Nilutamide is an oral, once-a day, antiandrogen for use in combination with orchiectomy for the treatment of metastatic (stage D) prostate carcinoma. Nilutamide is similar in action to bicalutamide and flutamide but differs from steroidal antiandrogens (e.g., finasteride) in that nilutamide is specific for the androgen receptor. Compared to placebo, patients experienced improvement in bone pain, longer progression-free survival, and longer median overall survival. Final FDA approval was granted September 19, 1996.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Nilutamide is administered with or without food.
Pain was reported in 26.8% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) in a multicenter, randomized study; however, this adverse event occurred at a lower frequency than in men who received placebo plus leuprolide (n = 202) in this study.
Increased haptoglobin levels were reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Hyperhidrosis (6.2% vs 3%), alopecia (5.7% vs 0.5%), xerosis (5.3% vs 2.5%), and rash (unspecified) (5.3% vs 4%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in a multicenter, randomized study. Pruritus was reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Malaise was reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide. Alcohol intolerance including symptoms of facial flushing, malaise, and hypotension occurred in 5% of men treated with nilutamide.
Delayed visual impairment, specifically ocular adaptation to the dark, has been reported in men treated with nilutamide in combination with orchiectomy or leuprolide. Typically this delay lasts from seconds to a few minutes and occurs when passing from a lighted area to a dark area. Advise patients who experience a delayed adaption to the dark to use caution when driving at night or through tunnels. Additionally, wearing tinted glasses may help to alleviate this event. Impaired adaptation to dark (12.9% vs 1.3%) and abnormal vision (6.7% vs 1.7%) occurred more often with nilutamide (n = 225) compared with placebo (n = 232) in men with metastatic prostate cancer also treated with an orchiectomy in a multicenter, randomized, double-blind study. Impaired adaptation to dark (56.9% vs 5.4%), chromatopsia (8.6% vs 0%), impaired adaptation to light (7.7% vs 1%), and abnormal vision (6.2% vs 4.5%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in another multicenter, randomized study. Cataracts and photophobia each occurred in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Anemia was reported in 7.2% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 6.4% of men who received placebo plus leuprolide (n = 202) in a randomized, multicenter study. Leukopenia was reported in 3% of men treated with nilutamide in combination with orchiectomy or leuprolide. Isolated cases of aplastic anemia have been reported in post-marketing surveillance of nilutamide.
Nausea (9.8% vs 6%) and constipation (7.1% vs 3.9%) occurred more often with nilutamide (n = 225) compared with placebo (n = 232) in men with metastatic prostate cancer also treated with an orchiectomy in a multicenter, randomized, double-blind study. Nausea (23.9% vs 8.4%), constipation (19.6% vs 16.8%), anorexia (11% vs 6.4%), abdominal pain (10% vs 5.4%), dyspepsia (6.7% vs 4.5%), and vomiting (5.7% vs 4%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in another multicenter, randomized study. Gastrointestinal (GI) adverse events that were each reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide include diarrhea, GI disorder, GI bleeding, xerostomia, and melena.
Peripheral edema occurred in 12.4% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) in a multicenter, randomized study; however, this adverse event occurred at a lower frequency than in men who received placebo plus leuprolide (n = 202) in this study. Additionally, edema was reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Bone pain was reported in 6.2% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 5% of men who received placebo plus leuprolide (n = 202) in a randomized, multicenter study; back pain was also reported in the nilutamide arm (11.5%) but at a lower frequency than in the placebo arm. Arthritis was reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Hot flashes/flushes occurred in 28.4% of men with metastatic prostate cancer who received an orchiectomy plus nilutamide (n = 225) compared with 22.4% of men who received an orchiectomy plus placebo (n = 232) in a multicenter, randomized, double-blind study. Hot flashes were reported in 66.5% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 59.5% of men who received placebo plus leuprolide (n = 202) in another multicenter, randomized study.
Hypertension occurred in 5.3% of men with metastatic prostate cancer who received an orchiectomy plus nilutamide (n = 225) compared with 2.6% of men who received an orchiectomy plus placebo (n = 232) in a multicenter, randomized, double-blind study. Chest pain (unspecified) was reported in 7.2% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 4.5% of men who received placebo plus leuprolide (n = 202) in another randomized, multicenter study; hypertension was also reported in the nilutamide arm (9.1%) but at a lower frequency than in the placebo arm. Other cardiovascular adverse events reported in men treated with nilutamide in combination with orchiectomy or leuprolide include angina (2%), heart failure (3%), and syncope (2%).
Dizziness occurred in 7.1% of men with metastatic prostate cancer who received an orchiectomy plus nilutamide (n = 225) compared with 3.4% of men who received an orchiectomy plus placebo (n = 232) in a multicenter, randomized, double-blind study. Insomnia (16.3% vs 15.8%), headache (13.9% vs 10.4%), depression (8.6% vs 7.4%), and hypoesthesia (5.3% vs 2%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in another multicenter, randomized study; dizziness was also reported in the nilutamide arm (10%) but at a lower frequency than in the placebo arm. Additionally, nervousness (anxiety) (2%) and paresthesias (3%) were reported in men treated with nilutamide in combination with orchiectomy or leuprolide.
Infection has been reported in men treated with nilutamide in combination with orchiectomy or leuprolide. Pneumonia was reported in 5.3% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 3.5% of men who received placebo plus leuprolide (n = 202) in a randomized, multicenter study; upper respiratory infection (8.1%) and urinary tract infection (8.6%) were also reported in the nilutamide arm but at a lower frequency than in the placebo arm. Urinary tract infection occurred in 8% of men with metastatic prostate cancer who received an orchiectomy plus nilutamide (n = 225) in a multicenter, randomized, double-blind study; however, this adverse event occurred at a lower frequency than in men who received an orchiectomy plus placebo (n = 232) in this study.
Testicular atrophy (16.3% vs 12.4%) and libido decrease (11% vs 4.5%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in a multicenter, randomized study; gynecomastia (10.5%) and impotence (erectile dysfunction) (11%) were also reported in the nilutamide arm (10.5%) but at a lower frequency than in the placebo arm.
Hematuria (8.1% vs 7.9%) and nocturia (6.7% vs 6.4%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in a multicenter, randomized study; urinary tract disorder was also reported in the nilutamide arm (7.2%) but at a lower frequency than in the placebo arm. Increased BUN and creatinine levels were each reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Asthenia was reported in 19.1% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) in a multicenter, randomized study; however, this adverse event occurred at a lower frequency than in men who received placebo plus leuprolide (n = 202) in this study.
Fever was reported in 5.3% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) in a multicenter, randomized study; however, this adverse event occurred at a lower frequency than in men who received placebo plus leuprolide (n = 202) in this study.
Influenza-like (flu) syndrome was reported in 7.2% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 3% of men who received placebo plus leuprolide (n = 202) in a randomized, multicenter study.
Weight loss was reported in 2% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Hyperglycemia was reported in 4% of men treated with nilutamide in combination with orchiectomy or leuprolide.
Hepatotoxicity (e.g., hepatitis, elevated hepatic enzymes) has been reported with nilutamide use. Rare cases of death or hospitalization due to severe liver injury in post-marketing surveillance of nilutamide; the majority of these cases occurred within the first 3 to 4 months of treatment. Symptoms of hepatotoxicity may include nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, or right upper quadrant tenderness. Increased AST (8% vs 3.9%) and ALT (7.6% vs 4.3%) levels occurred more often with nilutamide (n = 225) compared with placebo (n = 232) in men with metastatic prostate cancer also treated with an orchiectomy in a multicenter, randomized, double-blind study. Increased ALT levels (9.1% vs 8.9%) were reported more often with nilutamide plus leuprolide (n = 209) compared with placebo plus leuprolide (n = 202) in men with metastatic prostate cancer in another multicenter, randomized study; increased AST levels were also reported in the nilutamide arm (12.9%) but at a lower frequency than in the placebo arm. Increased alkaline phosphatase levels were reported in 3% of men treated with nilutamide in combination with orchiectomy or leuprolide. Evaluate baseline hepatic enzymes levels prior to starting nilutamide therapy, regularly during the first 4 months of treatment, and then periodically thereafter. Obtain liver function tests at the first sign or symptom suggestive of liver dysfunction. Discontinue nilutamide therapy in patients who develop jaundice or an increased ALT level greater than 2 times the upper limit of normal.
Interstitial pneumonitis has been reported in 2% of patients who received nilutamide in controlled clinical trials; most cases occurred during the first 3 months of therapy and resolved when therapy was discontinued. Signs and symptoms of interstitial pneumonitis may include exertional dyspnea, cough, chest pain, fever, interstitial or alveolo-interstitial changes on X-ray, and pulmonary function tests (PFTs) demonstrating a restrictive pattern with decreased diffusing capacity of the lung for carbon monoxide (DLco). Interstitial pneumonitis was reported in 17% of Japanese patients who received nilutamide in a small study (n = 47). Dyspnea was reported in 10.5% of men with metastatic prostate cancer who received nilutamide plus leuprolide (n = 209) compared with 7.4% of men who received placebo plus leuprolide (n = 202) in a randomized, multicenter study; interstitial pneumonitis occurred in 3% of patients in the nilutamide arm. Dyspnea occurred in 6.2% of men with metastatic prostate cancer who received an orchiectomy plus nilutamide (n = 225) in a multicenter, randomized, double-blind study; however, this adverse event occurred at a lower frequency than in men who received an orchiectomy plus placebo (n = 232) in this study. Additionally, 1 patient (< 1%) who received nilutamide developed interstitial pneumonitis. Other respiratory adverse events reported in men treated with nilutamide in combination with orchiectomy or leuprolide include cough (2%), interstitial lung disease (2%), lung disorder (4%), and rhinitis (2%). Interstitial changes including pulmonary fibrosis that led to hospitalization and death have been reported rarely in post-marketing surveillance of nilutamide. Obtain a chest X-ray prior to starting nilutamide therapy and consider performing baseline PFTs. Immediately discontinue therapy in patients who develop new or worsening shortness of breath and promptly evaluate if the symptoms are drug related.
Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in 1% of nilutamide-treated patients in controlled clinical trials. Nilutamide is contraindicated in patients with severe hepatic disease. Serum hepatic enzyme levels should be measured at baseline and at regular intervals (3 months); if transaminases increase over 2-3 times the upper limit of normal, treatment should be discontinued.
Nilutamide is contraindicated in patients with severe respiratory insufficiency. Nilutamide therapy has been associated with 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. Chest radiographs (X-rays) showed interstitial or alveolo-interstitial changes, and pulmonary function tests revealed a restrictive pattern with decreased diffusing capacity of the lung (DLco). A routine baseline chest X-ray should be performed before treatment. Baseline pulmonary function tests may be considered. Patients should be told to report immediately any new or worsening shortness of breath. Nilutamide therapy should be interrupted until it can be determined if the respiratory symptoms are drug related. Most cases occur within the first 3 months of therapy, and are reversible with drug discontinuation. Also, because interstitial pneumonitis was reported in 8 of 47 patients (17%) in a small study performed in Japan, specific caution should be observed in the treatment of Asian patients.
Nilutamide may cause visual disturbance. Delayed adaptation to dark, ranging from seconds to a few minutes, when passing from a lighted area to a dark area has been reported frequently in patients receiving nilutamide in clinical trials. Patients who experience this effect should be cautioned about driving at night or through tunnels.
Nilutamide should be used cautiously in patients with alcoholism. Nilutamide can cause ethanol intolerance when administered concomitantly with ethanol.
Safety and effectiveness of nilutamide in children have not been determined.
Given its indication for use, nilutamide would not be expected to be used during lactation. Use of nilutamide during breast-feeding is not indicated, and if excreted in milk, would be expected to have potential adverse effects in a nursing infant due to the anti-androgenic activity.
Nilutamide is not indicated for use in females; it should not be used in women, especially for non-serious or non-life threatening conditions. It is not known if nilutamide may cause fetal harm or affect reproductive capacity if administered to a pregnant woman; it should only be given during pregnancy if clearly needed.
For the treatment of metastatic prostate cancer in combination with orchiectomy:
Oral dosage:
Adult males: Beginning no later than post-op day 1, 300 mg PO once daily for 30 days, then 150 mg PO once daily.
Maximum Dosage Limits:
-Adults
300 mg PO/day.
-Elderly
300 mg PO/day.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Nilutamide is contraindicated for use in patients with severe hepatic disease. If during treatment, the ALT rises to > 2-3x the upper limit of normal, discontinue nilutamide and monitor liver function tests until resolution.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Ethanol: (Major) Advise patients to avoid alcohol and alcohol-containing products while taking nilutamide. Alcohol intolerance has been reported in about 5% of patients treated with nilutamide. Facial flushing, malaise, and hypotension may occur following ingestion of nilutamide with alcohol. The mechanism of this interaction is not known. (Moderate) Alcohol intolerance has been reported in about 5 percent of patients treated with nilutamide. Facial flushing, malaise, and hypotension may occur following ingestion of nilutamide with alcohol. The mechanism of this interaction is not known. It is recommended that intake of alcohol-containing beverages be avoided by patients who experience this reaction while taking nilutamide.
Fosphenytoin: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes, such as fosphenytoin. The dosage of fosphenytoin may need to be modified if administered concomitantly with nilutamide.
Phenytoin: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes including phenytoin.
Theophylline, Aminophylline: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes including aminophylline. (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes including theophylline.
Warfarin: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs by these enzymes. Drugs with a low therapeutic margin, such as warfarin, could have a delayed elimination and corresponding increase in serum half-life. Warfarin dose may need to be modified if administered concomitantly with nilutamide.
Nilutamide is a nonsteroidal antiandrogen that irreversibly binds to androgen receptors and inhibits androgen binding. It is an antagonist at cytoplasmic androgen receptors in the hypothalamus, pituitary, and the prostate and competes with 5-dihydrotestosterone (DHT) for binding at these receptors. Nilutamide does not interact with progestin or glucocorticoid receptors. Nilutamide is not suitable for inducing chemical castration since, by blocking the feedback mechanism for control of testosterone secretion, it causes increased testosterone concentrations.
Nilutamide is administered orally. After absorption, there is a detectable distribution phase. There is moderate binding to plasma proteins and low binding to erythrocytes. The binding is nonsaturable except in the case of alpha1-1-glycoprotein, which makes a minor contribution to the total concentration of proteins in the plasma. Nilutamide is extensively metabolized; five metabolites have been isolated. 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 25-50% 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. With multiple dosing, enzyme inhibition may occur. Approximately 62% of a single orally administered dose is eliminated in the urine during the first 120 hours; less than 2% of the dose is excreted unchanged. Fecal elimination is minor, ranging from 1.4% to 7% of the dose after 4-5 days. The mean elimination half-life of nilutamide ranged from 38 to 59 hours with most values between 41 and 49 hours. The elimination of at least one metabolite ranges 59-126 hours.
-Route-Specific Pharmacokinetics
Oral Route
Following oral dosing in patients with metastatic prostate cancer, nitulamide is rapidly and completely absorbed and yields high and persistent plasma concentrations.