Nilutamide is used in combination with orchiectomy in the treatment of metastatic prostate cancer (stage D2).1 For maximum benefit, nilutamide must begin on the same day as or on the day after surgical castration.1 Overall, results of controlled clinical studies in patients with metastatic prostate cancer indicate that nilutamide in combination with orchiectomy slows progression of the disease, relieves bone pain associated with metastatic disease, and improves overall survival rate after long-term therapy (8.5 years).3, 5, 6, 30, 34 Use of nilutamide in combination with androgen deprivation therapy (including orchiectomy) for metastatic prostate cancer is not supported by current guidelines in light of the strong evidence available for alternative therapies.36
The indication for nilutamide in metastatic prostate cancer is based principally on the results of a double-blind, randomized, multicenter study in 457 patients with prostate cancer and distant metastases.1, 5, 6 Patients were randomized to undergo treatment with orchiectomy plus nilutamide (300 mg daily for 1 month followed by 150 mg daily thereafter) or orchiectomy plus placebo.5 The assigned oral treatment was initiated on the day after orchiectomy.5 The mean age was 71 years in the nilutamide group and 72 years in the placebo group; the majority of patients were white.5 The median months of stage D2 diagnosis was 0.50 (range: 0-90) in the nilutamide group and 0.53 (range: 0-59) in the placebo group.5 Patients who received nilutamide had a median survival of 27.3 months, while patients who received placebo had a median survival of 23.6 months.1 Progression-free survival was also prolonged among patients receiving nilutamide compared with placebo (median 21.2 months versus 14.9 months).1 Complete or partial regression of the cancer was observed in 41% of patients receiving nilutamide and 24% of patients receiving placebo.1 More patients receiving nilutamide indicated improvement in bone pain than those receiving placebo (54% versus 37%).1 Nilutamide was also associated with improvement or delayed worsening in subjective parameters such as metastasis-related pain and urinary symptoms.6 At 8.5 years of follow-up, nilutamide combined with orchiectomy continued to demonstrate improvements in overall survival and progression-free survival compared with placebo plus orchiectomy.30
Meta-analyses of randomized controlled trials comparing nilutamide plus orchiectomy to placebo plus orchiectomy in metastatic prostate cancer have found that nilutamide plus orchiectomy is associated with reduced disease progression and potential survival benefits.3, 34
A joint guideline from the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO) states that, in light of the compelling evidence to support use of docetaxel, abiraterone acetate plus prednisone, apalutamide, or enzalutamide in combination with androgen deprivation therapy in men with newly diagnosed metastatic hormone-sensitive prostate cancer, long-term use of first-generation antiandrogens (i.e., bicalutamide, flutamide, nilutamide) in lieu of these agents cannot be supported.36 Androgen pathway-directed therapy (e.g., abiraterone plus prednisone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide) should not be offered without concomitant androgen deprivation therapy in metastatic hormone-sensitive prostate cancer.36
Nilutamide is administered orally without regard to meals.1
Store tablets between 20-25°C (excursions permitted between 15-30°C) and protect from light.1
For use in combination with orchiectomy in the management of metastatic (stage D2) prostate cancer, the usual dosage of nilutamide is 300 mg once daily for 30 days, followed by 150 mg once daily thereafter.1 For maximum benefit, treatment with nilutamide should be initiated on the day of or the day after orchiectomy.1
The use of nilutamide is contraindicated in patients with severe hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.
A boxed warning about the risk of interstitial pneumonitis is included in the prescribing information for nilutamide.1 Interstitial pneumonitis was reported in 2% of patients receiving the drug in controlled clinical trials and in 17% (8/47) of patients in a small Japanese study.1 Interstitial changes, including pulmonary fibrosis leading to hospitalization and death, have been reported rarely during post-marketing experience with the drug.1 Symptoms of interstitial pneumonitis included exertional dyspnea, cough, chest pain, and fever; chest radiographs showed interstitial or alveolo-interstitial changes, and pulmonary function tests showed a restrictive pattern with decreased carbon monoxide diffusing capacity.1 In most patients, interstitial pneumonitis occurred within the first 3 months of nilutamide therapy and resolved following discontinuation of the drug.1
Perform chest radiograph prior to initiation of nilutamide therapy.1 Baseline pulmonary function tests also may be considered.1 Nilutamide therapy should be discontinued immediately if symptoms occur until it can be determined if symptoms are drug related.1
Severe liver injury, in some cases leading to hospitalization and/or death, has been reported rarely in association with nilutamide therapy.1 Hepatotoxicity generally occurred within the first 3-4 months of nilutamide therapy.1 Hepatitis or a marked increase in serum concentrations of hepatic transaminases leading to discontinuation of nilutamide therapy was reported in 1% of patients receiving the drug in controlled clinical trials.1
Serum transaminase concentrations should be measured prior to initiation of nilutamide therapy, at regular intervals during the first 4 months of treatment, and periodically thereafter.1 If clinical signs or symptoms suggestive of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, right upper quadrant tenderness) occur, immediately measure serum transaminase concentrations.1 Immediately discontinue nilutamide in any patient who develops jaundice or an increase in serum ALT concentration to greater than 2 times the ULN, and closely monitor liver function.1
Nilutamide is not intended for use in women and should not be used in women, particularly for nonserious or nonlife-threatening conditions.1
Post-marketing cases of aplastic anemia have been reported with nilutamide, although a causal relationship has not been determined.1
Patients whose disease progresses while being treated with an antiandrogen, such as nilutamide, may experience clinical improvement with discontinuation of the antiandrogen.1
There are no available data on the use of nilutamide in pregnant women to evaluate the drug-associated risk in pregnancy.1 It is unknown whether nilutamide can cause fetal harm when administered to a pregnant patient.1 Administer nilutamide to a pregnant patient only if clearly needed.1
Nilutamide is not intended for use in women.1
There are no available data on use during lactation.1
The safety and efficacy of nilutamide in pediatric patients have not been established.1
The safety and efficacy of nilutamide in geriatric patients have not been established.1
Nilutamide is contraindicated for use in severe hepatic impairment.1 Evaluate serum transaminase levels prior to starting nilutamide, at regular intervals for the first 4 months of treatment, and then periodically thereafter.1 Additionally, obtain liver function tests if symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine, “flu-like” symptoms, or right upper quadrant tenderness are present.1 If at any time jaundice is present, or the ALT rises to above 2 times the ULN, immediately discontinue nilutamide and closely monitor liver function tests until resolution.1
In a pharmacokinetic study, only a small quantity of nonmetabolized nilutamide was found in the urine.35 Renal impairment is likely to have little effect on the pharmacokinetics of nilutamide.35
Adverse effects reported in ≥5% of patients in clinical trials receiving nilutamide with surgical castration include hypertension, nausea, constipation, hot flushes, increased ALT, increased AST, dizziness, dyspnea, impaired adaptation to the dark, abnormal vision, and urinary tract infection.1
Adverse effects reported in ≥10% of patients in clinical trials receiving nilutamide with leuprolide include pain, headache, asthenia, back pain, abdominal pain, nausea, constipation, anorexia, hot flushes, impotence, decreased libido, increased AST, peripheral edema, insomnia, dizziness, dyspnea, impaired adaptation to the dark, testicular atrophy, and gynecomastia.1
In vitro studies indicate that nilutamide inhibits the activity of cytochrome P-450 (CYP) isoenzymes in the liver, and may therefore reduce their metabolism.1
Drugs with Low Therapeutic Margin
Monitor drugs with a narrow therapeutic window such as warfarin, phenytoin, and theophylline while on nilutamide.1 These drugs could have a delayed elimination and increased serum half-life leading to a toxic level.1 Adjust the dosage of these drugs if necessary.1 Monitor prothrombin time carefully and adjust the dosage of warfarin, if necessary, when warfarin is used concomitantly with nilutamide.1
Since nilutamide may cause an intolerance to alcohol (reported in 5% of patients) resulting in facial flushes, malaise and hypotension, it is recommended that patients who experience this reaction avoid alcoholic beverages while taking nilutamide.1
Nilutamide is a nonsteroidal antiandrogen2, 5, 9, 15, 18 that is structurally and pharmacologically related to bicalutamide and flutamide.4, 11, 12, 17, 18
Nilutamide is a pure antiandrogen, possessing no intrinsic hormonal activity;2 the antiandrogenic mechanism of action of the drug is via androgen-receptor antagonism.2 Nilutamide inhibits the action of androgens by competitively blocking nuclear androgen receptors in target tissues such as the prostate, seminal vesicles, and adrenal cortex; blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis.2, 10, 11, 12, 13, 14 Nilutamide is a selective antiandrogen with no estrogenic, antiestrogenic, progestational, antiprogestational, or adrenocortical activity in various animal models.1, 2, 9, 13 The relative binding affinity of nilutamide at the androgen receptor is less than that of bicalutamide, but similar to that of hydroxyflutamide, the active metabolite of flutamide.2, 4
Common pharmacologic therapies for prostate cancer (i.e., gonadotropin-releasing hormone [GnRH] analogs, nonsteroidal antiandrogens) when used as monotherapy initially result in increased serum testosterone concentrations, which may limit the effects of the drugs.2, 3, 5, 7, 11, 16, 19, 20, 27, 31 Androgen receptors in the hypothalamus are blocked by nilutamide, which disrupts the inhibitory feedback of testosterone on luteinizing hormone (LH) release, resulting in a temporary increase in secretion of LH; the increase in LH stimulates an increase in the production of testosterone.2, 4, 11, 13, 19, 23, 31 As GnRH analogs have potent GnRH agonist properties, testicular steroidogenesis continues during the first few weeks after initiating therapy.2, 3, 5, 7, 16, 20, 30 However, the combination of orchiectomy or GnRH analog therapy to suppress testicular androgen production and an antiandrogen to block response of remaining adrenal androgens provides maximal androgen blockade.1, 3, 5, 7, 11, 23 Concomitant administration of antiandrogens such as nilutamide in patients initiating therapy with a GnRH analog can inhibit initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) that may occur during the first month of GnRH analog therapy.2, 16, 20, 21
Following multiple doses of 150 mg nilutamide twice daily, steady state is attained in most patients within 2-4 weeks.1 After multiple doses, the AUC was shown to be 110% higher than the AUC obtained from a single 150 mg dose, indicating that with multiple doses, metabolic enzyme inhibition may occur.1 Based on blood, urine, and fecal samples in patients with metastatic prostate cancer, nilutamide has been shown to be rapidly and completely absorbed.1 Nilutamide moderately binds to plasma proteins, and exhibits low binding to erythrocytes.1 Studies indicate that nilutamide does not exhibit nonlinear pharmacokinetics.1 Nilutamide undergoes extensive metabolism in the liver and lungs by CYP isoenzymes, with less than 2% of radiolabeled drug excreted unchanged in the urine after 5 days.1 Five metabolites of nilutamide have been isolated from human urine; however, the pharmacokinetics and pharmacodynamics of these metabolites have not been fully investigated.1 Following oral administration of a single 150 mg radiolabeled dose of nilutamide, 62% of the dose is eliminated in the urine during the first 5 days; however, excretion of radioactivity in the urine likely extends beyond this period.1 After 4-5 days, 1.4%-7% of the nilutamide dose is eliminated in the feces.1 The mean elimination half-life of nilutamide based on a single dose of 100-300 mg ranged from 38-59.1 hours, with most values ranging from 41-49 hours; however, the half-life of one metabolite of nilutamide ranges from 59-126 hours.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 150 mg |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions June 19, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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21. Kuhn JM, Billebaud T, Navratil H et al. Prevention of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med . 1989; 321:413-8. [PubMed 2503723]
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