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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(FLOO ta mide)
Generic Available (U.S.)
Yes
Index Terms
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of metastatic prostatic carcinoma in combination therapy with LHRH agonist analogues
Use: Unlabeled/Investigational
Female hirsutism
Pregnancy Risk Factor
D
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to flutamide or any component of the formulation; severe hepatic impairment; pregnancy
Warnings/Precautions
Boxed warnings:
• Liver failure: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Liver failure: [U.S. Boxed Warning]: Hospitalization and, rarely, death due to liver failure have been reported in patients taking flutamide. Elevated serum transaminase levels, jaundice, hepatic encephalopathy, and acute hepatic failure have been reported. In some patients, the toxicity reverses after discontinuation of therapy. About 50% of the cases occur within the first 3 months of treatment. Serum transaminase levels should be measured prior to starting treatment, monthly for 4 months, and periodically thereafter. Liver function tests should be obtained at the first suggestion of liver dysfunction (nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness). Should be immediately discontinued any time a patient has jaundice, and/or an ALT level greater than twice the upper limit of normal. Should not be used in patients whose ALT values are greater than twice the upper limit of normal.
Disease-related concerns:
• Cardiovascular disease: Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine, 2010).
• Hemoglobin M disease: Patients with hemoglobin M disease are at risk of toxicities associated with aniline exposure, including methemoglobinemia, hemolytic anemia, and cholestatic jaundice; monitor methemoglobin levels.
Special populations:
• Glucose-6 phosphate dehydrogenase deficiency: Patients with glucose-6 phosphate dehydrogenase deficiency are at risk of toxicities associated with aniline exposure, including methemoglobinemia, hemolytic anemia, and cholestatic jaundice; monitor methemoglobin levels.
• Smokers: Patients who smoke are at risk of toxicities associated with aniline exposure, including methemoglobinemia, hemolytic anemia, and cholestatic jaundice; monitor methemoglobin levels.
• Women: Product labeling states it is not for use in women, particularly for non-life-threatening conditions.
Adverse Reactions
>10%:
Endocrine & metabolic: Galactorrhea (9% to 42%), breast tenderness, gynecomastia, hot flashes, impotence, libido decreased, tumor flare
Gastrointestinal: Vomiting (11% to 12%), nausea
Hepatic: AST increased (transient; mild), LDH increased (transient; mild)
1% to 10%:
Cardiovascular: Hypertension (1%), edema
Central nervous system: Anxiety, confusion, depression, dizziness, drowsiness, headache, insomnia, nervousness
Dermatologic: Ecchymosis, photosensitivity, pruritus
Gastrointestinal: Upset stomach (4% to 6%), anorexia, appetite increased, constipation, diarrhea, indigestion
Hematologic: Anemia (6%), leukopenia (3%), thrombocytopenia (1%)
Neuromuscular & skeletal: Weakness (1%)
Miscellaneous: Herpes zoster
<1%: Discoloration of urine (yellow), hepatic failure, hepatitis, hypersensitivity pneumonitis, jaundice, malignant breast neoplasm (male), MI, pulmonary embolism, sulfhemoglobinemia, thrombophlebitis
Metabolism/Transport Effects
Substrate (major) of CYP1A2, 3A4; Inhibits CYP1A2 (weak)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: No effect on bioavailability of flutamide.
Herb/Nutraceutical: St John's wort may decrease flutamide levels.
Storage
Store at room temperature.
Mechanism of Action
Nonsteroidal antiandrogen that inhibits androgen uptake or inhibits binding of androgen in target tissues
Pharmacodynamics/Kinetics
Absorption: Oral: Rapid and complete
Protein binding: Parent drug: 94% to 96%; 2-hydroxyflutamide: 92% to 94%
Metabolism: Extensively hepatic to more than 10 metabolites, primarily 2-hydroxyflutamide (active)
Half-life elimination: 5-6 hours (2-hydroxyflutamide)
Excretion: Primarily urine (as metabolites)
Dosage
Oral: Adults:
Prostatic carcinoma: 250 mg 3 times/day; alternatively, once-daily doses of 0.5-1.5 g have been used (unlabeled dosing)
Female hirsutism (unlabeled use): 250 mg daily
Dosage: Combination Regimens
Prostate cancer:
FL
FZ
Administration: Oral
Usually administered orally in 3 divided doses. Contents of capsule may be opened and mixed with applesauce, pudding, or other soft foods. Mixing with a beverage is not recommended.
Monitoring Parameters
Serum transaminase levels should be measured prior to starting treatment and should be repeated monthly for the first 4 months of therapy, and periodically thereafter. LFTs should be checked at the first sign or symptom of liver dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness). Other parameters include tumor reduction, testosterone/estrogen, and phosphatase serum levels.
Patient Education
This medication will be prescribed in conjunction with another medication; take both exactly as directed; do not discontinue without consulting prescriber. May cause decreased libido, impotence, swelling of breasts, hot flashes, decreased appetite, or diarrhea. Report chest pain or palpitation; acute abdominal pain; pain, tingling, or numbness of extremities; swelling of extremities or unusual weight gain; respiratory difficulty; yellowing of skin or sclera; dark urine; pale stool; or unusual fatigue.
Geriatric Considerations
A study has shown that the addition of flutamide to leuprolide therapy in patients with advanced prostatic cancer increased median actuarial survival time to 34.9 months versus 27.9 months with leuprolide alone. No specific dose alterations are necessary in the elderly.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May rarely cause nervousness or confusion
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess serum transaminase levels prior to and periodically during therapy. Monitor for galactorrhea, CNS changes, ataxia, anorexia, vomiting, lacrimation, and anemia on a regular basis. Monitor liver function. Teach patient to report chest pain, respiratory difficulty, abdominal pain, and signs of liver dysfunction.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral: 125 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Flutamide)
125 mg (180): $263.99
125 mg (180): $264.00
References
Airhart RA, Barnett TF, Sullivan JW, “Flutamide Therapy for Carcinoma of the Prostate,” South Med J, 1978, 71(7):798-801.
Azziz R, “The Evaluation and Management of Hirsutism,” Obstet Gynecol, 2003, 101(5 Pt 1):995-1007.
Brogden RN and Chrisp P, “Flutamide. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Advanced Prostatic Cancer,” Drugs Aging, 1991, 1(2):104-15.
Brogden RN and Clissold SP, “Flutamide. A Preliminary Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Advanced Prostate Cancer,” Drugs, 1989, 38(2):185-203.
Delaere KP and Van Thillo EL, “Flutamide Monotherapy as Primary Treatment in Advanced Prostatic Carcinoma,” Semin Oncol, 1991, 18(5 Suppl 6):13-8.
Goldspiel BR and Kohler DR, “Flutamide: An Antiandrogen for Advanced Prostate Cancer,” DICP Ann Pharmacother, 1990, 24(6):616-23.
Hunter MH and Carek PJ, “Evaluation and Treatment of Women With Hirsutism,” Am Fam Physician, 2003, 67(12):2565-72.
Kassem NY, Nero RO, and Munroe JS, “Effect of Flutamide, An Antiandrogen, on Stage D Cancer of the Prostate,” Clin Pharmacol Ther, 1981, 29:256.
Labrie F, “Mechanism of Action and Pure Antiandrogenic Properties of Flutamide,” Cancer, 1993, 72(12 Suppl):3816-27.
Levine GN, D'Amico AV, Berger P, et al, “Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk. A Science Advisory from the American Heart Association, American Cancer Society, and American Urological Association,” Circulation, 2010, 121:831-38.
Luo S, Martel C, Chen C, “Daily Dosing With Flutamide or Casodex Exerts Maximal Antiandrogenic Activity,” Urology, 1997, 50(6):913-9.
Moghetti P, Tosi F, Tosti A, et al, “Comparison of Spironolactone, Flutamide, and Finasteride Efficacy in the Treatment of Hirsutism: A Randomized, Double Blind, Placebo-Controlled Trial,” J Clin Endocrinol Metab, 2000, 85(1):89-94.
Thrasher JB, Deeths J, and Bennett C, “Comparative Study of the Clinical Efficacy of Two Dosing Regimens of Flutamide,” Mol Urol, 2000, 4(3):259-63.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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