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flutamide
flutamide
SYNONYM(S): SCH 13521
COMMON TRADE NAME(S): Euflex® (multiple brands available)
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
In animal studies, accumulation occurs preferentially in the prostate.
| Cross blood brain barrier? | No information found. |
| PPB | 94-96% (flutamide), 92-94% (active metabolite) |
Rapid and extensive
| Active metabolites | 2-hydroxyflutamide |
| Inactive metabolites | yes |
Primarily in urine
| Feces | 4% of the dose within 72 hours |
| Urine | 28% in 24 hours |
| Half-life | 10 hours (active metabolite) |
- 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.
Emetogenic Potential:
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.
Dosage in myelosuppression:
- No adjustment required
- 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.
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.
| 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 |
| 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
| Monitor Type | Monitor Frequency |
|---|---|
| INR, in patients on anticoagulants | regular |
| Methemoglobin concentrations in at risk patients (e.g. G6PD deficiency, hemoglobin M disease). |
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
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