Nilutamide

Metastatic Prostate Cancer Nilutamide Tablets are indicated for use in combination with surgical castration for the treatment of metastatic prostate cancer (Stage D 2 ). For maximum benefit, treatment with Nilutamide Tablets must begin on the same day as or on the day after surgical castration.

The recommended dosage is 300 mg once a day for 30 days, followed thereafter by 150 mg once a day. Nilutamide Tablets can be taken with or without food.

Interstitial Pneumonitis Interstitial pneumonitis has been reported in 2% of patients in controlled clinical trials in patients exposed to nilutamide. A small study in Japanese subjects showed that 8 of 47 patients (17%) developed interstitial pneumonitis. Reports of interstitial changes including pulmonary fibrosis that led to hospitalization and death have been reported rarely post-marketing.

Symptoms included exertional dyspnea, cough, chest pain, and fever. X-rays showed interstitial or alveolo-interstitial changes, and pulmonary function tests revealed a restrictive pattern with decreased DLco. Most cases occurred within the first 3 months of treatment with Nilutamide Tablets, and most reversed with discontinuation of therapy.

A routine chest X-ray should be performed prior to initiating treatment with Nilutamide Tablets. Baseline pulmonary function tests may be considered. Patients should be instructed to report any new or worsening shortness of breath that they experience while on Nilutamide Tablets.

If symptoms occur, Nilutamide Tablets should be immediately discontinued until it can be determined if the symptoms are drug related. Hepatitis Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Nilutamide Tablets. Hepatotoxicity in these reports generally occurred within the first 3 to 4 months of treatment.

Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in 1% of Nilutamide Tablet patients in controlled clinical trials. Serum transaminase levels should be measured prior to starting treatment with Nilutamide Tablets, at regular intervals for the first 4 months of treatment, and periodically thereafter. Liver function tests should also be obtained at the first sign or symptom suggestive of liver dysfunction, e.g. nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or right upper quadrant tenderness.

If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, Nilutamide Tablets should be immediately discontinued with close follow-up of liver function tests until resolution. Use in Women Nilutamide Tablets have no indication for women, and should not be used in this population, particularly for non-serious or non-life threatening conditions. Other Foreign post-marketing surveillance has revealed isolated cases of aplastic anemia in which a causal relationship with Nilutamide Tablets could not be ascertained.

Nilutamide Tablets are contraindicated: • in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment) • in patients with severe respiratory insufficiency • in patients with hypersensitivity to nilutamide or any component of this preparation.

Pregnancy Animal reproduction studies have not been conducted with nilutamide. It is also not known whether nilutamide can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Nilutamide should be given to a pregnant woman only if clearly needed.

Clinical Trial Experience The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide Tablets + surgical castration versus placebo + surgical castration. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilutamide Tablets in combination with surgical castration are listed below. For comparison, adverse experiences seen with surgical castration and placebo are also listed. Adverse Experience Nilutamide Tablets + surgical castration (N=225) % All Placebo + surgical castration (N=232) % All Cardiovascular System Hypertension 5.3

2.6Digestive System Nausea

9.8

6.0Constipation

7.1

3.9Endocrine System Hot

flushes 28.4

22.4Metabolic and Nutritional System Increased

AST 8.0

3.9Increased

ALT 7.6

4.3Nervous System Dizziness

7.1

3.4Respiratory System Dyspnea

6.2

7.3Special Senses Impaired

adaptation to dark 12.9

1.3Abnormal

vision 6.7

1.7Urogenital System Urinary

tract infection 8.0

9.1The

overall incidence of adverse experiences was 86% (194/225) for the Nilutamide Tablets group and 81% (188/232) for the placebo group. The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide Tablets + leuprolide versus placebo + leuprolide. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilutamide Tablets in combination with leuprolide are listed below.

For comparison, adverse experiences seen with leuprolide and placebo are also listed. Adverse Experience Nilutamide Tablets + leuprolide (N=209) % All Placebo + leuprolide (N=202) % All Body as a Whole Pain 26.8

27.7Headache

13.9

10.4Asthenia

19.1

20.8Back

pain 11.5

16.8Abdominal

pain 10.0

5.4Chest

pain 7.2

4.5Flu

syndrome 7.2

3.0Fever

5.3

6.4Cardiovascular System Hypertension

9.1

9.9Digestive System Nausea

23.9

8.4Constipation

19.6

16.8Anorexia

11.0

6.4Dyspepsia

6.7

4.5Vomiting

5.7

4.0Endocrine System Hot

flushes 66.5

59.4Impotence

11.0

12.9Libido

decreased 11.0

4.5Hemic and Lymphatic System Anemia

7.2

6.4Metabolic and Nutritional System Increased

AST 12.9

13.9Peripheral

edema 12.4

17.3Increased

ALT 9.1

8.9Musculoskeletal System Bone Pain

6.2

5.0Nervous System Insomnia

16.3

15.8Dizziness

10.0

11.4Depression

8.6

7.4Hypesthesia

5.3

2.0Respiratory System Dyspnea

10.5

7.4Upper

respiratory infection 8.1

10.9Pneumonia

5.3

3.5Skin and Appendages Sweating

6.2

3.0Body

hair loss 5.7

0.5Dry

skin 5.3

2.5Rash

5.3

4.0Special Senses Impaired

adaptation to dark 56.9

5.4Chromatopsia

8.6

0.0Impaired

adaptation to light 7.7

1.0Abnormal

vision 6.2

4.5Urogenital System Testicular

atrophy 16.3

12.4Gynecomastia

10.5

11.9Urinary

tract infection 8.6

21.3Hematuria

8.1

7.9Urinary

tract disorder 7.2

10.4Nocturia

6.7

6.4The

overall incidence of adverse experiences is 99.5% (208/209) for the Nilutamide Tablets group and 98.5% (199/202) for the placebo group. Some frequently occurring adverse experiences, for example hot flushes, impotence, and decreased libido, are known to be associated with low serum androgen levels and known to occur with medical or surgical castration alone. Notable was the higher incidence of visual disturbances (variously described as impaired adaptation to darkness, abnormal vision, and colored vision), which led to treatment discontinuation in 1% to 2% of patients.

Interstitial pneumonitis occurred in one (<1%) patient receiving Nilutamide Tablets in combination with surgical castration and in seven patients (3%) receiving Nilutamide Tablets in combination with leuprolide and one patient receiving placebo in combination with leuprolide. Overall, it has been reported in 2% of patients receiving Nilutamide Tablets. This included a report of interstitial pneumonitis in 8 of 47 patients (17%) in a small study performed in Japan.

In addition, the following adverse experiences were reported in 2 to 5% of patients treated with Nilutamide Tablets in combination with leuprolide or orchiectomy. Body as a Whole: Malaise (2%). Cardiovascular System: Angina (2%), heart failure (3%), syncope (2%). Digestive System: Diarrhea (2%), gastrointestinal disorder (2%), gastrointestinal hemorrhage (2%), melena (2%).

Metabolic and Nutritional System: Alcohol intolerance (5%), edema (2%), weight loss (2%). Musculoskeletal System: Arthritis (2%). Nervous System: Dry mouth (2%), nervousness (2%), paresthesia (3%). Respiratory System: Cough increased (2%), interstitial lung disease (2%), lung disorder (4%), rhinitis (2%).

Skin and Appendages: Pruritus (2%). Special Senses: Cataract (2%), photophobia (2%). Laboratory Values: Haptoglobin increased (2%), leukopenia (3%), alkaline phosphatase increased (3%), BUN increased (2%), creatinine increased (2%), hyperglycemia (4%). To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.