Label: NILANDRON- nilutamide tablet

  • NDC Code(s): 24987-111-14
  • Packager: Covis Pharmaceuticals, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated 06/14

If you are a consumer or patient please visit this version.

  • DESCRIPTION

    NILANDRON® 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:

    chemical structure

    Nilutamide is a microcrystalline, white to practically white powder with a molecular weight of 317.25.

    Its molecular formula is C12H10F3N3O4.

    It is freely soluble in ethyl acetate, acetone, chloroform, ethyl alcohol, dichloromethane, and methanol. It is slightly soluble in water [<0.1% W/V at 25°C (77°F)]. It melts between 153°C and 156°C (307.4°F and 312.8°F).

    Each NILANDRON tablet contains 150 mg of nilutamide. Other ingredients in NILANDRON tablets are corn starch, lactose, povidone, docusate sodium, magnesium stearate, and talc.

    Close
  • CLINICAL 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.

    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.

    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%

    Close
  • INDICATIONS AND USAGE

    Metastatic Prostate Cancer

    NILANDRON tablets are indicated for use in combination with surgical castration for the treatment of metastatic prostate cancer (Stage D2).

    For maximum benefit, NILANDRON treatment must begin on the same day as or on the day after surgical castration.

    Close
  • CONTRAINDICATIONS

    NILANDRON 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.
    Close
  • WARNINGS

    Interstitial Pneumonitis

    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 NILANDRON, and most reversed with discontinuation of therapy. A routine chest X-ray should be performed prior to initiating treatment with NILANDRON. 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 NILANDRON. 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.

    Close
  • PRECAUTIONS

    General

    Antiandrogen Withdrawal Syndrome

    Patients whose disease progresses while being treated with an antiandrogen may experience clinical improvement with discontinuation of the antiandrogen.

    Information For Patients

    Patients should be informed that NILANDRON tablets should be started on the day of, or on the day after, surgical castration. They should also be informed that they should not interrupt their dosing of NILANDRON or stop taking this medication without consulting their physician.

    Because of the possibility of interstitial pneumonitis, patients should also be told to report immediately any dyspnea or aggravation of pre-existing dyspnea.

    Because of the possibility of hepatitis, patients should be told to consult with their physician should nausea, vomiting, abdominal pain, or jaundice occur.

    Because of the possibility of an intolerance to alcohol (facial flushes, malaise, hypotension) following ingestion of NILANDRON, it is recommended that intake of alcoholic beverages be avoided by patients who experience this reaction. This effect has been reported in about 5% of patients treated with NILANDRON.

    In clinical trials, 13% to 57% of patients receiving NILANDRON reported 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.

    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.

    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 NILANDRON. 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).

    Pregnancy

    Pregnancy Category 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.

    Pediatric Use

    Safety and effectiveness in pediatric patients have not been determined.

    Animal Pharmacology and Toxicology

    Administration of NILANDRON to beagle dogs resulted in drug-related deaths at dose levels that produce AUC exposures in dogs much lower than the AUC exposures of men receiving the therapeutic doses of 150 and 300 mg/day. Nilutamide-induced toxicity in dogs was cumulative with progressively lower doses producing death when given for longer durations. Nilutamide given to dogs at 60 mg/kg/day (1–2 times human AUC exposure) for 1 month produced 100% mortality. Administration of 20 and 30 mg/kg/day nilutamide (1/2–1 times human AUC exposure) for 6 months resulted in 20% and 70% mortality in treated dogs. Administration to dogs of 3, 6, and 12 mg/kg/day nilutamide (1/10–1/2 human AUC exposure) for 1 year resulted in 8%, 33%, and 50% mortality, respectively. A "no-effect level" for nilutamide-induced mortality in dogs was not identified. Pathology data from the one-year oral toxicity study suggest that the deaths in dogs were secondary to liver toxicity. Marked-to-massive hepatocellular swelling and vacuolization were observed in affected dogs. Liver toxicity in dogs was not consistently associated with elevations of liver enzymes.

    Administration of nilutamide to rats at a dose level of 45 mg/kg/day (AUC exposure in rats 1–2 times human therapeutic AUC exposures) for 18 months increased the incidence of lung pathology (granulomatous inflammation and chronic alveolitis).

    The hepatic and pulmonary adverse effects observed in nilutamide-treated animals and men are similar to effects observed with another nitroaromatic compound, nitrofurantoin. Nilutamide and nitrofurantoin are both metabolized in vitro to nitroanion free-radicals by microsomal NADPH-cytochrome P450 reductase in the lungs and liver of rats and humans.

    Close
  • ADVERSE REACTIONS

    The following adverse experiences were reported during a multicenter clinical trial comparing NILANDRON + surgical castration versus placebo + surgical castration. The most frequently reported (greater than 5%) adverse experiences during treatment with NILANDRON tablets in combination with surgical castration are listed below. For comparison, adverse experiences seen with surgical castration and placebo are also listed.

    Adverse Experience NILANDRON
    +
    surgical
    castration
    (N=225)
    % All
    Placebo
    +
    surgical
    castration
    (N=232)
    % All

    Cardiovascular System

      Hypertension

    5.3

    2.6

    Digestive System

      Nausea

    9.8

    6.0

      Constipation

    7.1

    3.9

    Endocrine System

      Hot flushes

    28.4

    22.4

    Metabolic and Nutritional System

      Increased AST

    8.0

    3.9

      Increased ALT

    7.6

    4.3

    Nervous System

      Dizziness

    7.1

    3.4

    Respiratory System

      Dyspnea

    6.2

    7.3

    Special Senses

      Impaired adaptation to dark

    12.9

    1.3

      Abnormal vision

    6.7

    1.7

    Urogenital System

      Urinary tract infection

    8.0

    9.1

    The overall incidence 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%).

    Close
  • 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.

    Close
  • DOSAGE AND ADMINISTRATION

    The recommended dosage is 300 mg once a day for 30 days, followed thereafter by 150 mg once a day. NILANDRON tablets can be taken with or without food.

    Close
  • HOW SUPPLIED

    NILANDRON 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.

    Store at 25°C (77°F); excursions permitted between 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.

    Revised May 2013

    Distributed by
    Covis Pharmaceuticals, Inc.
    Cary, NC 27511

    Country of Origin: France

    © 2013 Covis Pharmaceuticals, Inc. All rights reserved.

    Close
  • PRINCIPAL DISPLAY PANEL

    NDC 24987-111-14

    Nilandron®         150 mg
    nilutamide
    Tablets

    30 Tablets

    carton label

    Carton Label

    Close
  • INGREDIENTS AND APPEARANCE
    NILANDRON 
    nilutamide tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:24987-111
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Nilutamide (Nilutamide) Nilutamide 150 mg
    Inactive Ingredients
    Ingredient Name Strength
    STARCH, CORN  
    LACTOSE  
    POVIDONES  
    DOCUSATE SODIUM  
    MAGNESIUM STEARATE  
    TALC  
    Product Characteristics
    Color WHITE Score no score
    Shape ROUND (Cylindrical) Size 10mm
    Flavor Imprint Code 168D
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:24987-111-14 1 in 1 CARTON
    1 30 in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020169 07/15/2013
    Labeler - Covis Pharmaceuticals, Inc. (969968986)
    Close