Nilutamide

INDICATIONS AND USAGE 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.

CLINICAL PHARMACOLOGY Mechanism of Action Prostate cancer is known to be androgen sensitive and responds to androgen ablation. In animal studies, nilutamide has demonstrated antiandrogenic activity without other hormonal (estrogen, progesterone, mineralocorticoid, and glucocorticoid) effects. In vitro , nilutamide blocks the effects of testosterone at the androgen receptor level. In vivo , nilutamide interacts with the androgen receptor and prevents the normal androgenic response. Pharmacokinetics Absorption Analysis of blood, urine, and feces samples following a single oral 150-mg dose of [ 14 C]-nilutamide in patients with metastatic prostate cancer showed that the drug is rapidly and completely absorbed and that it yields high and persistent plasma concentrations. Distribution After absorption of the drug, there is a detectable distribution phase. There is moderate binding of the drug to plasma proteins and low binding to erythrocytes. The binding is nonsaturable except in the case of alpha-1-glycoprotein, which makes a minor contribution to the total concentration of proteins in the plasma. The results of binding studies do not indicate any effects that would cause nonlinear pharmacokinetics. Metabolism The results of a human metabolism study using 14 C-radiolabelled tablets show that nilutamide is extensively metabolized and less than 2% of the drug is excreted unchanged in urine after 5 days. Five metabolites have been isolated from human urine. Two metabolites display an asymmetric center, due to oxidation of a methyl group, resulting in the formation of D- and L-isomers. One of the metabolites was shown, in vitro , to possess 25 to 50% of the pharmacological activity of the parent drug, and the D-isomer of the active metabolite showed equal or greater potency compared to the L-isomer. However, the pharmacokinetics and the pharmacodynamics of the metabolites have not been fully investigated. Elimination The majority (62%) of orally administered [ 14 C]-nilutamide is eliminated in the urine during the first 120 hours after a single 150-mg dose. Fecal elimination is negligible, ranging from 1.4% to 7% of the dose after 4 to 5 days. Excretion of radioactivity in urine likely continues beyond 5 days. The mean elimination half-life of nilutamide determined in studies in which subjects received a single dose of 100 to 300 mg ranged from 38.0 to 59.1 hours with most values between 41 and 49 hours. The elimination of at least one metabolite is generally longer than that of unchanged nilutamide (59 to 126 hours). During multiple dosing of 150 mg nilutamide (given as 3 × 50 mg) twice a day, steady state was reached within 2 to 4 weeks for most patients, and mean steady state AUC 0–12 was 110% higher than the AUC 0–∞ obtained from the first 150 mg dose. These data and in vitro metabolism data suggest that, upon multiple dosing, metabolic enzyme inhibition may occur for this drug. Clinical Studies Nilutamide through its antiandrogenic activity can com

DOSAGE AND ADMINISTRATION 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.

ADVERSE REACTIONS 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 2.6 Digestive System Nausea 9.8 6.0 Constipation 7.1 3.9 Endocrine System Hot flushes 28.4 22.4 Metabolic and Nutritional System Increased AST 8.0 3.9 Increased ALT 7.6 4.3 Nervous System Dizziness 7.1 3.4 Respiratory System Dyspnea 6.2 7.3 Special Senses Impaired adaptation to dark 12.9 1.3 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 27.7 Headache 13.9 10.4 Asthenia 19.1 20.8 Back pain 11.5 16.8 Abdominal pain 10.0 5.4 Chest pain 7.2 4.5 Flu syndrome 7.2 3.0 Fever 5.3 6.4 Cardiovascular System Hypertension 9.1 9.9 Digestive System Nausea 23.9 8.4 Constipation 19.6 16.8 Anorexia 11.0 6.4 Dyspepsia 6.7 4.5 Vomiting 5.7 4.0 Endocrine System Hot flushes 66.5 59.4 Impotence 11.0 12.9 Libido decreased 11.0 4.5 Hemic and Lymphatic System Anemia 7.2 6.4 Metabolic and Nutritional System Increased AST 12.9 13.9 Peripheral edema 12.4 17.3 Increased ALT 9.1 8.9 Musculoskeletal System Bone Pain 6.2 5.0 Nervous System Insomnia 16.3 15.8 Dizziness 10.0 11.4 Depression 8.6 7.4 Hypesthesia 5.3 2.0 Respiratory System Dyspnea 10.5 7.4 Upper respiratory infection 8.1 10.9 Pneumonia 5.3 3.5 Skin and Appendages Sweating 6.2 3.0 Body hair loss 5.7 0.5 Dry skin 5.3 2.5 Rash 5.3 4.0 Special Senses Impaired adaptation to dark 56.9 5.4 Chromatopsia 8.6 0.0 Impaired adaptation to light 7.7 1.0 Abnormal vision 6.2 4.5 Urogenital System Testicular atrophy 16.3 12.4 Gynecomastia 10.5 11.9 Urinary tract infection 8.6 21.3 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 leuprol

WARNINGS 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.

CONTRAINDICATIONS 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.

OVERDOSAGE 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.