Nilandron

Generic Name: Nilutamide
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 5,5-Dimethyl-3-(4-nitro-3-[trifluoromethyl)phenyl]-2,4-imidazolidinedione
Molecular Formula: C12H10F3N3O4
CAS Number: 63612-50-0

Warning(s)

  • Interstitial Pneumonitis
  • Interstitial pneumonitis, rarely resulting in hospitalization or death, reported.1 Manifestations generally occurred within the first 3 months of therapy and resolved following discontinuance of the drug.1

  • Immediately discontinue therapy if dyspnea or worsening of preexisting dyspnea occurs.1 9 (See Interstitial Pneumonitis under Cautions.)

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen2 5 9 15 18 structurally and pharmacologically related to bicalutamide and flutamide.4 11 12 17 18

Uses for Nilandron

Prostate Cancer

Adjunct to orchiectomy in the treatment of metastatic prostate cancer involving distant lymph nodes, bone, or visceral organs (stage D2).1 2 3 5 6 7 8 24 30 33

Slideshow: Flashback: FDA Drug Approvals 2013

Slows progression of the disease, relieves bone pain associated with metastatic disease, and improves overall survival rate after long-term therapy (8.5 years).3 5 6 7 9 30

Nilandron Dosage and Administration

General

  • Determine PSA concentrations periodically during therapy to monitor therapeutic response, including successful remission or possible progression of cancer.9 30

  • If PSA concentrations increase substantially and consistently during therapy, evaluate the possibility of clinical progression.29

Administration

Oral Administration

Administer orally once daily without regard to meals.1 9

Dosage

Adults

Prostate Cancer
Oral

300 mg once daily for 30 days, followed by 150 mg given once daily thereafter.1 For maximum benefit, initiate nilutamide on the day of or the day after orchiectomy.1

Duration of therapy depends on the duration of clinical response of the patient.29

Cautions for Nilandron

Contraindications

  • Severe hepatic impairment.1

  • Severe respiratory insufficiency.1

  • Known hypersensitivity to nilutamide or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Interstitial Pneumonitis

Interstitial pneumonitis reported (i.e., progressive exertional dyspnea, cough, chest pain, fever, interstitial or alveolo-interstitial changes on chest radiographs, and pulmonary function tests show a restrictive pattern with decreased carbon monoxide diffusing capacity),1 rarely resulting in hospitalization or death.1 Manifestations generally occurred within the first 3 months of therapy and resolved following discontinuance of the drug.1

Obtain a chest radiograph prior to the initiation of therapy.1 9 Baseline pulmonary function tests also may be considered.1

Immediately discontinue therapy if dyspnea or worsening of preexisting dyspnea occurs; perform tests to determine if respiratory symptoms are drug related.1 9

Hepatic Effects

Severe hepatic injury (i.e., hepatitis, increased serum transaminase concentrations) reported, sometimes resulting in hospitalization and/or rarely death;1 9 generally occurred within the first 3–4 months of therapy.1

Measure serum transaminase concentrations prior to initiation of therapy, at regular intervals during the first 4 months of treatment, and periodically thereafter.1 Immediately measure serum transaminase concentrations if clinical signs or symptoms suggestive of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, or right upper quadrant tenderness) occur.1 Discontinue immediately and closely monitor liver function if jaundice develops or serum ALT concentration is >2 times ULN.1

Use in Women

Safety and efficacy not established in women.1 29

Not intended for use in women, particularly for nonserious or non-life-threatening conditions.1

Hematologic Effects

Isolated cases of aplastic anemia reported, but a causal relationship with nilutamide not established.a

General Precautions

Ocular Effects

Possible difficulty in visual adaptation to changes in light level; delays, ranging from seconds to a few minutes, in adapting to changes from light to dark reported.1 Such effect may not diminish during continued therapy with the drug.1 To minimize this effect, advise patients to wear tinted glasses during exposure to bright light.1

Alcohol Intolerance

Possible alcohol intolerance (e.g., facial flushing, malaise, hypotension); avoid concomitant use.1 32

Specific Populations

Pregnancy

Category C.1 (See Use in Women under Cautions.)

Pediatric Use

Safety and efficacy not established.1 29

Common Adverse Effects

Hypertension, nausea, constipation, hot flushes, increased AST/ALT concentrations, dizziness, impaired adaptation to dark, abnormal vision.a

Interactions for Nilandron

Inhibits the activity of CYP isoenzymes; may reduce the metabolism of drugs metabolized by these systems.a

Specific Drugs

Drug

Interaction

Comment

Alcohol

Possible alcohol intolerance (e.g., facial flushing, malaise, hypotension)1 32

Avoid concomitant use1 32

Phenytoin

Increased plasma phenytoin concentrationsa

Monitor for phenytoin toxicity and adjust dosages as neededa

Theophylline

Increased plasma theophylline concentrationsa

Monitor for theophylline toxicity and adjust dosages as neededa

Vitamin K antagonists (e.g., warfarin sodium)

Increased plasma vitamin K antagonist concentrationsa

Monitor PT and adjust dosages as neededa

Nilandron Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed to yield high and persistent plasma concentrations.a

Distribution

Plasma Protein Binding

Moderately bound to plasma proteins; minimally bound to erythrocytes.a

Elimination

Metabolism

Extensively metabolized in the liver and lungs by CYP isoenzymes to mainly inactive metabolites.a

Elimination Route

Eliminated almost exclusively by hepatic metabolism.b Excreted principally in urine as metabolites; <2% is excreted unchanged in urine.a

Half-life

Mean elimination half-life is approximately 30–59 hours following a single 100–300-mg dose.a

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Protect from light.1

Actions

  • Pure antiandrogen, possesses no intrinsic estrogenic, antiestrogenic, progestational, antiprogestational, or adrenocortical activity.1 2 9 13

  • Competitively blocks nuclear androgen receptors in target tissues (e.g., prostate, seminal vesicles, adrenal cortex).2 10 11 12 13 14

  • Blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis.2 10 11 12 13 14

  • The relative binding affinity of nilutamide at androgen receptors is less than that of bicalutamide, but similar to that of hydroxyflutamide, the active metabolite of flutamide.2 4

Advice to Patients

  • Risk of interstitial pneumonitis.1 Importance of immediately notifying clinicians of dyspnea or worsening of preexisting dyspnea.1

  • Risk of hepatic toxicity.1 Importance of notifying clinicians if symptoms of nausea, vomiting, abdominal pain, or jaundice occur.1

  • Risk of delay in visually adapting to changes from light to dark.1 Importance of wearing tinted glasses during exposure to bright light and of exercising caution when driving at night or through tunnels.1

  • Risk of alcohol intolerance (e.g., facial flushing, malaise, hypotension).1 32 Importance of avoiding alcohol consumption if such intolerance occurs.1 32

  • Importance of taking only as prescribed; do not interrupt or discontinue therapy unless otherwise instructed by a clinician.a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Nilutamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

150 mg

Nilandron (with povidone)

Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nilandron 150MG Tablets (SANOFI-AVENTIS U.S.): 30/$511.79 or 90/$1,500.83

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Aventis Pharmaceuticals Inc. Nilandron (nilutamide) tablets prescribing information. Kansas City, MO; 2000 Oct.

2. Harris MG, Coleman SG, Faulds D et al. Nilutamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging. 1993; 3:9-25. [PubMed 8453188]

3. Bertagna C, De Gery A, Hucher M et al. Efficacy of the combination of nilutamide plus orchidectomy in patients with mestatatic prostatic cancer. A meta-analysis of seven randomized double-blind trials (1056 patients). Br J Urol. 1994; 73:396-402. [PubMed 8199827]

4. Dole EJ, Holdsworth MT. Nilutamide: an anitandrogen for the treatment of prostate cancer. Ann Pharmacother. 1997; 31: 65-75.

5. Janknegt RA, Abbou CC, Bartoletti R et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol. 1993; 149: 77-83. [IDIS 397019] [PubMed 7678043]

6. Dijkman GA, de Moral PF, Debruyne FMJ et al. Improved subjective responses to orchiectomy plus nilutamide (anandron) in comparison to orchiectomy plus placebo in metastatic prostate cancer. Eur Urol. 1995; 27:196-201. [PubMed 7601182]

7. Beland G, Elhilali M, Fradet Y et al. A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma. Cancer. 1990; 66: 1074-9. [IDIS 271667] [PubMed 2203517]

8. Prostate Cancer Trialists’ Colliaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet. 1995; 346:265-9. [IDIS 352509] [PubMed 7630245]

9. Hoechst Marion Roussel. Nilandron (nilutamide) tablets product monograph. Kansas City, MO: 1996.

10. Kennealey GT, Furr BJA. Use of the nonsteroidal anti-androgen Casodex in advanced prostatic carcinoma. Urol Clin North Am. 1991; 18:99-110. [PubMed 1992575]

11. Daneshgari F, Crawford ED. Endocrine therapy of advanced carcinoma of the prostate. Cancer. 1993; 71(Suppl):1089-97. [IDIS 313146] [PubMed 8428333]

12. Denis L. Prostate cancer: primary hormonal treatment. Cancer. 1993; 71(Suppl):1050-8. [IDIS 313142] [PubMed 8428327]

13. McLeod DG. Antiandrogenic drugs. Cancer. 1993; 71(Suppl):1046-9. [IDIS 313141] [PubMed 8428326]

14. Geller J. Basis for hormonal management of advanced prostate cancer. Cancer. 1993; 71(Suppl):1039-45. [IDIS 313140] [PubMed 7679038]

15. Gomella LG, Ismail M, Nathan FE. Antiandrogen withdrawal syndrome with nilutamide. J Urol. 1997; 157:1366. [IDIS 383663] [PubMed 9120950]

16. Mahler C. Is disease flare a problem? Cancer. 1993; 72(Suppl):3799-802. (IDIS 323226)

17. Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J Health-Syst Pharm. 1996; 53:381-96. [IDIS 360612] [PubMed 8673658]

18. McLeod DG, Kolvenbag GJCM. Defining role of antiandrogens in the treatment of prostate cancer. Urology. 1996; 47(Suppl 1A):85-9. [PubMed 8560682]

19. Brogden RN, Clissold SP. Flutamide: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer. Drugs. 1989; 38:185-203. [PubMed 2670515]

20. Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989; 321: 419-24. [IDIS 258377] [PubMed 2503724]

21. Kuhn JM, Billebaud T, Navratil H et al. Prevention of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med. 1989; 321:413-8. [IDIS 258376] [PubMed 2503723]

22. Smith PH. Deferred therapy in patients with advanced disease. Cancer. 1993; 71(Suppl):1074-7. [IDIS 313144] [PubMed 8428330]

23. Santen RJ. Endocrine treatment of prostate cancer. J Clin Endocrinol Metab. 1992; 75:685-9. [IDIS 302863] [PubMed 1517354]

24. Prostate cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

25. Hoechst Marion Roussel, Kansas City, MO: Personal communication.

26. Tyrrell CJ, Altwein JE, Klippel F et al et al. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol. 1991; 146:1321-6. [IDIS 290344] [PubMed 1834864]

27. Soloway MS, Matzkin H. Antiandrogenic agents as monotherapy in advanced prostatic carcinoma. Cancer. 1993; 71(Suppl):1083-8. [IDIS 313145] [PubMed 8428332]

28. Vogelzang NJ, Kennealey GT. Recent developments in endocrine treatment of prostate cancer. Cancer. 1992; 70:966-76. [IDIS 300575] [PubMed 1386283]

29. Hoechst Marion Roussel, Kansas City, MO: Personal communication.

30. Dijkman GA, Janknegt RA, De Reijke TM et al. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997; 158: 160-3. [IDIS 388943] [PubMed 9186345]

31. Decensi AU, Boccardo F, Guarneri D et al. Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated patients with metastatic carcinoma of the prostate. J Urol. 1991; 146: 377-81. [PubMed 1856935]

32. Kirschenbaum A. Management of hormonal treatment effects. Cancer. 1995; 75:1983-6.

33. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

a. Aventis Pharmaceuticals Inc. Nilandron (nilutamide) tablets prescribing information. Kansas City, MO; 2004 Apr.

b. Creaven PJ, Pendyala L, Tremblay D. Pharmacokinetics and metabolism of nilutamide. Urology. 1991; 37(2 Suppl):13-9. [PubMed 1992598]

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