.3. Pharmacokinetics

AbsorptionBicalutamide 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.DistributionBicalutamide is highly protein-bound (96%)






[see Drug Interactions




(7)]





.




Metabolism/EliminationBicalutamide 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 3.Table 3. Pharmacokinetics of Bicalutamide Active EnantiomerParameterMeanStandard DeviationNormal Males (n=30)Apparent Oral Clearance (L/hr)0.3200.103Single Dose Peak Concentration (µg/mL)0.7680.178Single Dose Time to Peak Concentration (hours)31.314.6Half-life (days)5.82.29Patients with Prostate Cancer (n=40)C





ss (µg/mL)





8.9393.504

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 0.7 times the human exposure at the recommended dose) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1.5 times the human exposure at the recommended dose). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient populationA small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times the human exposure at the recommended dose) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) 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.





In repeat-dose toxicology studies, atrophy of seminiferous tubules of the testes has been observed for all species examined, which is a predicted class effect with antiandrogens. In the 6- and 12-month rat study, testicular atrophy was seen at approximately 2 times the human exposure at the recommended dose. In the 12- month dog study, the incidence of testicular atrophy was seen at approximately 7 times the human exposure at the recommended dose. In male rats administered 250 mg/kg/day (approximately 2 times human exposure at the recommended dose), 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.Female rats dosed at 1, 10 and 250 mg/kg/day (less than to 2 times the human exposure at the recommended dose) had increased estrous cycle irregularity but there was no effect on fertility.In a peri- and post-natal development study, female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended clinical dose) and above had reduced pregnancy rates. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above. Affected male offspring were also impotent.

14.1. Bicalutamide Tablets 50 Mg Daily In Combination With An Lhrh-A

In a multi-center, 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).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.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.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.

14.2 Safety Data From Clinical Studies Using Bicalutamide Tablets 150 Mg

Bicalutamide tablet 150 mg is not approved for use either alone or with other treatments.Two identical multi-center, randomized, open-label trials comparing bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, M0) or metastatic (M1) prostate cancer.Monotherapy — M1 GroupBicalutamide 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 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 treated group compared to that in the castrated group, respectively.Locally Advanced (T





3-4, NX, M0) Group





Bicalutamide 150 mg daily is not approved for use in patients with locally advanced (T





3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, M0 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 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 group.





In addition to the above two studies, there are three other ongoing clinical studies that provide additional safety information for bicalutamide 150 mg, a dose that is not approved for use. These are three multi-center, randomized, double-blind, parallel group trials comparing 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 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 arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the 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).

16. How Supplied/Storage And Handling

Product: 63629-8308NDC: 63629-8308-1 30 TABLET in a BOTTLENDC: 63629-8308-2 100 TABLET in a BOTTLE

17. Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).Dose and Schedule: Inform patients that therapy with bicalutamide 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 healthcare provider





[see





Dosage and Administration (2.1)].





Hepatitis: Inform patients that bicalutamide can cause hepatitis, which may result in hepatic failure and death. Advise patients that liver function tests should be monitored regularly during treatment and to report signs and symptoms of hepatitis





[see





Warnings and Precautions (5.1)].






Hemorrhage with Concomitant Use of Coumarin Anticoagulant: Inform patients that serious bleeding has occurred with reported increased anticoagulant effects while taking bicalutamide. Advise patients to notify their healthcare provider of any bleeding or spontaneous bruising while on bicalutamide and taking anticoagulants




[see


Warnings and Precautions (5.2) and


Adverse reaction (6.2) ]


.





Glucose Tolerance: Inform patients 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 in combination with LHRH agonists





[see





Warnings and Precautions (5.4)].





Somnolence: During treatment with bicalutamide, somnolence has been reported. Advise patients who experience this symptom to observe caution when driving or operating machines





[see





Adverse Reactions (6.1)].





Photosensitivity: Inform patients that cases of photosensitivity have been reported during treatment with bicalutamide and that they should avoid direct exposure to excessive sunlight or UV-light exposure. Consideration should be given to the use of sunscreen





[see





Adverse Reactions (6.2)].





Contraception and fertility: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the last dose of bicalutamide therapy. Advise male patients that bicalutamide may impair fertility





[see





Use in Specific Populations (8.3)].






Manufactured For: Accord Healthcare, Inc., 1009, Slater Road, Suite 210-B, Durham, NC 27703, USA. Manufactured By: Intas Pharmaceuticals Limited, Plot No. : 457, 458, Village - Matoda, Bavla Road, Ta.:Sanand, Dist.: Ahmedabad : 382 210. India.
10 0857 3 691691Issued January 2019

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