Nilandron Information
Nilandron (Nilutamide) Description
Nilandron (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 CHFNO.
It is freely soluble in ethyl acetate, acetone, chloroform, ethyl alcohol, dichloromethane, and methanol. It is slightly soluble in water [
Each Nilandron (Nilutamide) tablet contains 150 mg of nilutamide. Other ingredients in Nilandron (Nilutamide) tablets are corn starch, lactose, povidone, docusate sodium, magnesium stearate, and talc.
Nilandron (Nilutamide) Clinical Pharmacology
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 (Nilutamide) , 232 treated with orchiectomy and placebo), the Nilandron (Nilutamide) group showed a statistically significant benefit in time to progression and time to death. The results are summarized below.
Nilandron (Nilutamide) Contraindications
Nilandron (Nilutamide) tablets are contraindicated:
Nilandron (Nilutamide) Warnings
Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Nilandron (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 Nilandron (Nilutamide) patients in controlled clinical trials.
Serum transaminase levels should be measured prior to starting treatment with Nilandron (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, Nilandron (Nilutamide) should be immediately discontinued with close followup of liver function tests until resolution.
Nilandron (Nilutamide) Precautions
Patients should be informed that Nilandron (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 Nilandron (Nilutamide) 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 (Nilutamide) , 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 (Nilutamide) .
In clinical trials, 13% to 57% of patients receiving Nilandron (Nilutamide) 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.
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.
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) . 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).
Administration of Nilandron (Nilutamide) 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. 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.
Nilandron (Nilutamide) Adverse Reactions
The following adverse experiences were reported during a multicenter clinical trial comparing Nilandron (Nilutamide) + surgical castration versus placebo + surgical castration. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilandron (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 Nilandron (Nilutamide) group and 81% (188/232) for the placebo group.
The following adverse experiences were reported during a multicenter clinical trial comparing Nilandron (Nilutamide) + leuprolide versus placebo + leuprolide. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilandron (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 Nilandron (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 (
In addition, the following adverse experiences were reported in 2 to 5% of patients treated with Nilandron (Nilutamide) in combination with leuprolide or orchiectomy.
Nilandron (Nilutamide) 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.
Nilandron (Nilutamide) Dosage And Administration
The recommended dosage is 300 mg once a day for 30 days, followed thereafter by 150 mg once a day. Nilandron (Nilutamide) tablets can be taken with or without food.
Nilandron (Nilutamide) How Supplied
Nilandron (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 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.
Nilandron (Nilutamide)
Nilandron (Nilutamide) Principal Display Panel - Mg/ Tablet Box
