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Bicalutamide (bicalutamide 50 mg) Dailymed

  1. Human Prescription
  2. Archived
    • May Be Discontinued
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  3. Mylan Pharmaceuticals Inc.

Generic: bicalutamide

Bicalutamide tablet, film coated - (bicalutamide 50 mg) image

IMPRINT: M C17     SHAPE: round
    COLOR: white

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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 D2 metastatic carcinoma of the prostate.

Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments [see Clinical Studies (14.2)].

  • •Bicalutamide tablets 50 mg are an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate. (1)
  • •Bicalutamide tablets 150 mg daily are 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)


The recommended dose for bicalutamide tablets therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets be taken at the same time each day. Treatment with bicalutamide tablets should be started at the same time as treatment with an LHRH analog. If a dose of bicalutamide tablets is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose.

2.2 Dosage Adjustment in Renal Impairment


No dosage adjustment is necessary for patients with renal impairment [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 are available containing 50 mg of bicalutamide, USP.
  • •The 50 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and C17 on the other side.


50 mg tablets (3)

4 Contraindications


Bicalutamide tablets are contraindicated in:
  • • Hypersensitivity: Bicalutamide tablets are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported.
  • • Women: Bicalutamide tablets have no indication for women, and should not be used in this population.
  • • Pregnancy: Bicalutamide tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

  • •Hypersensitivity (4)
  • •Women (4)
  • •Pregnancy (4 and 8.1)

5 Warnings And Precautions


  • •Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting treatment with bicalutamide tablets, at regular intervals for the first four months of treatment and periodically thereafter, and for symptoms or signs suggestive of hepatic dysfunction. Use bicalutamide tablets with caution in patients with hepatic impairment. (5.1)
  • •Gynecomastia and breast pain have been reported during treatment with bicalutamide tablets 150 mg when used as a single agent. (5.2)
  • •Bicalutamide tablets are 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 tablets in combination with LHRH agonists. (5.3)
  • •Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. (5.4)

5.1 Hepatitis


Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported postmarketing in association with the use of bicalutamide tablets. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of bicalutamide tablets patients in controlled clinical trials.

Serum transaminase levels should be measured prior to starting treatment with bicalutamide tablets, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like†symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, bicalutamide tablets should be immediately discontinued with close follow-up of liver function.

5.2 Gynecomastia and Breast Pain


In clinical trials with bicalutamide tablets 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 tablets in combination with LHRH agonists.

5.4 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 tablets therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.

6 Adverse Reactions


Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


Adverse reactions that occurred in more than 10% of patients receiving bicalutamide tablets 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience


In patients with advanced prostate cancer treated with bicalutamide tablets 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 tablets 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.
Table 1. Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality

Body System Adverse Reaction

Treatment Group Number of Patients (%)

Bicalutamide Tablets Plus LHRH Analog (n = 401)

Flutamide Plus LHRH Analog

 

(n = 407)

Body as a Whole

Pain (General)
142
(35)
127
(31)

Back Pain
102
(25)
105
(26)

Asthenia
89
(22)
87
(21)

Pelvic Pain
85
(21)
70
(17)

Infection
71
(18)
57
(14)

Abdominal Pain
46
(11)
46
(11)

Chest Pain
34
(8)
34
(8)

Headache
29
(7)
27
(7)

Flu Syndrome
28
(7)
30
(7)

Cardiovascular

Hot Flashes
211
(53)
217
(53)

Hypertension
34
(8)
29
(7)

Digestive

Constipation
87
(22)
69
(17)

Nausea
62
(15)
58
(14)

Diarrhea
49
(12)
107
(26)

Increased Liver Enzyme Test
30
(7)
46
(11)

Dyspepsia
30
(7)
23
(6)

Flatulence
26
(6)
22
(5)

Anorexia
25
(6)
29
(7)

Vomiting
24
(6)
32
(8)

Hemic and Lymphatic

Anemia
45
(11)
53
(13)

Metabolic and Nutritional

Peripheral Edema
53
(13)
42
(10)

Weight Loss
30
(7)
39
(10)

Hyperglycemia
26
(6)
27
(7)

Alkaline Phosphatase Increased
22
(5)
24
(6)

Weight Gain
22
(5)
18
(4)

Musculoskeletal

Bone Pain
37
(9)
43
(11)

Myasthenia
27
(7)
19
(5)

Arthritis
21
(5)
29
(7)

Pathological Fracture
17
(4)
32
(8)

Nervous System

Dizziness
41
(10)
35
(9)

Paresthesia
31
(8)
40
(10)

Insomnia
27
(7)
39
(10)

Anxiety
20
(5)
9
(2)

Depression
16
(4)
33
(8)

Respiratory System

Dyspnea
51
(13)
32
(8)

Cough Increased
33
(8)
24
(6)

Pharyngitis
32
(8)
23
(6)

Bronchitis
24
(6)
22
(3)

Pneumonia
18
(4)
19
(5)

Rhinitis
15
(4)
22
(5)

Skin and Appendages

Rash
35
(9)
30
(7)

Sweating
25
(6)
20
(5)

Urogenital

Nocturia
49
(12)
55
(14)

Hematuria
48
(12)
26
(6)

Urinary Tract Infection
35
(9)
36
(9)

Gynecomastia
36
(9)
30
(7)

Impotence
27
(7)
35
(9)

Breast Pain
23
(6)
15
(4)

Urinary Frequency
23
(6)
29
(7)

Urinary Retention
20
(5)
14
(3)

Urinary Impaired
19
(5)
15
(4)

Urinary Incontinence
15
(4)
32
(8)

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide tablets-LHRH analog treatment group are uled 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 Infarction; 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 tablets-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 tablets. 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.

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 tablets, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5-fold (for Cmax) and 1.9-fold (for AUC). Hence, caution should be exercised when bicalutamide tablets are co-administered with CYP 3A4 substrates.

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 tablets and adjustment of the anticoagulant dose may be necessary.

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

8 Use In Specific Populations


  • •Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception. (8.3)
  • •Pediatric patients: Efficacy has not been demonstrated for the treatment of familial male-limited precocious puberty (testotoxicosis). (8.4)

8.1 Pregnancy


Bicalutamide tablets are contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide tablets are not indicated for use in females. There are no human data on the use of bicalutamide tablets in pregnant women. In animal reproduction studies, oral administration of bicalutamide to pregnant rats during organogenesis caused abnormal development of reproductive organs in male fetuses at exposures approximately 0.7 to 2 times the human exposure at the recommended dose (see Data).


Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above (approximately 0.7 to 2 times the human exposure at the recommended dose). In a pre- and post-natal development study, female rats were dosed from gestation day 7 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



Bicalutamide tablets are 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


Males

Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology (13.1)]. Based on findings in animal reproduction studies and its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the final dose of bicalutamide tablets [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].


Males

Based on animal studies, bicalutamide tablets 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 tablets in pediatric patients have not been established.

Bicalutamide orodispersible tablet was studied in combination with ARIMIDEX® (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 tablets dose was 12.5 mg. Bicalutamide tablets were titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5 mcg/mL 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 tablets 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 tablets: 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 tablets, 8 patients were on 50 mg bicalutamide tablets, and 4 patients were on 100 mg bicalutamide tablets; 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 tablets/ARIMIDEX treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (- 4.7 to 1.5) p = 0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI (- 1.2 to 1.0) p = 0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.
Table 2. Growth Rates

Endpoint
Analysis Population
Pre-study Mean
Change from Pre-study to 12 Months
% Patients with Growth ReductionChange compared to pre-study growth rate.

Mean
Median
(Min, Max)

Growth Rate(cm/yr)
All Treated(n = 13)
10.8
- 1.6
- 2.8
(- 7.4, 8.4)
9/13 (69%)

PTPT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrazole or other aromatase inhibitors. (n = 6)
10.3
- 0.2
- 2.6Median calculated as midpoint of 3rd and 4th ranked observations.

(- 7.2, 8.4)
4/6 (67%)

NPTNPT = 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 mg 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 tablets should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide tablets are extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide tablets 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 tablets daily and these dosages have been well tolerated. A single dose of bicalutamide tablets 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 tablets, 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 tablets are highly protein bound and are 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 (±)-4'-Cyano-α,α,α-trifluoro-3-[(p-fluorophenyl)sulfonyl]-2-methyl-m-lactotoluidide. The structural and molecular formulas are:

Bicalutamide has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide, USP is a white crystalline 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 are colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, sodium starch glycolate (potato), titanium dioxide and triacetin.

12 Clinical Pharmacology


12.1 Mechanism of Action


Bicalutamide tablets are 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 tablets are combined with LHRH analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide tablets 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 tablets and a LHRH agonist, and who discontinue bicalutamide tablets 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



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.


Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].


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 tablets in normal males and patients with prostate cancer are presented in Table 3.
Table 3.

Parameter

Mean

Standard Deviation

Normal Males (n = 30)

Apparent Oral Clearance (L/hr)
0.320
0.103

Single Dose Peak Concentration (mcg/mL)
0.768
0.178

Single Dose Time to Peak Concentration (hours)
31.3
14.6

Half-life (days)
5.8
2.29

Patients with Prostate Cancer (n = 40)

Css (mcg /mL)
8.939
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 mg/kg/day, 15 mg/kg/day 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 population.

A 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 mg/kg/day, 10 mg/kg/day 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 Clinical Studies


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 tablets 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 tablets-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 tablets 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 tablets 150 mg are not approved for use either alone or with other treatments.

Two identical multi-center, randomized, open-label trials comparing bicalutamide tablets 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, M0) or metastatic (M1) prostate cancer.


M1 Group

Bicalutamide tablets 150 mg daily are 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 tablets 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 tablets treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, M0) Group

Bicalutamide tablets 150 mg daily are 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, 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 tablets 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 tablets group.

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


Bicalutamide Tablets, USP are available containing 50 mg of bicalutamide, USP.

The 50 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and C17 on the other side. They are available as follows:

NDC 0378-7017-93bottles of 30 tablets

16.1 Storage and Handling


Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

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 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 healthcare provider [see Dosage and Administration (2.1) ].

Hepatitis: Inform patients that bicalutamide tablets 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)].

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 tablets in combination with LHRH agonists [see Warnings and Precautions (5.3)].

Somnolence: During treatment with bicalutamide tablets, 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 tablets 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 tablets therapy. Advise male patients that bicalutamide tablets may impair fertility [see Use in Specific Populations (8.3)].

Patient Information


Bicalutamide Tablets, USP (bye'' ka loo' ta mide)

Read this Patient Information before you start taking bicalutamide tablets 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.

What are bicalutamide tablets?

Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat Stage D2 metastatic prostate cancer.

Bicalutamide tablets are not for use in women.

It is not known if bicalutamide tablets are safe and effective in children.

Who should not take bicalutamide tablets?

Do not take bicalutamide tablets if you:
  • •are a woman.
  • •are pregnant or may become pregnant. Bicalutamide tablets may harm your unborn baby.
  • •are allergic to any of the ingredients in bicalutamide tablets. See the end of this leaflet for a complete ul of ingredients in bicalutamide tablets. Get medical help right away if you get any of the following symptoms of an allergic reaction: itching, hives (raised bumps), swelling of the face, lips or tongue, trouble breathing or swallowing.

What should I tell my healthcare provider before taking bicalutamide tablets?

Before you take bicalutamide tablets, tell your healthcare provider about all your medical conditions, including if you:
  • •have liver problems.
  • •take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
  • •have diabetes (poor blood sugar control has been reported in people taking bicalutamide tablets in combination with LHRH medicines).
  • •have a partner that is pregnant or could become pregnant. You should use effective birth control methods while you are taking bicalutamide tablets and for 130 days after stopping bicalutamide tablets. Talk to your doctor if you have any questions about birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over the counter 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 ul 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 your healthcare provider tells you to take it.
  • •Take bicalutamide tablets at the same time every day.
  • •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?

Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you.

Some people have had skin sensitivity to sunlight while taking bicalutamide tablets. You should avoid sunlight or sunlamps and tanning beds and consider using sunscreen while being treated with bicalutamide tablets.

What are the possible side effects of bicalutamide tablets?

Bicalutamide tablets may cause serious side effects, including:
  • •Liver problems, including liver failure that may need to be treated in a hospital or that may lead to death. Your healthcare provider should do blood tests to check your liver function before and during treatment with bicalutamide tablets. Tell your healthcare provider right away if you get any of these symptoms of a liver problem during treatment:
yellowing of the skin and eyes (jaundice)tirednessdark urineloss of appetiteright upper stomach painchillsnauseafevervomiting
o
o
o
o
o
o
o
o
o
  • •Trouble breathing with or without a cough or fever. Some people taking 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. 
  • •Enlargement of breast (gynecomastia) and breast pain.
  • •Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines. Your healthcare provider may check your blood sugar during bicalutamide tablets therapy.

The most common side effects of bicalutamide tablets include:
hot flashes, or short periods of feeling warm and sweatingnauseawhole body pain in your back, pelvis, stomachswelling in your ankles, legs or feetfeeling weakdiarrheaconstipationblood in your urineinfectionwaking from sleep to urinate at nighta decrease in red blood cells (anemia)feeling dizzy
o
o
o
o
o
o
o
o
o
o
o
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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 room temperature between 20° to 25°C (68° to 77°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 uled 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in bicalutamide tablets?

Active ingredient: bicalutamide

Inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, sodium starch glycolate (potato), titanium dioxide and triacetin.

This Patient Information has been approved by the U.S. Food and Drug Administration.

The brands uled are trademarks of their respective owners.

Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Revised: 7/2017BCLT:R6p/PL:BCLT:R5p

Package Label.principal Display Panel


PRINCIPAL DISPLAY PANEL - 50 mg

NDC 0378-7017-93

Bicalutamide Tablets, USP 50 mg

PHARMACIST: Dispense the accompanying Patient Information Leaflet to each patient.

Rx only      30 Tablets

Each film-coated tablet contains:Bicalutamide, USP           50 mg

Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.

Keep container tightly closed.

Keep this and all medication out of the reach of children.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Usual Dosage: See accompanyingprescribing information.

Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Mylan.com

RM7017H3

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."

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