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Eulexin

Generic Name: Flutamide
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide
Molecular Formula: C11H11F3N2O3
CAS Number: 13311-84-7

Warning(s)

  • Hepatotoxicity
  • Severe liver injury (i.e., increased serum transaminase concentrations, jaundice, hepatic encephalopathy, acute hepatic failure) reported, sometimes resulting in hospitalization and/or rarely death; manifestations generally occurred within first 3 months and in some patients, were reversible after discontinuance.1

  • Measure serum transaminase concentrations prior to initiation of therapy, monthly during first 4 months, and periodically thereafter.1

  • Immediately measure serum transaminase (especially ALT) concentrations if manifestations suggestive of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, hyperbilirubinuria, jaundice, right upper quadrant tenderness) occur.1

  • Immediately discontinue if jaundice develops or serum ALT concentration is >2 times ULN; monitor liver function closely until resolves.1

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.1 2 3 5 6 7 9 11 16 19 23 24 25 26 27

Uses for Eulexin

Prostate Cancer

First-line therapy in combination with a luteinizing hormone-releasing hormone (LHRH) analog (e.g., goserelin, leuprolide acetate, triptorelin) for prostate cancer.1 3 5 6 7 20 22 23

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Treatment of locally confined (stage B2 or C)1 20 22 23 and metastatic (stage D2) prostate cancer;1 3 5 6 7 20 should be used in conjunction with an LHRH analog.1 3 5 6 7 20 22 23

Eulexin Dosage and Administration

General

  • In patients with stage B2 or C prostate cancer, initiate flutamide and LHRH analog 8 weeks prior to and continue during radiation therapy.1

  • In patients with stage D2 metastatic prostate cancer, initiate flutamide and LHRH analog concomitantly and continue until disease progression.1

Administration

Oral Administration

Administer orally 3 times daily at 8-hour intervals1 2 3 5 6 7 12 14 17 without regard to meals29 .

Dosage

Adults

Prostate Cancer
Oral

250 mg 3 times daily, at 8-hour intervals.1 2 3 5 6 7 12 14 17 24 25 27 28

Cautions for Eulexin

Contraindications

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

  • Severe hepatic impairment.1

Warnings/Precautions

Warnings

Hepatic Effects

For warnings regarding hepatotoxicity, see Boxed Warning.

Use in Women

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if used in pregnant women.1

Aniline Toxicity

Metabolized in part to 4-nitro-3-fluoro-methylaniline; toxicities associated with aniline exposure (i.e., methemoglobinemia, hemolytic anemia, cholestatic jaundice) reported.1

Monitor methemoglobin concentrations periodically in susceptible patients (e.g., those with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease, smokers).1

Sensitivity Reactions

Photosensitivity

Photosensitivity reactions (i.e., erythema, ulceration, bullous eruptions, epidermal necrolysis) reported.1

General Precautions

Endocrine Effects

Possible gynecomastia.1 27

Laboratory Monitoring

Regularly monitor serum PSA to assess response; if PSA increases, evaluate possible disease progression.1

For patients with objective progression of disease and elevated serum PSA, consider temporarily withdrawing flutamide while continuing LHRH analog.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings.)

Lactation

Not intended for use in women.1

Pediatric Use

Not studied in pediatric patients.1

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment. (See Boxed Warning.)1

Women

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

Common Adverse Effects

Combined therapy with LHRH analog: hot flashes, loss of libido, impotence, diarrhea, nausea, vomiting, gynecomastia.1

Cystitis, rectal bleeding, proctitis, skin rash, hematuria also frequent when flutamide combined with LHRH analog and radiation therapy.1

Interactions for Eulexin

Specific Drugs

Drug

Interaction

Comments

Alcohol

Increased risk of facial flushing31

Avoid alcohol consumption during therapy31

LHRH analog (e.g., goserelin, leuprolide)

Pharmacokinetic interaction unlikely1

Warfarin

Increased PT reported1

Closely monitor PT; adjust anticoagulant dosage as needed1

Eulexin Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration, with peak plasma concentrations of active metabolite (2-hydroxyflutamide) attained within about 2 hours.1 27

Food

Food does not affect bioavailability.1

Special Populations

In patients with chronic renal impairment, there appears to be no correlation between creatinine clearance and maximum plasma concentrations or AUC of flutamide; renal impairment did not affect maximum plasma concentrations or AUC of active metabolite.1

Distribution

Plasma Protein Binding

Flutamide: 94–96%; 2-hydroxyflutamide: 92–94%.1 27

Elimination

Metabolism

Rapidly and extensively metabolized to ≥6 metabolites, including an active α-hydroxylated derivative, 2-hydroxyflutamide.1 27

Elimination Route

Excreted principally in urine and to lesser extent in feces (4.2%) as unchanged drug and metabolites.1

Half-life

2-Hydroxyflutamide: about 6 hours after a single 250-mg dose.1

Special Populations

In patients with renal impairment (Clcr <29 mL/minute), half-life of active metabolite was slightly prolonged; no dosage adjustment necessary in chronic renal impairment.1

In geriatric patients, half-life of active metabolite is about 8 hours after a single 250-mg dose.1

Pharmacokinetics not studied in patients with hepatic impairment, women, or pediatric patients.1

Stability

Storage

Oral

Capsules

2–30°C.1 Protect unit dose packages from excessive moisture.1

Actions

  • A selective antiandrogen with no estrogenic, antiestrogenic, progestational, antiprogestational, antigonadotropic, or adrenocortical activity in various animal models.3

  • Competitively blocks nuclear androgen receptors in target tissues (e.g., prostate, seminal vesicles, adrenal cortex).1 3 8 9 10 11 12 24 25

  • 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.1 3 8 9 10 11 12 24 25

  • Inhibits initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) associated with the first month of LHRH analog therapy.6 10 11 18

Advice to Patients

  • Risk of liver toxicity.1 Importance of adhering to schedule for laboratory monitoring of serum transaminases and reporting signs or symptoms of hepatic toxicity to clinician immediately.1

  • Importance of initiating flutamide concomitantly with LHRH analog and of not interrupting or discontinuing therapy without consulting a clinician.1

  • Risk of facial flushing, particularly if used in conjunction with alcohol.31 Avoidance of alcohol recommended if flushing occurs.31

  • Not intended for use in women.1

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Flutamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

125 mg*

Eulexin (with parabens and povidone;)

Schering

Flutamide Capsules

Barr, Genpharm, Sandoz, Teva

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.

Flutamide 125MG Capsules (PAR): 180/$275.97 or 360/$526.94

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Schering. Eulexin (flutamide) capsules prescribing information. Kenilworth, NJ; 2000 Dec.

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

3. 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.

4. 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.

5. Schellhammer PF, Sharifi R, Block NL et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostatecarcinoma. Cancer. 1996; 78:2164-9. [IDIS 376113] [PubMed 8918410]

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

7. Schellhammer PF, Venner P, Haas GP et al. Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade. J Urol. 1997; 157: 1731-5. [IDIS 385276] [PubMed 9112515]

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

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

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

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, Murphy GP. Overview of phase II trials on combined androgen treatment in patients with metastatic prostate cancer. Cancer. 1993; 72: 3888-3895.

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

14. 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]

15. Blackledge G. Casodexmechanisms of action and opportunities for usage. Cancer. 1993; 72(Suppl):3830-3. [IDIS 323230] [PubMed 7504578]

16. 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]

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

18. Chrisp P, Goa KL. Goserelin: a review of its pharmacodynamic and pharmacokinetic properties, and clinical use in sex hormone-related conditions. Drugs. 1991; 41:254-88. [PubMed 1709853]

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

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

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

22. Anon. Drugs of choice for cancer. Treat Guide Med Lett. 2003; 1:41-52.

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

24. Erlichman C, Loprinzi CL. Hormonal therapies. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia, PA: J. B. Lippincott; 1997:395-405.

25. Wilson JD. Androgens. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:1441-57.

26. McLeod DG, Kolvenbag GJ. Defining the role of antiadnrogens in the treatment of prostate cancer. Urology. 1996: 47; 85-9.

27. Goldspiel BR, Kohler DR. Flutamide: an antiandrogen for advanced prostate cancer. DICP. 1990: 24; 616-23. (IDIS 266817)

28. Anon. Flutamide for prostate cancer. Med Lett Drugs Ther. 1989: 31; 72. (IDIS 257670)

29. Schering, Kenilworth, NJ: Personal communication.

30. Wysowski DK, Fourcroy JL. Flutamide hepatotoxicity. J Urol. 1996; 155: 209-12. [IDIS 357656] [PubMed 7490837]

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

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