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:

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.

Last updated on RxList: 10/14/2008

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.

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.

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 0088-1111-14). 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 June 2006. Sanofi-aventis U.S. LLC Bridgewater, NJ 08807. Country of Origin: France. FDA Rev date: 7/26/2004

Last updated on RxList: 10/14/2008

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.

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.

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%).

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.

Last updated on RxList: 10/14/2008

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.

General

Antiandrogen Withdrawal Syndrome

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

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.

Last updated on RxList: 10/14/2008

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.

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.

Last updated on RxList: 10/14/2008

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 x 50 mg) twice a day, steady state was reached within 2 to 4 weeks for most patients, and mean steady state AUC_0-12 was 110% higher than the AUC_{0- ∞} 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.

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.

Last updated on RxList: 10/14/2008

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.

Last updated on RxList: 10/14/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NILUTAMIDE - ORAL

(nye-LOO-tuh-mide)

COMMON BRAND NAME(S): Nilandron

WARNING: Rarely, nilutamide has caused severe (sometimes fatal) lung problems (interstitial pneumonitis). Immediately tell your doctor if you develop symptoms of lung problems (cough, shortness of breath with regular activity, chest pain, fever). Lung problems can happen at any time while you are taking nilutamide, but they occur most often during the first 3 months of treatment. Your doctor will tell you whether to stop or continue nilutamide.

Your doctor may give you a chest X-ray and breathing tests before you start nilutamide.

USES: This medication is used in men along with surgery (removal of the testicles) or other medications to treat prostate cancer. Nilutamide belongs to a class of drugs known as anti-androgens (anti-testosterone). Testosterone, a natural hormone in men, helps prostate cancer to grow and spread. Nilutamide works by blocking the effects of testosterone, thereby slowing the growth and spread of prostate cancer.

HOW TO USE: Take this medication by mouth with or without food, usually once daily or as directed by your doctor. If you are taking nilutamide after surgery, it is usually started on the day of surgery or the morning of the day after. You will start at a higher dose for the first 30 days that you take nilutamide.

Dosage is based on your medical condition and response to therapy. The length of treatment depends on how your body and the cancer respond to nilutamide and other treatments.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. Do not stop any medications for your prostate cancer unless told to do so by your doctor. Stopping your medications could allow the cancer to spread more rapidly.

Inform your doctor if your condition persists or worsens (e.g., urination becomes more difficult, bone pain increases).

SIDE EFFECTS: See also Warning and Precautions sections.

Because nilutamide may be used with other medications, the side effects may be due to either one medicine or the combination of medications. Hot flashes, sweating, dizziness, loss of sexual interest/ability, vision changes (e.g., difficulty seeing when moving into the dark or light, changes in color vision), abdominal pain, body aches, constipation, nausea, sleeping problems, shrinkage of testicles (if they have not been removed), signs of alcohol intolerance (e.g., flushing, tiredness) and loss of body hair may occur. Less common side effects include dry skin, decreased sense of touch, vomiting, and diarrhea. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: chest pain, swelling of feet/ankles/legs.

Tell your doctor immediately if any of these rare but very serious side effects occur: tiredness, weakness, pale skin, bluish fingernails/lips/skin, fast heartbeat at rest, feeling short of breath at rest, signs of infection (e.g., high fever, shaking, chills, cough, persistent sore throat), bloody/black stools, easy bruising/bleeding.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking nilutamide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: serious liver problems, severe breathing problems (e.g., severe emphysema, severe chronic obstructive pulmonary disease-COPD).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: any other lung disease (e.g., asthma), mild liver problems.

This drug may rarely make you dizzy, drowsy, or cause vision changes. Until you know how this medication affects you, use caution while driving, using machinery, or doing any activity that requires alertness or clear vision. You may also develop intolerance to alcohol. Avoid alcoholic beverages while taking this medication.

Rarely, nilutamide has caused severe (sometimes fatal) liver problems. Immediately tell your doctor if you develop symptoms of liver problems (appetite loss, persistent nausea, vomiting, stomach/abdominal pain, severe tiredness, dark urine, yellowing eyes/skin, aching muscles, joint pain). Liver problems can happen at any time while taking nilutamide, but they occur most often during the first 3-4 months of treatment. Your doctor will tell you whether to stop or continue nilutamide. Your doctor will be monitoring your liver function with blood tests while you are taking nilutamide. Keep all medical and laboratory appointments.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially drowsiness.

Nilutamide should not be used in women. Women who are pregnant should avoid touching or accidentally taking this medication. It may harm an unborn baby. Consult your doctor for more information.

It is not known whether this drug passes into breast milk. Women who are breastfeeding should avoid touching or accidentally taking this medication. Consult your doctor for more information.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: testosterone (patch, gel, injection), illegal anabolic steroids, over-the-counter androgens/anabolics/testosterone precursors, DHEA.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting nilutamide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: warfarin, phenytoin, theophylline.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., liver blood tests, blood PSA test) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is within 4 hours of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.