ron. if symptoms occur, nilandron 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 nilandron. 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 nilandron patients in controlled clinical trials. serum transaminase levels should be measured prior to starting treatment with nilandron, 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, nilandron should be immediately discontinued with close followup of liver function tests until resolution. use in women nilandron has no indication for women, and should not be used in this population, particularly for non-serious or non-life threatening conditions. other foreign postmarketing surveillance has revealed isolated cases of aplastic anemia in which a causal relationship with nilandron could not be ascertained.

ence of adverse experiences was 86% (194/225) for the nilandron group and 81% (188/232) for the placebo group. the following adverse experiences were reported during a multicenter clinical trial comparing nilandron + leuprolide versus placebo + leuprolide. the most frequently reported (greater than 5%) adverse experiences during treatment with nilandron tablets in combination with leuprolide are listed below. for comparison, adverse experiences seen with leuprolide and placebo are also listed. adverse experience nilandron + 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 nilandron 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 nilandron in combination with surgical castration and in seven patients (3%) receiving nilandron in combination with leuprolide and one patient receiving placebo in combination with leuprolide. overall, it has been reported in 2% of patients receiving nilandron. 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 nilandron 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 concordia pharmaceuticals at 1-877-370-1142 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

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 100–300 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 (59–126 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 complement surgical castration, which suppresses only testicular androgens. the effects of the combined therapy were studied in patients with previously untreated metastatic prostate cancer. in a double-blind, randomized, multicenter study that enrolled 457 patients (225 treated with orchiectomy and nilandron, 232 treated with orchiectomy and placebo), the nilandron group showed a statistically significant benefit in time to progression and time to death. the results are summarized below. nilandron placebo median survival (months) 27.3 23.6 progression-free survival (months) 21.1 14.9 complete or partial regression 41% 24% improvement in bone pain 54% 37%

abolites 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 100–300 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 (59–126 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.

suppressive effects on fetuses were found. the maximal dose at which nilutamide did not affect reproductive function in either sex or have an effect on fetuses was estimated to be 45 mg/kg orally (auc exposures in rats approximately 1–2 times human therapeutic auc exposures).

ed a delay in adaptation to dark, ranging from seconds to a few minutes, when passing from a lighted area to a dark area. this effect sometimes does not abate as drug treatment is continued. patients who experience this effect should be cautioned about driving at night or through tunnels. this effect can be alleviated by the wearing of tinted glasses.