Revised 01 Aug 2007
SYNONYM(S):
COMMON TRADE NAME(S): APO-FLUTAMIDE®, EUFLEX®, NOVO-FLUTAMIDE®
CLASSIFICATION: hormonal agent
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION:
Flutamide is a nonsteroidal antiandrogen which competitively inhibits the binding of androgens to the androgen receptor.1 It is devoid of other endocrine activity. Flutamide is structurally and pharmacologically related to bicalutamide and nilutamide.2
Prostate cancer is primarily an androgen-dependent cancer and can be treated with surgical or medical castration. Luteinizing hormone releasing hormone agonists (LHRHa) suppress pituitary release of luteinizing hormone (LH) and result in medical castration. Unlike medical castration, nonsteroidal antiandrogens do not decrease the production of androgens. The initial stimulation of the pituitary caused by LHRHa produces an acute increase in the concentration of plasma testosterone accompanied by temporary worsening of symptoms (flare reaction). To avoid the flare reaction, antiandrogens should be given concurrently with the first administration of LHRHa.
Antiandrogens are also used in combination with LHRHa to inhibit the effects of testicular and adrenal androgens (maximum androgen blockade). In some patients with metastatic prostate cancer (15-20%),3 antiandrogen withdrawal may lead to a paradoxical decrease in serum prostate-specific antigen level (antiandrogen withdrawal syndrome).1
PHARMACOKINETICS:
|
Oral Absorption |
rapid and complete |
|
Distribution |
steady-state achieved after the fourth dose |
|
cross blood brain barrier? |
no information found |
|
volume of distribution |
no information found |
|
plasma protein binding |
94-96%, 2-hydroxyflutamide: 92-94% |
|
Metabolism |
hepatic, rapid and extensive, involves the hepatic microsomal enzyme oxidation system4 |
|
active metabolite2 |
2-hydroxyflutamide |
|
inactive metabolite(s)5-7 |
>10 metabolites including 4-nitro-3-fluoro-methylaniline |
|
Excretion |
mainly renal7 |
|
urine8 |
primarily, <1% unchanged |
|
feces |
4% |
|
terminal half life |
4.7 h, 2-hydroxyflutamide: 6 h |
|
clearance |
no information found |
|
Elderly |
terminal half life of 2-hydroxyflutamide: 8-9.6 h |
Adapted from standard reference1 unless specified otherwise.
USES:
|
Primary uses: |
Other uses: |
|
*Prostate cancer |
|
*Health Canada approved indication
SPECIAL PRECAUTIONS:
Contraindicated in patients with the following conditions1:
- a history of hypersensitivity reaction to flutamide
- severe hepatic impairment or serum transaminase levels > 2 times the upper limit of normal
Caution:
Use flutamide with caution in patients with cardiac disease due to the potential for fluid retention secondary to elevated plasma testosterone and estradiol levels.1
Special populations:
- Patients with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease, and smokers are at risk of toxicities associate with 4-nitro-3-fluoro-methylaniline exposure, a metabolite of flutamide. These toxicities include methemoglobinemia, hemolytic anemia, and cholestatic jaundice. Methemoglobin concentrations should be periodically monitored in this population.2,5
- Because of its intended use, safety and efficacy have not been established in women and children. Flutamide is indicated only for use in male patients.1
Carcinogenicity: Flutamide is carcinogenic in rats at doses equivalent to > 3 times the human dose.1 No detailed information found in humans; although a causal relationship has not been established, malignant breast tumours have rarely been reported in men receiving flutamide.
Mutagenicity: Flutamide is not mutagenic in Ames test.1 It is not known if flutamide is mutagenic in mammalian in vitro mutation test. It is not known if flutamide is clastogenic in mammalian in vitro and in vivo chromosome tests.
Fertility: A decrease in sperm count has been reported with flutamide use.1 Because of its intended use, safety and efficacy have not been established in women.2
Pregnancy: FDA Pregnancy Category D.5 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding is not recommended due to the potential secretion into breast milk; because of its intended use, safety and efficacy have not been established in women.1
SIDE EFFECTS:
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.9 When placebo-controlled trials are available, adverse events are included if the incidence is >5% higher in the treatment group.
ORGAN SITE |
SIDE EFFECT |
|
Clinically important side effects are in bold, italics
Side effects and incidences are those of flutamide when used with surgical or medical castration unless otherwise specified. |
|
blood/bone marrow/
febrile neutropenia |
anemia (6%); hemolytic and macrocytic anemia, methemoglobinemia, and sulfhemoglobinemia have been reported |
|
leukopenia (3%), neutropenia (<1%) |
|
thrombocytopenia (1%) |
|
cardiovascular (general) |
hypertension (1%) |
|
myocardial infarction (<1%) |
|
constitutional symptoms |
fatigue |
|
increased appetite (4-6%),6,7 weight gain10 |
|
insomnia (<1%) |
|
dermatology/skin |
photosensitivity reactions (<1%)11; including erythema, ulcerations, bullous eruptions, and epidermal necrolysis |
|
rash (3%), pruritis12 (<1%)12 |
|
endocrine |
gynecomastia (9%), monotherapy (34-42%)6; reversible, breast tenderness (<1% ); sometimes accompanied by reversible galactorrhea |
|
hot flashes (61%)12 |
|
gastrointestinal |
emetogenic potential: rare13 |
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anorexia (4-6%)7 |
|
constipation |
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diarrhea (12%, severe 5%); more likely than bicalutamide to cause severe diarrhea resulting in treatment discontinuation12 |
|
gastrointestinal disorders not otherwise specified (6%) |
|
indigestion (4-6%)5,7 |
|
nausea and vomiting (11%) |
|
hepatobiliary/pancreas |
hepatic dysfunction including hepatic necrosis; see paragraph following the Side Effects table |
|
lymphatics |
edema (4%) |
|
metabolic/laboratory |
elevated serum transaminases; see paragraph following the Side Effects table |
|
elevated bilirubin |
|
elevated BUN; transient6 |
|
elevated gamma-glutamyl transferase |
|
elevated plasma testosterone and estradiol levels |
|
elevated serum creatinine; transient6 |
|
musculoskeletal |
weakness (<1%) |
|
neurology |
CNS reactions (1%); including drowsiness, dizziness, insomnia, confusion, depression, anxiety, and nervousness |
|
ocular/visual |
blurred vision (<1%) |
|
pain |
headache (<1%) |
|
pulmonary |
interstitial pneumonitis5 (<1%)5,14 |
|
renal/genitourinary |
change in urine colour to amber or yellow-green (<1%)5 |
|
secondary malignancy |
malignant breast neoplasms (<1%); causality not established |
|
sexual/reproductive function |
decreased sperm counts |
|
loss of libido, impotence (<100%)9; decreased incidence with monotherapy6 |
|
syndromes |
lupus-like syndrome |
|
vascular |
pulmonary embolism (<1%) |
|
thrombophlebitis (<1%) |
Adapted from standard reference1 unless specified otherwise.
Hepatic dysfunction (<1%)5,12 including elevated serum transaminase levels, jaundice, hepatic encephalopathy, hepatic necrosis, and death have been reported with flutamide.1 These toxicities typically occur within the first three months of treatment.1 Appropriate liver function tests should be measured every three months.15 Liver function tests should also be obtained at the first signs and symptoms suggestive of liver dysfunction; e.g., nausea, vomiting, abdominal pain, lack of appetite, pruritis, fatigue, dark urine, persistent anorexia, unexplained “flu-like” symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness.1,11 If at any time a patient has jaundice, or transaminase levels rise > 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.1
INTERACTIONS:
AGENT |
EFFECT |
MECHANISM |
MANAGEMENT |
|
grapefruit juice4,16 |
may increase plasma level of flutamide |
may inhibit CYP3A4 metabolism of flutamide in the intestinal wall |
avoid grapefruit and grapefruit juice for the duration of treatment |
|
LHRH agonists17 |
no documented influence on flutamide pharmacokinetics |
|
|
|
warfarin1,17 |
increased prothrombin time |
unknown |
monitor prothrombin time; adjust warfarin dose as required |
Flutamide is a major CYP3A4 and 1A2 substrate5; therefore, drugs or herbs that are CYP3A4 or 1A2 inducers may decrease the levels/effects of flutamide. Likewise, drugs or herbs that are CYP3A4 or 1A2 inhibitors may increase the levels/effects of flutamide.16
Flutamide is also a weak CYP1A2 inhibitor.5
SUPPLY AND STORAGE:
Tablets: Apotex supplies flutamide as a 250 mg film-coated scored tablet. Selected non-medicinal ingredients: lactose. Store at room temperature, protect from light and excessive moisture.1
Novopharm supplies flutamide as a 250 mg tablet. Selected non-medicinal ingredients: lactose. Store at room temperature.11
Schering Canada supplies flutamide as a 250 mg scored tablet. Selected non-medicinal ingredients: lactose. Store at room temperature, protect from light and excessive moisture.18
DOSAGE GUIDELINES:
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.
Adults:
|
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BCCA usual dose noted in bold, italics |
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Oral: |
250 mg PO three times a day1,15,19
- administer with food or on an empty stomach2; administering with food may help reduce nausea
|
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Concurrent radiation: |
no dose adjustment required9 |
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|
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Dosage in myelosuppression: |
modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression" |
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Dosage in renal failure: |
no adjustment required2,20; half-life may be prolonged in patients with renal failure12 |
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|
|
|
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Dosage in hepatic failure: |
not recommended in patients whose serum transaminase levels are >2 times the upper limit of normal1 |
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|
|
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Dosage in dialysis: |
not significantly removed by dialysis8,12; supplemental dose not required8 |
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|
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Children:
|
|
no information found regarding the use of flutamide in pediatric oncology |
References:
1. Apotex Inc. APO-FLUTAMIDE® product monograph. Weston, Ontario; 28 October 2002.
2. McEvoy GK, editor. AHFS 2006 Drug Information®. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 1056-7.
3. Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the treatment of prostate cancer. European Urology 2007;51(2):306-14.
4. Juurlink D. Cytochrome P450 drug interactions. In: Welbanks L, editor. Compendium of Pharmaceutical Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2006. p. L53-9.
5. Anonymous. Flutamide. In: Rose BD, editor. UpToDate®. Waltham, Massachusetts: UpToDate 15.1; 2007.
6. DRUGDEX® Evaluations (database on the Internet). Flutamide. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 23 February 2007.
7. Solimando DA, Jr. Cancer chemotherapy update: Updates of flutamide and nilutamide. Hospital Pharmacy 1997;32(5):635.
8. Anjum S, Swan SK, Lambrecht LJ, et al. Pharmacokinetics of flutamide in patients with renal insufficiency. British Journal of Clinical Pharmacology 1999;47(1):43-7.
9. Judy Sutherland, MD. Personal communication. BCCA Genitourinary Tumour Group;11 June 2007.
10. Spry NA, Kristjanson L, Hooton B, et al. Adverse effects to quality of life arising from treatment can recover with intermittent androgen suppression in men with prostate cancer. European Journal of Cancer 2006;42(8):1083-92.
11. Novopharm Limited. NOVO-FLUTAMIDE® product monograph. Toronto, Ontario; 4 September 2002.
12. USPDI® Drug Information for the Health Care Professional (database on the Internet). Antiandrogens, Nonsteroidal (Systemic). Thompson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 23 February 2007.
13. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
14. MARTINDALE- The Complete Drug Reference (database on the Internet). Flutamide. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 23 February 2007.
15. B.C. Cancer Agency Genitourinary Tumour Group. (GUPNSAA) BCCA Protocol Summary for Non-Steroidal Treatment of Prostate Cancer. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
16. Anonymous. Flutamide. In: Rose BD, editor. Lexi-Interact™ Online. Waltham, Massachusetts: UpToDate 15.1; 2007.
17. Drug Interaction Facts (database on the Internet). Flutamide. Facts and Comparisons 4.0, 2007. Available from http://online.factsandcomparisons.com. Accessed February 23, 2007.
18. Schering Canada. EUFLEX® product monograph. Pointe Claire, Quebec; 21 February 2003.
19. B.C. Cancer Agency Genitourinary Tumour Group. (GUPLHRH) BCCA Protocol Summary for Therapy for Prostate Cancer Using LHRH Agonist (Goserelin, Leuprolide or Buserelin). Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
20. Aronoff GR, Berns JS, Brier ME, et al. Drug prescribing in renal failure: dosing guidelines for adults. 4th ed. Philadelphia (PA): American College of Physicians; 1999. p. 74.