BICALUTAMIDE- bicalutamide tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP)
Available from:
Northstar RxLLC
INN (International Name):
BICALUTAMIDE
Composition:
BICALUTAMIDE 50 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Bicalutamide 50 mg daily is 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 150 mg daily is not  approved for use alone or with other treatments [see Clinical Studies (14.2)] . Bicalutamide is contraindicated in: -   Hypersensitivity Bicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported. - Women Bicalutamide has no indication for women, and should not be used in this population. - Pregnancy Bicalutamide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . 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
Product summary:
Bicalutamide tablets, USP are available as follows: 50 mg – White, round, film-coated, biconvex tablets marked with “B 50” on one side with “” on the other side are supplied in bottles of 30 tablets (NDC 16714-571-01), 100 tablets (NDC 16714-571-02), and 500 tablets (NDC 16714-571-03). Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Dispense in a tight, light-resistant container as defined in the USP.
Authorization status:
Abbreviated New Drug Application
Authorization number:
16714-571-01, 16714-571-02, 16714-571-03

BICALUTAMIDE- bicalutamide tablet, film coated

Northstar RxLLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BICALUTAMIDE TABLETS safely and

effectively. See full prescribing information for BICALUTAMIDE TABLETS.

BICALUTAMIDE tablets, for oral use

Initial U.S. Approval: 1995

RECENT MAJOR CHANGES

Warnings and Precautions (5.2) 10/2017

INDICATIONS AND USAGE

Bicalutamide 50 mg is an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing

hormone-releasing hormone (LHRH) analog for the treatment of Stage D metastatic carcinoma of the prostate. (1)

Bicalutamide 150 mg daily is not approved for use alone or with other treatments. (1)

DOSAGE AND ADMINISTRATION

The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily

(morning or evening). (2)

DOSAGE FORMS AND STRENGTHS

50 mg tablets (3)

CONTRAINDICATIONS

Hypersensitivity (4)

Women (4)

Pregnancy (4, 8.1)

WARNINGS AND PRECAUTIONS

Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting

treatment with bicalutamide, at regular intervals for the first four months of treatment and periodically thereafter, and

for symptoms or signs suggestive of hepatic dysfunction. Use bicalutamide with caution in patients with hepatic

impairment. (5.1)

Hemorrhage with Concomitant Use of Coumarin Anticoagulant. Closely monitor the Prothrombin Time (PT) and

International Normalized Ratio (INR), and adjust the anticoagulant dose as needed. (5.2)

Gynecomastia and breast pain have been reported during treatment with bicalutamide 150 mg when used as a single

agent. (5.3)

Bicalutamide is used in combination with an LHRH agonist. LHRH agonists have been shown to cause a reduction in

glucose tolerance in males. Consideration should be given to monitoring blood glucose in patients receiving

bicalutamide in combination with LHRH agonists. (5.4)

Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. (5.5)

ADVERSE REACTIONS

Adverse reactions that occurred in more than 10% of patients receiving bicalutamide plus an LHRH-A were: hot flashes,

pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea,

diarrhea, hematuria, nocturia, and anemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-

FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when bicalutamide is co-administered with

CYP 3A4 substrates. (7)

PT/INR should be closely monitored in patients already receiving coumarin anticoagulants who are started on

bicalutamide. (7)

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)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedule

2.2 Dosage Adjustment in Renal Impairment

2.3 Dosage Adjustment in Hepatic Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hepatitis

5.2 Hemorrhage with Concomitant Use of Coumarin Anticoagulant

5.3 Gynecomastia and Breast Pain

5.4 Glucose Tolerance

5.5 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Bicalutamide 50 mg Daily in Combination with an LHRH-A

14.2 Safety Data from Clinical Studies Using Bicalutamide 150 mg

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Storage and Handling

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

Bicalutamide 50 mg daily is indicated for use in combination therapy with a luteinizing hormone-

releasing hormone (LHRH) analog for the treatment of Stage D metastatic carcinoma of the prostate.

Bicalutamide 150 mg daily is not approved for use alone or with other treatments [see Clinical Studies

(14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedule

The recommended dose for bicalutamide 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 be

taken at the same time each day. Treatment with bicalutamide 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 50 mg tablets for oral administration.

4 CONTRAINDICATIONS

Bicalutamide is contraindicated in:

Hypersensitivity

Bicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or

any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria

have been reported.

Women

Bicalutamide has no indication for women, and should not be used in this population.

Pregnancy

Bicalutamide can cause fetal harm when administered to a pregnant woman [see Use in Specific

Populations (8.1)].

5 WARNINGS AND PRECAUTIONS

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 Causality

Treatment Group Number of Patients (%)

Bicalutamide Plus

Flutamide Plus

LHRH Analog

LHRH Analog

Body System

Adverse Reaction

(n=401)

(n=407)

Body as a Whole

Pain (General)

142 (35)

127 (31)

Back Pain

102 (25)

105 (26)

Asthenia

89 (22)

87 (21)

Pelvic Pain

85 (21)

70 (17)

Infection

71 (18)

57 (14)

Abdominal Pain

46 (11)

46 (11)

Chest Pain

34 (8)

34 (8)

Headache

29 (7)

27 (7)

Flu Syndrome

28 (7)

30 (7)

Cardiovascular

Hot Flashes

211 (53)

217 (53)

Hypertension

34 (8)

29 (7)

Digestive

Constipation

87 (22)

69 (17)

Nausea

62 (15)

58 (14)

Diarrhea

49 (12)

107 (26)

Increased Liver Enzyme Test

30 (7)

46 (11)

Dyspepsia

30 (7)

23 (6)

Flatulence

26 (6)

22 (5)

Anorexia

25 (6)

29 (7)

Vomiting

24 (6)

32 (8)

Hemic and Lymphatic

Anemia

45 (11)

53 (13)

Metabolic and Nutritional

Peripheral Edema

53 (13)

42 (10)

Weight Loss

30 (7)

39 (10)

Hyperglycemia

26 (6)

27 (7)

Alkaline Phosphatase Increased

22 (5)

24 (6)

Weight Gain

22 (5)

18 (4)

Musculoskeletal

Bone Pain

37 (9)

43 (11)

Myasthenia

27 (7)

19 (5)

Arthritis

21 (5)

29 (7)

Pathological Fracture

17 (4)

32 (8)

Nervous System

Dizziness

41 (10)

35 (9)

Paresthesia

31 (8)

40 (10)

Insomnia

27 (7)

39 (10)

Anxiety

20 (5)

9 (2)

Depression

16 (4)

33 (8)

Respiratory System

Dyspnea

51 (13)

32 (8)

Cough Increased

33 (8)

24 (6)

Pharyngitis

32 (8)

23 (6)

Bronchitis

24 (6)

22 (3)

Pneumonia

18 (4)

19 (5)

Rhinitis

15 (4)

22 (5)

Skin and Appendages

Rash

35 (9)

30 (7)

Sweating

25 (6)

20 (5)

Urogenital

Nocturia

49 (12)

55 (14)

Hematuria

48 (12)

26 (6)

Urinary Tract Infection

35 (9)

36 (9)

Gynecomastia

36 (9)

30 (7)

Impotence

27 (7)

35 (9)

Breast Pain

23 (6)

15 (4)

Urinary Frequency

23 (6)

29 (7)

Urinary Retention

20 (5)

14 (3)

Urinary Impaired

19 (5)

15 (4)

Urinary Incontinence

15 (4)

32 (8)

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-

LHRH analog treatment group are listed below by body system and are in order of decreasing

frequency within each body system regardless of causality.

Body as a Whole: Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst

Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest;

Coronary Artery Disorder; Syncope

Digestive: Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal

Abscess; Gastrointestinal Carcinoma

Metabolic and Nutritional: Edema; BUN Increased; Creatinine Increased; Dehydration; Gout;

Hypercholesterolemia

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 coadministration of

bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5-fold (for C

) and

1.9-fold (for AUC). Hence, caution should be exercised when bicalutamide is coadministered with CYP

3A4 substrates.

In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from

binding sites. PT/INR should be closely monitored in patients concomitantly receiving coumarin

anticoagulants and bicalutamide. Adjustment of the anticoagulant dose may be necessary [see Warnings

and Precautions (5.2) and Adverse Reactions (6.2)].

8 USE IN SPECIFIC POPULATIONS

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).

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from

gestation days 6-15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above

(approximately 0.7 to 2 times the human exposure at the recommended dose).

In a pre- and post-natal development study, female rats were dosed from gestation day 7-16 and allowed

to litter and rear their offspring to weaning. Male offspring of rats receiving doses of 10 mg/kg/day

(approximately 0.7 times the human exposure at the recommended dose) and above, were observed to

have reduced anogenital distance.

In a peri- and post-natal development study, female rats were dosed from gestation day 16 to lactation

day 22 and allowed to litter and rear their offspring to weaning. Survival and weights of offspring

during lactation were reduced for litters from maternal rats receiving doses of 250 mg/kg/day

(approximately 2 times the human exposure at the recommended dose). Male offspring of rats receiving

doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and

above, were observed to have reduced anogenital distance, smaller secondary sex organs,

cryptorchidism and hypospadias resulting in an inability to mate and impregnate their female partners.

Female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure

at the recommended dose) and above had reduced pregnancy rates.

8.2 Lactation

Risk Summary

Bicalutamide is not indicated for use in pregnant women. There is no information available on the

presence of bicalutamide in human milk, or on the effects on the breastfed infant or on milk production.

Bicalutamide has been detected in rat milk.

8.3 Females and Males of Reproductive Potential

Contraception

Males

Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology

(13.1)]. Based on findings in animal reproduction studies and its mechanism of action, advise male

patients with female partners of reproductive potential to use effective contraception during treatment

and for 130 days after the final dose of bicalutamide [see Use in Specific Populations (8.1) and Clinical

Pharmacology (12.1)].

Infertility

Males

Based on animal studies, bicalutamide can lead to inhibition of spermatogenesis and may impair fertility

in males of reproductive potential. The long-term effects of bicalutamide on male fertility have not been

studied [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of bicalutamide 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 greater than or equal to 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 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 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 less than 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 greater than or equal to 6 months prior to entering the

study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the

growth rate was reduced during treatment. During bicalutamide/anastrozole treatment the mean growth

rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS

decreased by 0.1 SD, 95% CI (–1.2 to 1.0) p=0.88. Table 2 shows descriptive data for growth rates for

the overall population and for subgroups defined by history of previous treatment for testotoxicosis

with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.

Table 2. Growth Rates

Endpoint

Analysis

population

Pre-

study

Mean

Change from pre-study to 12

months

% patients with growth

reduction

Mean

Median

(Min, Max)

Growth

rate

(cm/yr)

All treated

(n=13)

10.8

-1.6

-2.8

(-7.4, 8.4)

9/13 (69%)

PT (n=6)

10.3

-0.2

-2.6

(-7.2, 8.4)

4/6 (67%)

NPT (n=7)

11.2

-2.8

-2.8

(-7.4, 1.1)

5/7 (71%)

Growth

rate

(SD units)

All treated

(n=13)

-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)

-0.7

-0.4

(-2.7, 0.5)

5/7 (71%)

Change compared to pre-study growth rate.

PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other

aromatase inhibitors

NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or

other aromatase inhibitors

Median calculated as midpoint of 3rd and 4th ranked observations

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 (greater than 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 less than 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 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

molecular formulas are:

Bicalutamide, USP 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, USP is a racemate with its antiandrogenic activity being almost exclusively exhibited by

the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.

The inactive ingredients of bicalutamide tablets are lactose monohydrate, magnesium stearate,

polyethylene glycol, polyvinyl alcohol, povidone, sodium starch glycolate (type A), talc and titanium

dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of

androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to

be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes

the source of androgen.

When bicalutamide is combined with LHRH analog therapy, the suppression of serum testosterone

induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single

agent for prostate cancer, rises in serum testosterone and estradiol have been noted.

In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who

discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate

Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be

observed.

12.3 Pharmacokinetics

Absorption

Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is

unknown. Coadministration of bicalutamide with food has no clinically significant effect on rate or

extent of absorption.

Distribution

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

Metabolism/Elimination

Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by

glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to

an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are

eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with

the R-enantiomer accounting for about 99% of total steady-state plasma levels.

Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate

cancer are presented in Table 3.

Table 3. Pharmacokinetics of Bicalutamide Active Enantiomer

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)

2.29

Patients with Prostate Cancer (n=40)

C (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, 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 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, 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 CLINICAL STUDIES

14.1 Bicalutamide 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).

Fig ure 1 - The Kaplan-Meier probability of death for both antiandrog en treatment g roups.

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).

Fig ure 2 - Kaplan-Meier curve for time to prog ression for both antiandrog en treatment g roups.

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 150 mg

Bicalutamide 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 Group

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 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 (T3-4, NX, M0) Group

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, 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 on-going 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

Bicalutamide tablets, USP are available as follows:

50 mg – White, round, film-coated, biconvex tablets marked with “B 50” on one side with “

” on the

other side are supplied in bottles of 30 tablets (NDC 16714-571-01), 100 tablets (NDC 16714-571-02),

and 500 tablets (NDC 16714-571-03).

16.1 Storage and Handling

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

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

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 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 tablets. Advise

patients to notify their healthcare provider of any bleeding or spontaneous bruising while on

bicalutamide tablets and taking anticoagulants [see Warnings and Precautions (5.2) and Adverse Reactions

(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 tablets in combination

with LHRH agonists [see Warnings and Precautions (5.4)].

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 may impair fertility [see Use in Specific Populations

(8.3)].

Manufactured for:

Northstar Rx LLC

Memphis, TN 38141

Manufactured by:

Intas Pharmaceuticals Ltd.

Ahmedabad, India – 382210 INDIA

Revised: December 2017

PATIENT INFORMATION

Bicalutamide (bye″ ka loo′ ta mide) Tablets, USP

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 D

metastatic prostate cancer

Bicalutamide 150 mg daily is not approved for use alone or with other treatments.

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

Do not take bicalutamide tablets if you are:

allergic to bicalutamide or any of the ingredients in bicalutamide tablets. See the end of this Patient

Information leaflet for a complete list of ingredients in bicalutamide tablets. Get medical help right

away if you develop any of the following symptoms of an allergic reaction:

itching

hives (raised bumps)

swelling of the face, lips or tongue

trouble breathing or swallowing

female. Bicalutamide tablets are not for use by women.

pregnant or may become pregnant. Bicalutamide may harm your unborn baby.

Before taking 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.

have a female partner who can become pregnant. Males who have a female partner who can become

pregnant should use effective birth control during treatment with bicalutamide tablets and for 130

days after the final dose. Talk to your healthcare provider 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 may affect the way

other medicines work and other medicines may affect how bicalutamide tablets work, causing side

effects.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare

providers when you get a new medicine.

How should I take bicalutamide tablets?

Take bicalutamide tablets exactly as your healthcare provider tells you to take it.

Do not stop taking bicalutamide tablets unless your healthcare provider tells you to.

Bicalutamide tablets can be taken either in the morning or in the evening, but you should take it 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 bicalutamide tablets dose do not take the missed dose, take the next dose at your next

scheduled 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 go to the nearest hospital

emergency room right away.

What should I avoid during treatment with bicalutamide tablets?

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

tablets affect you. Bicalutamide can make you sleepy.

Avoid sunlight, sunlamps, and tanning beds, and consider using sunscreen during treatment with

bicalutamide tablets. Some people have had skin sensitivity to sunlight during treatment with

bicalutamide tablets.

What are the possible side effects of bicalutamide tablets?

Bicalutamide tablets may cause serious side effects, including:

Liver problems. Severe liver problems, including liver failure that may need to be treated in a

hospital or that may lead to death have happened in people who take bicalutamide tablets. 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 develop any of these

symptoms of liver problems during treatment:

yellowing of the skin and eyes

(jaundice)

dark urine

right upper stomach pain

nausea

vomiting

tiredness

loss of appetite

chills

fever

Bleeding problems. Serious bleeding problems have happened in people who take bicalutamide

tablets in combination with a blood thinner medicine (coumarin anticoagulants). Bleeding problems

have happened days to weeks after starting bicalutamide tablets treatment. If you take a blood thinner

medicine during treatment with bicalutamide tablets, tell your healthcare provider if you develop any

bleeding or unexplained bruising.

bleeding or unexplained bruising.

Breast enlargement (gynecomastia) and breast pain.

Blood sugar problems. Poor blood sugar control can happen in people who take bicalutamide

tablets in combination with LHRH medicines.

Your healthcare provider may do blood tests during treatment with bicalutamide tablets to check for

side effects.

Your prostate cancer may get worse during treatment with 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.

Tell your healthcare provider if you have trouble breathing with or without a cough or fever. Some

people taking bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.

The most common side effects of bicalutamide tablets include:

hot flashes (short periods of

feeling warm and sweating)

infection

diarrhea

body pain (including back,

pelvis, stomach)

·nausea

blood in your urine

feeling weak

swelling in your arms, ankles,

legs or feet

frequent urination at

night

constipation

shortness of breath (dyspnea)

a decrease in red

blood cells (anemia)

dizziness

Bicalutamide may have an effect on male fertility which could be reversible. Talk to your healthcare

provider if this is a concern for you.

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 68°F to 77°F (20°C to 25°C).

Keep bicalutamide tablets and all medicines out of the reach of children.

General information about the safe and effective use of bicalutamide tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use bicalutamide tablets for a condition for which they were 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.

What are the ingredients in bicalutamide tablets?

Active ingredient: bicalutamide, USP

Inactive ingredients: lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl

alcohol, povidone, sodium starch glycolate (type A), talc and titanium dioxide.

Manufactured for: Northstar Rx LLC Memphis, TN 38141

Manufactured by: Intas Pharmaceuticals Ltd., Ahmedabad, India – 382210, INDIA

For more information, call 1-800-206-7821.

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

Revised – 12/2017

PRINCIPAL DISPLAY PANEL

NDC 16714-571-01

Rx Only

Bicalutamide Tablets, USP

50 mg

PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET.

30 Tablets

NORTHSTAR

BICALUTAMIDE

bicalutamide tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-571

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

BICALUTAMIDE (UNII: A0 Z3NAU9 DP) (BICALUTAMIDE - UNII:A0 Z3NAU9 DP)

BICALUTAMIDE

50 mg

Northstar RxLLC

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

PO VIDO NE K3 0 (UNII: U725QWY32X)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND (bico nvex)

S iz e

Flavor

Imprint Code

B;50

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-571-0 1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /28 /20 0 9

2

NDC:16 714-571-0 2

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /28 /20 0 9

3

NDC:16 714-571-0 3

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /28 /20 0 9

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 6 34

0 8 /28 /20 0 9

Labeler -

Northstar RxLLC (830546433)

Revised: 12/2017

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