Nilutamide Drug Information

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.

Digestive System Nausea 9.8 6.0 Constipation 7.1 3.9 Endocrine System Hot flushes

28.4

Metabolic and Nutritional System Increased

AST 8.0

Increased

ALT 7.6

Nervous System Dizziness 7.1 3.4 Respiratory System Dyspnea 6.2 7.3 Special Senses

Impaired adaptation to dark 12.9

Abnormal vision 6.7 1.7 Urogenital System Urinary tract infection 8.0 9.1

The 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

Headache 13.9 10.4 Asthenia 19.1 20.8 Back pain 11.5 16.8 Abdominal pain

10.0

Chest pain 7.2 4.5 Flu syndrome 7.2 3.0 Fever 5.3 6.4 Cardiovascular

System Hypertension 9.1

Digestive System Nausea 23.9 8.4 Constipation 19.6 16.8 Anorexia 11.0 6.4 Dyspepsia

6.7

Vomiting 5.7 4.0 Endocrine System Hot flushes 66.5 59.4 Impotence 11.0 12.9

Libido decreased 11.0

Hemic and Lymphatic System Anemia 7.2 6.4 Metabolic and Nutritional System Increased

AST 12.9

Peripheral edema 12.4 17.3 Increased

ALT 9.1

Musculoskeletal System Bone Pain 6.2 5.0 Nervous System Insomnia 16.3 15.8 Dizziness

10.0

Depression 8.6 7.4 Hypesthesia 5.3 2.0 Respiratory System Dyspnea 10.5 7.4 Upper

respiratory infection 8.1

Pneumonia 5.3 3.5 Skin and Appendages Sweating 6.2 3.0 Body hair loss

5.7

Dry skin 5.3 2.5 Rash 5.3 4.0 Special Senses Impaired adaptation to

dark 56.9

Urogenital System Testicular atrophy 16.3 12.4 Gynecomastia 10.5 11.9 Urinary tract infection

8.6

Hematuria 8.1 7.9 Urinary tract disorder 7.2 10.4 Nocturia 6.7 6.4

The 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.

Drug Interactions In vitro, nilutamide has been shown to inhibit the activity of liver cytochrome P-450 isoenzymes and, therefore, may reduce the metabolism of compounds requiring these systems. Consequently, drugs with a low therapeutic margin, such as vitamin K antagonists, phenytoin, and theophylline, could have a delayed elimination and increases in their serum half-life leading to a toxic level. The dosage of these drugs or others with a similar metabolism may need to be modified if they are administered concomitantly with nilutamide.

For example, when vitamin K antagonists are administered concomitantly with nilutamide, prothrombin time should be carefully monitored and, if necessary, the dosage of vitamin K antagonists should be reduced.

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.

Pediatric Use Safety and effectiveness in pediatric patients have not been determined.

• 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.

One case of massive overdosage has been published. A 79-year-old man attempted suicide by ingesting 13 g of nilutamide (i.e., 43 times the maximum recommended dose). Despite immediate gastric lavage and oral administration of activated charcoal, plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion. There were no clinical signs or symptoms or changes in parameters such as transaminases or chest X-ray.

Maintenance treatment (150 mg/day) was resumed 30 days later. In repeated-dose tolerance studies, doses of 600 mg/day and 900 mg/day were administered to 9 and 4 patients, respectively. The ingestion of these doses was associated with gastrointestinal disorders, including nausea and vomiting, malaise, headache, and dizziness.

In addition, a transient elevation in hepatic enzyme levels was noted in one patient. Since nilutamide is protein bound, dialysis may not be useful as treatment for overdose. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.

If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.