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A - Drug Name

flutamide

SYNONYM(S):   SCH 13521

COMMON TRADE NAME(S):   Euflex® (multiple brands available)

 
B - Mechanism of Action and Pharmacokinetics

Flutamide is a non-steroidal antiandrogen that inhibits androgen uptake and/or nuclear binding of androgen in target tissues.  When used as monotherapy, it causes a gradual increase in plasma testosterone due to blockage of feedback inhibition of the hypothalamus and pituitary by testosterone.  The increase does not occur when flutamide is used in combination with an LHRH agonist, nor in a previously orchidectomized patient



Absorption
Oral: Rapid and almost complete. With 250mg tid dosing, steady state is reached after the fourth dose.
Distribution

In animal studies, accumulation occurs preferentially in the prostate.

Cross blood brain barrier? No information found.
PPB 94-96% (flutamide), 92-94% (active metabolite)
Metabolism

Rapid and extensive

Active metabolites 2-hydroxyflutamide
Inactive metabolites yes
Elimination

Primarily in urine

Feces 4% of the dose within 72 hours
Urine 28% in 24 hours
Half-life 10 hours (active metabolite)
 
C - Indications and Status
Health Canada Approvals:

  • Metastatic prostate cancer (Stage D2) in conjunction with LHRH agonist or orchiectomy
  • Stage B2 or C prostate cancer prior to or during radiation treatment in combination with LHRH agonist.


 
D - Adverse Effects

Emetogenic Potential:  

Not applicable

Extravasation Potential:   Not applicable

The following table contains adverse effects reported in combination use with a LHRH agonist.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arterial thromboembolism (rare) D
Cardiotoxicity (rare) D
Hypertension (1%) D
QT interval prolonged (rare) E  D
Venous thromboembolism (rare) D
Dermatological Photosensitivity (may be severe) E
Rash (3%) (may be severe) E
Gastrointestinal Anorexia (4%) E
Diarrhea (12%) E
Nausea (or vomiting - 11%) I
General Edema (4%) D
Hematological Hemolysis (rare) E  D
Myelosuppression (6%) (mild, including anemia) E
Other (methemoglobinemia - rare) E
Hepatobiliary ↑ LFTs (may be severe) D
Immune Autoimmune disorder (Lupus-like syndrome - rare) E
Injection site Injection site reaction (3%) (with LHRH agonist) I
Metabolic / Endocrine Glucose intolerance E  D
Musculoskeletal Osteoporosis D
Neoplastic Secondary malignancy (breast cancer - rare) L
Nervous System Cognitive disturbance (1%) D
Dizziness (rare) E
Headache (rare) E
Sleep disorder (1%) E
Ophthalmic Blurred vision (1%) D
Renal Creatinine increased (rare) E
Reproductive and breast disorders Androgen deprivation symptoms (up to 61%) E
Respiratory Pneumonitis (rare) E
Urinary Urine discoloration (amber / yellow-green) I


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common adverse effects are androgen deprivation symptoms including gynecomastia, which is much less frequent when flutamide is used with an LHRH agonist. It is sometimes accompanied by galactorrhea. These effects usually disappear upon dose reduction or drug discontinuation.

Hepatotoxicity has been reported, usually in the first three months of treatment. Appropriate laboratory testing should be done regularly and at the first symptom/sign of liver impairment. Hepatic injury is usually reversible after discontinuation of therapy, but there have been reports of death following severe hepatic injury associated with flutamide.

The combined use of anti-androgen plus LHRH analogue / surgical castration increases risk of cardiovascular disease and osteoporosis. Androgen deprivation can adversely affect cardiovascular risk factors, such as increased body weight, reduced insulin sensitivity and/or dyslipidemia. Bone loss may occur during the hypoandrogenic state caused by long-term combined androgen blockade. Risk factors such as older patients, pre-existing osteopenia, family history of osteoporosis, chronic use of corticosteroids or anticonvulsants, or chronic alcohol/tobacco abuse should be carefully considered before starting treatment. Reduction of glucose tolerance has also been observed in patients receiving combined androgen blockade. Continuous androgen blockade has the potential to increase QTc, especially in patients with risk factors such as congenital long QT syndrome, abnormal electrolytes and concomitant medications which prolong QTc. Anemia is also a known physiologic effect of testosterone suppression.

Antiandrogen withdrawal syndrome has been reported. After discontinuation for disease progression, 6-8 weeks should elapse before making further treatment decisions.

 
E - Dosing

Refer to protocol by which patient is being treated. Flutamide should be used in combination with orchiectomy or with an LHRH agonist.  Start simultaneously / 24 hours prior to LHRH agonist.  If patient is receiving external beam radiation, start flutamide 8 weeks prior to radiation and continue throughout radiation treatment.

Adults:

Oral: 250 mg PO every 8 hours (TID)
Dosage with Toxicity:

Dosage in myelosuppression:

  • No adjustment required


Dosage with Hepatic Impairment:

Discontinue flutamide if jaundice or liver transaminases ≥ 2-3 x ULN.

Dosage with Renal Impairment:

No adjustment required; slightly prolonged half-life in patients with CrCl < 29 mL/min. Not significantly removed by hemodialysis.

 
F - Administration Guidelines

  • Oral self-administration; drug available by outpatient prescription.
  • Swallow tablet whole with a glass of water; may be given with or without food.
  • If a dose is missed, skip this and give the next dose as scheduled. Never double the dose to make up for the missed one.
  • Avoid alcohol consumption as this may exacerbate flushing during flutamide treatment.


 
G - Special Precautions
Other:

Flutamide is contraindicated in patients who have moderate to severe hepatic impairment (LFTs ≥ 2-3 x ULN, increased bilirubin or jaundice), or who are hypersensitive to the drug or any component of its preparation. Flutamide is indicated only for use in male patients.

Use with caution in patients with cardiac disease since fluid retention may occur with the increase in testosterone and estradiol levels. Contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Use with caution in patients with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease, or smokers, as exposure to the 4-nitro-3-fluoro-methylaniline metabolite may cause methemoglobinemia, hemolytic anemia, and cholestatic jaundice in these patients.

Although flutamide is not mutagenic, it is fetotoxic, teratogenic and may be carcinogenic and should not be used in women or during pregnancy. A few cases of breast cancer have been reported in male patients taking flutamide.  Flutamide should not be used in breastfeeding since it suppresses lactation in animals and its secretion in breast milk is unknown. Increases in breast and testicular neoplasms have been seen in animal models.  Fertility may be impaired.

 

 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Oral anticoagulant ↑ prothrombin time Unknown Monitor INR closely; may require anticoagulant dose adjustment
Theophylline ↑ theophylline concentration Competition with flutamide for CYP1A2 Monitor
CYP 1A2, 3A4 inducers (strong) ↓ flutamide levels May ↑ flutamide metabolism; Enzyme induction Monitor
CYP1A2, 3A4 inhibitors (e.g. abiraterone) ↑ flutamide levels May ↓ flutamide metabolism; Enzyme inhibition Monitor; consider dose adjustment with strong inhibitors
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) ↑ risk of QT prolongation Additive Caution
 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

Monitor Type Monitor Frequency
Blood glucose, HgA1c; in diabetic patients or patients at risk of hyperglycemia regular
Liver function tests baseline, monthly for the first 4 months, then periodically and as clinically indicated
ECG and electrolyte for patients at risk of QT prolongation
Clinical evaluation for symptoms of hypogonadism, gynecomastia, osteoporosis, hyperglycemia, cardiovascular and GI effects

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Monitor Type Monitor Frequency
INR, in patients on anticoagulants regular
Methemoglobin concentrations in at risk patients (e.g. G6PD deficiency, hemoglobin M disease).
 
J - Supplementary Public Funding

ODB - General Benefit (

)
  • flutamide ()

 
K - References

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.

Flutamide: e-AHFS Drug Information. American Society of Health-Systems Pharmacists. Accessed Aug 15, 2013. Available from: http://www.ahfsdruginformation. com

Product Monograph: Euflex® (flutamide). Merck, October 15, 2012.

Flutamide:  Merck Manual for Health Care Professionals. Available from:  http://www.merckmanuals.com/professional/lexicomp/flutamide.html.  Accessed July 15, 2014.


October 2017 Modified adverse effects, dosing, administration guidelines, special precautions, interactions and monitoring sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.