Nilutamide (Page 2 of 3)

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 Nilutamide 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 Nilutamide Tablets 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 Nilutamide Tablets, 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 Nilutamide Tablets.

In clinical trials, 13% to 57% of patients receiving Nilutamide Tablets 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 to 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 Tablets. 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 to 2 times human therapeutic AUC exposures).

Pregnancy

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 Nilutamide Tablets 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 to 2 times human AUC exposure) for 1 month produced 100% mortality. Administration of 20 and 30 mg/kg/day nilutamide (1/2 to 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 to 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 to 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.

ADVERSE REACTIONS

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.

Adverse Experience

Nilutamide

Tablets +

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 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.

Adverse Experience

Nilutamide
Tablets +

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 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.

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