Nilutamide

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Nilutamide
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Black Box Warning

Warning
See full prescribing information for complete Boxed Warning.
Interstitial Pneumonia: 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, and most reversed with discontinuation of therapy. A routine chest X-ray should be performed prior to initiating treatment with Nilutamide 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 If symptoms occur, Nilutamide should be immediately discontinued until it can be determined if the symptoms are drug related.

Overview

Nilutamide is an antiandrogen that is FDA approved for the treatment of metastatic prostate cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, hot sweats, constipation, nausea, dizziness an abnormal vision.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Metastasic Prostate Cancer
  • Dosage: 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Nilutamide in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilutamide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Nilutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Nilutamide in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilutamide in pediatric patients.

Contraindications

Nilutamide tablets are contraindicated:

Warnings

Warning
See full prescribing information for complete Boxed Warning.
Interstitial Pneumonia: 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, and most reversed with discontinuation of therapy. A routine chest X-ray should be performed prior to initiating treatment with Nilutamide 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 If symptoms occur, Nilutamide 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. 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 patients in controlled clinical trials.
  • Serum transaminase levels should be measured prior to starting treatment with Nilutamide 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 should be immediately discontinued with close followup of liver function tests until resolution.
Use in Women
  • Nilutamide 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 Nilutamide could not be ascertained.

Adverse Reactions

Clinical Trials Experience

he following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide + 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.

Nilutamide AR1.png

The overall incidence of adverse experiences was 86% (194/225) for the Nilutamide group and 81% (188/232) for the placebo group.

The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide + 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.

Nilutamide AR2.png

The overall incidence of adverse experiences is 99.5% (208/209) for the Nilutamide 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 in combination with surgical castration and in seven patients (3%) receiving Nilutamide in combination with leuprolide and one patient receiving placebo in combination with leuprolide. Overall, it has been reported in 2% of patients receiving Nilutamide 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 in combination with leuprolide or orchiectomy.

Postmarketing Experience

There is limited information regarding Nilutamide Postmarketing Experience in the drug label.

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nilutamide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Nilutamide during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Nilutamide in women who are nursing.

Pediatric Use

Safety and effectiveness in pediatric patients have not been determined.

Geriatic Use

There is no FDA guidance on the use of Nilutamide in geriatric settings.

Gender

There is no FDA guidance on the use of Nilutamide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Nilutamide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Nilutamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Nilutamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Nilutamide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Nilutamide in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Nilutamide Administration in the drug label.

Monitoring

There is limited information regarding Nilutamide Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Nilutamide and IV administrations.

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.

Pharmacology

Nilutamide
Nilutamide Structure.png
Clinical data
Trade namesNilutamide
AHFS/Drugs.comMonograph
MedlinePlusa697044
Routes of
administration
oral
ATC code
Legal status
Legal status
  • pr
Pharmacokinetic data
Elimination half-life38.0 to 59.1 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC12H10F3N3O4
Molar mass317.221 g/mol
3D model (JSmol)
  (verify)

Mechanism of Action

Structure

  • Nilutamide tablets contain nilutamide, a nonsteroidal, orally active antiandrogen having the chemical name 5,5-dimethyl-3-4-nitro-3-(trifluoromethyl)phenyl-2,4-imidazolidinedione with the following structural formula:
Nilutamide Structure.png

Pharmacodynamics

There is limited information regarding Nilutamide Pharmacodynamics in the drug label.

Pharmacokinetics

Absorption

  • Analysis of blood, urine, and feces samples following a single oral 150-mg dose of [14C]-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 14C-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 [14C]-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 AUC0–12 was 110% higher than the AUC0–∞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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

  • Administration of nilutamide to rats for 18 months at doses of 0, 5, 15, or 45 mg/kg/day produced benign Leydig cell tumors in 35% of the high-dose male rats (AUC exposures in high-dose rats were approximately 1–2 times human AUC exposures with therapeutic doses). The increased incidence of Leydig cell tumors is secondary to elevated luteinizing hormone (LH) concentrations resulting from loss of feedback inhibition at the pituitary. Elevated LH and testosterone concentrations are not observed in castrated men receiving Nilutamide. Nilutamide had no effect on the incidence, size, or time of onset of any spontaneous tumor in rats.
  • Nilutamide displayed no mutagenic effects in a variety of in vitro and in vivo tests (Ames test, mouse micronucleus test, and two chromosomal aberration tests).
  • In reproduction studies in rats, nilutamide had no effect on the reproductive function of males and females, and no lethal, teratogenic, or growth-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).

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 Nilutamide 232 treated with orchiectomy and placebo), the Nilutamide group showed a statistically significant benefit in time to progression and time to death. The results are summarized below.
Nilutamide CS.png

How Supplied

Nilutamide 150 mg tablets are supplied in boxes of 30 tablets. Each box contains 3 child-resistant, PVC, aluminum foil-backed blisters of 10 tablets (NDC 24987-111-14). Each white, biconvex, cylindrical (10 mm in diameter) tablet has a triangular logo on one side and an internal reference number (168D) on the other.

Storage

Store at 25°C (77°F); excursions permitted between 15–30°C (59–86°F). Protect from light.

Images

Drug Images

Package and Label Display Panel

Nilutamide Package.png
Nilutamide Appearance.png

Patient Counseling Information

There is limited information regarding Nilutamide Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Nilutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Nilutamide Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


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