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 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 Nilutamide Tablet contains 150 mg of nilutamide. The inactive ingredients in Nilutamide Tablets include: calcium stearate, docusate sodium, lactose, povidone, corn starch, and talc.

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

Metastatic Prostate Cancer

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

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

Nilutamide Tablets are contraindicated:

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in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment)

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in patients with severe respiratory insufficiency

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in patients with hypersensitivity to nilutamide or any component of this preparation.

Clinical Trial Experience

The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide Tablets + 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 Tablets group and 81% (188/232) for the placebo group.

The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide Tablets + 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 Tablets 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 Tablets in combination with surgical castration and in seven patients (3%) receiving Nilutamide Tablets in combination with leuprolide and one patient receiving placebo in combination with leuprolide. Overall, it has been reported in 2% of patients receiving Nilutamide Tablets. 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 Tablets 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%).

To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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.

Nilutamide Tablets, 150 mg, are supplied in boxes of 30 tablets. Each box contains 3 child-resistant, PVC, aluminum foil-backed blisters of 10 tablets (NDC 62559-173-31). Each round, biconvex, white to off-white tablet is debossed with “ANI” and “173” on one side and plain on the other side.

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

Manufactured by:

ANI Pharmaceuticals, Inc.

Baudette, MN 56623







9625 Rev 07/17

Nilutamide Tablets, 150 mg

NDC 62559-173-31

Rx only

30 (3 x 10) Unit-of-Use Tablets