Nilutamide

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# Black Box Warning

# 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)
- 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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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.

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

# 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.

# Warnings
- 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.
- Nilutamide has no indication for women, and should not be used in this population, particularly for non-serious or non-life threatening conditions.
- 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.
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.
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.
- Body as a Whole: Malaise
- Cardiovascular System: Angina, heart failure, syncope.
- Digestive System: Diarrhea, gastrointestinal disorder, gastrointestinal hemorrhage, melena.
- Metabolic and Nutritional System: Alcohol intolerance, edema, weight loss.
- Musculoskeletal System: Arthritis
- Nervous System: Dry mouth, nervousness, paresthesia.
- Respiratory System: Cough increased, interstitial lung disease, lung disorder, rhinitis.
- Skin and Appendages: Pruritus
- Special Senses: Cataract, photophobia
- Laboratory Values: Haptoglobin increased (2%), leukopenia, alkaline phosphatase increased, BUN increased, creatinine increased, hyperglycemia.

## 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

## 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.

## 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:

## 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 -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 -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 100300 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 (59126 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 AUC012 was 110% higher than the AUC0obtained 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 12 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 12 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.

# 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 25C (77F); excursions permitted between 1530C (5986F). Protect from light.

# Images

## Drug Images

## Package and Label Display Panel

# 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
- Nilandron

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

# Drug Shortage Status

# Price