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Casodex 150 Mg 28 Tablets

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE

2. DOSAGE AND ADMINISTRATION

2.1. Dosage Adjustment in Renal Impairment

2.2. Dosage Adjustment in Hepatic Impairment

3. DOSAGE FORMS & STRENGTHS

4. CONTRAINDICATIONS

4.1. Hypersensitivity

4.2. Women

4.3. Pregnancy

5. WARNINGS AND PRECAUTIONS

5.1. Hepatitis

5.2. Gynecomastia and Breast Pain

5.3. Glucose Tolerance

5.4. Laboratory Tests

6. ADVERSE REACTIONS

6.1. Clinical Trials Experience

6.2. Postmarketing Experience

7. DRUG INTERACTIONS

8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

8.3. Nursing Mothers

8.4. Pediatric Use

8.5. Geriatric Use

8.6. Hepatic Impairment

8.7. Renal Impairment

8.8. Women

10. OVERDOSAGE

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of Action

12.3. Pharmacokinetics

13. NONCLINICAL TOXICOLOGY

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

14. CLINICAL STUDIES

14.1. CASODEX 50 mg Daily in Combination with an LHRH-A

14.2. Safety Data from Clinical Studies using CASODEX 150 mg

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1. Storage and Handling

17. PATIENT COUNSELING INFORMATION

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

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

CASODEX 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.

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

2. DOSAGE AND ADMINISTRATION

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

2.1. Dosage Adjustment in Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

2.2. Dosage Adjustment in Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary [see Use in Specific Populations (8.6)].

3. DOSAGE FORMS & STRENGTHS

CASODEX® (bicalutamide) 50 mg Tablets for oral administration.

4. CONTRAINDICATIONS

4.1. Hypersensitivity

CASODEX is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported [see Adverse Reactions (6.2)].

4.2. Women

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

4.3. Pregnancy

CASODEX may cause fetal harm when administered to a pregnant woman. CASODEX is contraindicated in women, including those who are or may become pregnant. There are no studies in pregnant women using CASODEX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5. WARNINGS AND PRECAUTIONS

5.1. Hepatitis

Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported post-marketing in association with the use of CASODEX. 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 CASODEX patients in controlled clinical trials.

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

5.2. Gynecomastia and Breast Pain

In clinical trials with CASODEX 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 CASODEX 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 CASODEX 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 CASODEX in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).

In the multicenter, double-blind, controlled clinical trial comparing CASODEX 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 (%)

 

CASODEX 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)

Muscoloskeletal

 

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 CASODEX-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.

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

Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope

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

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

Musculoskeletal: Myalgia; Leg Cramps

Nervous: Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness

Respiratory: Lung Disorder; Asthma; Epistaxis; Sinusitis

Skin and Appendages: Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder

Special Senses: Cataract Specified

Urogenital: Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder

Abnormal Laboratory Test Values:

Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, and creatinine and decreased hemoglobin and white cell count have been reported in both CASODEX-LHRH analog treated and flutamide-LHRH analog treated patients.

6.2. Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CASODEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Uncommon cases of hypersensitivity reactions, including angioneurotic edema and urticaria have been seen [see Contraindications (4.1)]. Cases of interstitial lung disease (some fatal), including interstitial pneumonitis and pulmonary fibrosis, have been reported with CASODEX. Interstitial lung disease has been reported most often at doses greater than 50 mg. A few cases of fatal hepatic failure have been reported.

Reduction in glucose tolerance, manifesting as diabetes or a loss of glycemic control in those with pre-existing diabetes, has been reported during treatment with LHRH agonists.

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 CASODEX, 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 CASODEX is 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 CASODEX and adjustment of the anticoagulant dose may be necessary.

8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

PREGNANCY CATEGORY X [see Contraindications (4.3)]. Based on its mechanism of action, CASODEX may cause fetal harm when administered to a pregnant woman. CASODEX is contraindicated in women, including those who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

While there are no human data on the use of CASODEX in pregnancy and CASODEX is not for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus.

In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day (approximately 2/3 of clinical exposure at the recommended dose) and above, were observed to have reduced anogenital distance and hypospadias. These pharmacological effects have been observed with other antiandrogens. No other teratogenic effects were observed in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 of clinical exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day (approximately 2 times the clinical exposure at the recommended dose).

8.3. Nursing Mothers

CASODEX is not indicated for use in women.

8.4. Pediatric Use

The safety and effectiveness of CASODEX in pediatric patients have not been established.

CASODEX (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 CASODEX dose was 12.5 mg. CASODEX was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5-15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved CASODEX 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 CASODEX: 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 CASODEX, 8 patients were on 50 mg CASODEX, and 4 patients were on 100 mg CASODEX; 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 CASODEX/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

*Change compared to pre-study growth rate

†PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrazole or other aromatase inhibitors

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

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

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)

0.4

-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 anastrazole by investigators. For the patient who developed elevated ALT and AST, the elevation was <3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.

8.5. Geriatric Use

In two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.

8.6. Hepatic Impairment

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

8.8. Women

Bicalutamide has not been studied in women.

10. OVERDOSAGE

Long-term clinical trials have been conducted with dosages up to 200 mg of CASODEX daily and these dosages have been well tolerated. A single dose of CASODEX that results in symptoms of an overdose consid

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Casodex 150 Mg 28 Tablets

  • Manufacturer: Astra Zeneca
  • Generic Name: Bicalutamide
  • Availability: In Stock
  • $176.00

Tags: Casodex 150 Mg 28 Tablets, Astra Zeneca, All Products