Anandron (Nilutamide)

ANANDRON®

Hoechst Marion Roussel

Nilutamide

Nonsteroidal Antiandrogen

Action And Clinical Pharmacology: Nilutamide is a pure, nonsteroidal antiandrogen which blocks androgens binding at receptor target cells. Nilutamide is specific and does not bind to any other steroidal receptors; therefore, it does not have any other hormonal or antihormonal activity.

Nilutamide demonstrates potent antiandrogenic effects by inhibiting androgen uptake and/or inhibiting nuclear binding of androgen in target tissues. In adult male rats, ventral prostate and seminal vesicle weights were markedly reduced by daily administration of nilutamide.

Androgen-sensitive prostatic carcinoma cells respond to treatment that counteracts the effect of androgen and/or removes the source of androgen e.g., castration. Combined with castration, nilutamide exerts a total peripheral antiandrogenic activity by antagonizing the action of androgens of adrenal origin which otherwise may maintain the proliferation of prostatic cancer cells.

Nilutamide also inhibits the consequences of the initial rise of testosterone plasma levels observed after treatment with LHRH agonists.

Clinical studies with nilutamide have demonstrated improvement in metastatic bone pain, diminished consumption of analgesics, regression of the cancer together with reduced rate of objective progression and higher survival actuarial rate of patients with metastatic prostate cancer.

Nilutamide is rapidly and completely absorbed as indicated by the low level of fecal radioactivity measured after administration of radiolabeled nilutamide. Unchanged nilutamide represents the major active compound. In patients, nilutamide has a long half-life of 56 hours (range from 23 to 87 hours). Nilutamide is 84% bound to plasma proteins. The plasma concentrations are dose-related and steady-state levels are reached approximately 2 weeks after initiation of treatment. No evidence of accumulation has been demonstrated.

Nilutamide is mainly excreted in the urine as metabolites. Using radiolabeled nilutamide, unchanged drug accounts for only 3% of recovered urinary radioactivity. Fecal excretion accounts for 1.4 to 7% of the total administered dose after 4 to 5 days. The major metabolic pathway is by reduction of the nitro group and the amino derivative of nilutamide represents the major metabolite. Among the metabolites of nilutamide only the hydroxymethylnitro derivative shows some androgen receptor binding affinity.

Indications And Clinical Uses: In the treatment of metastatic prostatic carcinoma (Stage D2) in conjunction with surgical castration.

Contra-Indications: Patients with known hypersensitivity to the drug or to any constituents of the drug product and in patients with severe hepatic dysfunction or with severe respiratory insufficiency.

Nilutamide is contraindicated in women and children.

Manufacturers’ Warnings In Clinical States: The hepatic and respiratory state of the patient should be evaluated and the necessity to report any respiratory symptoms as soon as they appear should be emphasized.

Cases of interstitial lung disease have been reported with the use of nilutamide. If dyspnea or worsening of dyspnea occurs, treatment should be interrupted and a chest x-ray performed immediately. If interstitial pneumopathy is diagnosed, nilutamide must be discontinued and corticosteroid treatment may be considered.

Cases of hepatic dysfunction have been reported with the use of nilutamide. If clinical symptoms give rise to a suspicion of liver dysfunction, transaminases should be measured. If an increase in serum transaminases above 3 times the upper limit of normal laboratory range is shown, treatment must be interrupted.

Precautions: Information for the Patient: Patients should be informed that they should not interrupt their dosing or stop taking nilutamide without consulting their physician(s).

Occupational Hazards: Where patients are participating in activities such as driving an automobile or operating machinery, attention should be drawn to possible visual disturbances mainly due to an increase in adaptation time when passing from a well lit area to a more dimly lit area. These disturbances, should they occur, can decrease even if treatment is continued and can be ameliorated with the use of sunglasses.

Patients should be informed about signs/symptoms suggestive of liver dysfunction (e.g., right upper quadrant tenderness, dark urine, persistent anorexia, nausea, vomiting, jaundice, pruritus or unexplained flu-like symptoms) and be advised to contact their physician should these occur.

Patients administered nilutamide should be warned against consuming alcohol because of a possible disulfiram-like reaction.

Drug Interactions: Nilutamide, apparently through an effect on certain oxidative microsomal enzymes, may reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, chlordiazepoxide, lidocaine, diazepam and theophylline, thereby delaying elimination and increasing blood levels of these drugs. Benzodiazepines that are not oxidized by the hepatic system do not exhibit this effect.

Dosage of the drugs mentioned above, and other similarly metabolized drugs, may require adjustment when starting or stopping concomitantly administered nilutamide, to maintain safe optimum therapeutic blood levels.

In case of associated treatment with warfarin-type anticoagulants, close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary.

Alcohol intolerance (disulfiram-like reaction) may occur if alcohol is consumed during treatment with nilutamide.

Specific Patient Populations: In an uncontrolled pilot study conducted in a Japanese population, interstitial pneumonitis was reported and was considered possibly or probably related to nilutamide in 6 out of 47 patients (12.8%). This incidence figure is higher than the incidence of interstitial pneumonitis available from the international database of placebo-controlled trials in orchiectomized patients (1.1%; see Adverse Effects). In concurrent pharmacokinetics/metabolism investigations in Japanese vs Caucasian patients, no differences in the results could account for the higher incidence of this event in this race. The incidence rate of raised transaminases in the Japanese study was 19%. Special care should be observed when treating Asian patients.

Adverse Reactions: Clinical Trials: Adverse Drug Reactions: Table I lists the possibly or probably drug-related adverse events (adverse reactions) most frequently reported during placebo-controlled clinical trials of nilutamide in conjunction with surgical castration. Hot flushes, decreased libido and impotence are known to occur with surgical castration.

Adverse Events Irrespective of Relationship with Nilutamide: Other adverse events reported overall in clinical trials (of which most occurred with similar frequencies in patients receiving placebo), others known to commonly occur in elderly patients or expected in patients with metastatic prostate cancer included:

Cardiovascular: cerebrovascular accident (1.4%), heart failure (1.0%). Rare cases of tachycardia.

Digestive: constipation (2.6%), gastrointestinal disorder (2.0%). Rare cases of diarrhea.

Metabolic and Nutritional: peripheral edema (1.5%).

Nervous System: headache (2.6%), depression (1.1%), insomnia (1.1%). Rare cases of drowsiness and anxiety.

Skin and Appendages: pruritus (1.1%). Rare cases of maculopapular rash and hirsutism.

Special Senses: rare cases of dazzle and dry mouth.

Urogenital: urinary tract infection (1.3%).

No causal relationship of these experiences with drug treatment has been established.

Post-Marketing Surveillance: The adverse events which have been spontaneously reported worldwide further to marketing of nilutamide and which are considered possibly or probably related to the drug (adverse reactions) include the following: interstitial pneumonitis (most of the cases showed a favorable outcome after treatment discontinuation, however, there have been reports of fatality), hepatocellular or mixed liver injury, and unspecified vision disorders. Isolated cases of angina pectoris, anxiety dyspnea palpitation, cold extremities, dizziness, headache, gynecomastia, maculopapular rash, urticaria, vomiting and weight increase have been reported.

Aplastic anemia (including 1 fatality) has been reported rarely in patients treated with nilutamide but no specific relationship to the drug product has been ascertained.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: At the dose of 900 mg (3 to 6 times the recommended daily dose), nilutamide caused malaise, dizziness, nausea and vomiting which disappeared upon discontinuation of treatment.

The effects of ingestion of a very high dose of nilutamide have been described in 1 case report. A 79-year-old man was admitted 2 hours after the ingestion of 13 g of nilutamide (170 mg/kg or 43 times the therapeutic dose). He had been receiving nilutamide 300 mg/day for 2 weeks. On admission, he underwent gastric lavage immediately, followed by administration of a 20 g oral dose of activated charcoal. Clinical and biological parameters were monitored. There were no changes in the biological parameters as compared to the pre-treatment values either early post ingestion or upon control on days 4, 9 and 30. The clinical manifestations were limited to moderate vomiting and diarrhea during the first 12 hours post ingestion and the patient recovered. Plasma and serum concentrations were measured. The initial level reached 6 times the usual therapeutic range of 4.4 to 8.5 mg/L. Levels 3.5 times greater than the normal range were measured 72 hours post-ingestion.

The ingested dose (170 mg/kg) is close to the lethal dose in animals, the oral LD50 being 215 mg/kg (180 to 240) in mice and 195 mg/kg (160 to 230) in rats. However, the extent of absorption was probably limited by early therapeutic intervention. The lethal dose in man has not been established.

Dosage And Administration: Treatment with nilutamide should be initiated immediately after surgical castration.

Initial Dosage: 300 mg once daily for the first month of treatment. Maintenance treatment may be started earlier should intolerance occur.

Maintenance Dosage: 150 mg once daily.

Nilutamide should be taken before breakfast, until more information is available.

Discontinuation of nilutamide should be considered once objective evidence of disease progression is noted.

Availability And Storage: 50 mg: Each biconvex, white tablet about 7 mm in diameter, engraved “ANANDRON” on one side and the strength “50” on the other, contains: nilutamide 50 mg. Nonmedicinal ingredients: lactose, magnesium stearate, maize starch, povidone, sodium docusate and talc. Lactose: 30 mg. Bottles of 90.

100 mg: Each biconvex, white tablet about 9 mm in diameter, scored, engraved “ANANDRON” on one side and the strength “100” on the other, contains: nilutamide 100 mg. Nonmedicinal ingredients: lactose, magnesium stearate, maize starch, povidone, sodium docusate and talc. Lactose: 60 mg. Bottles of 90.

Store at room temperature and protect from light. (Shown in Product Recognition Section)

ANANDRON® Hoechst Marion Roussel Nilutamide Nonsteroidal Antiandrogen

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