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Flutamide

Pronunciation

Pronunciation

(FLOO ta mide)

Index Terms

  • Eulexin
  • Flucinom
  • Flugerel
  • Niftolid
  • SCH 13521

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 125 mg

Pharmacologic Category

  • Antineoplastic Agent, Antiandrogen

Pharmacology

Nonsteroidal antiandrogen that inhibits androgen uptake and/or inhibits binding of androgen in target tissues.

Absorption

Oral: Rapid and complete

Metabolism

Extensively hepatic to ≥6 metabolites, primarily 2-hydroxyflutamide (active)

Excretion

Primarily urine (as metabolites); feces (~4%)

Time to Peak

~2 hours (2-hydroxyflutamide)

Half-Life Elimination

~6 hours (2-hydroxyflutamide)

Protein Binding

Parent drug: 94% to 96%; 2-hydroxyflutamide: 92% to 94%

Special Populations: Renal Function Impairment

The half-life is slightly prolonged

Special Populations: Elderly

The half-life is slightly prolonged, ~9.6 hours (active metabolite at steady state)

Use: Labeled Indications

Prostate cancer: Management of locally confined Stage B2 to C and Stage D2 metastatic prostate cancer (in combination with a luteinizing hormone-releasing hormone [LHRH] agonist). For Stage B2 to C prostate cancer, flutamide treatment (and goserelin) should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy. To achieve treatment benefit in Stage D2 metastatic prostate cancer, initiate flutamide with the LHRH agonist and continue until disease progression.

Contraindications

Hypersensitivity to flutamide or any component of the formulation; severe hepatic impairment (evaluate baseline hepatic enzymes prior to treatment).

Dosing: Adult

Prostate cancer, metastatic: Males: Oral: 250 mg 3 times daily (every 8 hours)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment is necessary in patients with chronic renal insufficiency.

Dosing: Hepatic Impairment

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

Administration

May be administered with or without food. Administer orally in 3 divided doses (every 8 hours). Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense with a child-resistant closure in a tight, light-resistant container.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Monitor therapy

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Osimertinib: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Adverse Reactions

>10%:

Endocrine & metabolic: Hot flash (46% to 61%), galactorrhea (9% to 42%), decreased libido (36%), increased lactate dehydrogenase (transient; mild)

Gastrointestinal: Diarrhea (12% to 40%), vomiting (11% to 12%)

Genitourinary: Impotence (33%), cystitis (16%), breast tenderness

Hematologic & oncologic: Rectal hemorrhage (14%), tumor flare

Hepatic: Increased serum AST (transient; mild)

1% to 10%:

Cardiovascular: Edema (4%), hypertension (1%)

Central nervous system: Anxiety, confusion, depression, dizziness, drowsiness, headache, insomnia, nervousness

Dermatologic: Skin rash (3% to 8%), ecchymoses, pruritus

Endocrine & metabolic: Gynecomastia (9%)

Gastrointestinal: Nausea (9%), proctitis (8%), gastric distress (4% to 6%), anorexia (4%), constipation, dyspepsia, increased appetite

Genitourinary: Hematuria (7%)

Hematologic & oncologic: Anemia (6%), leukopenia (3%), thrombocytopenia (1%)

Infection: Herpes zoster

Neuromuscular & skeletal: Weakness (1%)

<1% (Limited to important or life-threatening): Cholestatic jaundice, hemolytic anemia, hepatic encephalopathy, hepatic failure, hepatic necrosis, hepatitis, hypersensitivity pneumonitis, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased serum ALT, increased serum bilirubin, increased serum creatinine, jaundice, macrocytic anemia, malignant neoplasm of breast (male), methemoglobinemia, myocardial infarction, oligospermia, pulmonary embolism, skin photosensitivity, sulfhemoglobinemia, thrombophlebitis, urine discoloration (amber, yellow-green)

ALERT: U.S. Boxed Warning

Hepatic injury:

There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.

Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice, right upper quadrant tenderness). If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.

Warnings/Precautions

Concerns related to adverse effects:

• Gynecomastia: Gynecomastia may occur in patients receiving flutamide in combination with medical castration.

• Hepatic failure: [U.S. Boxed Warning]: Hospitalization and death (rare) 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. Hepatotoxicity was reversible after discontinuation in some cases. In about 50% of the cases, the onset of hepatotoxicity was within the first 3 months of treatment. Monitor serum transaminase levels at baseline, monthly for 4 months, and periodically thereafter. Also obtain liver function tests at the first symptoms suggestive of liver dysfunction (nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness). Use is not recommended in patients with ALT values greater than 2 times ULN; discontinue use immediately in patients with jaundice or if ALT rises above 2 times ULN. Use is contraindicated in patients with severe hepatic impairment.

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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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: Not indicated for use in women and should not be used in women, particularly for nonserious or nonlife-threatening conditions.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

Serum transaminases (at baseline, monthly for 4 months, and periodically thereafter); monitor liver function tests 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); monitor prostate specific antigen (PSA)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. May cause fetal harm if administered in pregnancy. Flutamide is not indicated for use in women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hot flashes, nausea, vomiting, enlarged breasts, decreased libido, or sexual dysfunction. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), blood in urine, rectal pain, rectal bleeding, severe headache, loss of strength and energy, bruising, bleeding, swelling of arms or legs, or severe diarrhea (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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