Euflex 250 mg

Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labelled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. It is excreted mainly in the urine with 4.2% of the dose excreted in the feces over 72 hours. The composition of plasma radioactivity showed that flutamide is rapidly and extensively metabolized, with flutamide comprising 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.

Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of varying amounts of flutamide were detected. The biologically active alpha-hydroxylated metabolite reaches maximum plasma levels in about 2 hours, indicating that it is rapidly formed from flutamide. The plasma half-life for this metabolite is about 6 hours.

Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8 hours and at steady-state is 9.6 hours.

Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL is 94 to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92 to 94% bound to plasma proteins.

In male rats neither flutamide nor any of its metabolites are preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of ¹⁴C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied.

Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.

Interactions between flutamide and leuprolide have not occurred. In patients receiving long-term oral anticoagulant therapy, increases in prothrombin time have been reported after flutamide monotherapy was initiated. Therefore, close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide is administered concomitantly. Cases of increased theophylline plasma concentrations have been reported in patients receiving concomitant theophylline and flutamide tablets. Theophylline is primarily metabolized by CYP 1A2, which is the primary enzyme responsible for the conversion of flutamide to its active agent 2-hydroxyflutamide.

Patients should be informed prior to initiating this medication, of the possibility of its causing hepatic dysfunction. Instruct the patient to consult the doctor immediately if symptoms of hepatic dysfunction appear. These include itching of the skin, dark urine (amber or yellow-green urine is not a cause of concern), nausea, vomiting, persistent lack of appetite, yellow eyes or skin, tenderness in the right upper abdomen, or “flu-like” symptoms.

Flutamide is indicated only for use in male patients.

Patients should be informed that flutamide and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.

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 prompt 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, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice, or 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.

See Pregnancy.

Gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.

No studies have been conducted in pregnant or lactating women. Therefore, the possibility that flutamide may cause fetal harm if administered to a pregnant woman, or may be present in the breast milk of lactating women must be considered.

There was decreased 24-hour survival in the offspring of rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose) during pregnancy. A slight increase in minor variations in the development of the sternebra and vertebra was seen in fetuses of rats at the two higher doses. Feminization of the males also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day; equal to 1.4 times the human dose).

In some patients with metastatic prostate cancer, antiandrogens (steroidal or non-steroidal), may promote, rather than inhibit, the growth of prostate cancer. A decrease in PSA and/or clinical improvement following the discontinuation of antiandrogens have been reported. It is recommended that patients prescribed an antiandrogen, who have PSA progression, should have the antiandrogen discontinued immediately and be monitored for 6-8 weeks for a withdrawal response prior to any decision to proceed with other prostate cancer therapy.

Nausea/vomiting occurred in 11%; diarrhea 12%, anorexia 4%, and other GI disorders occurred in 6% of patients. Increased appetite, indigestion and constipation have also been reported.

In addition, the following adverse experiences have been reported during worldwide marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions—including erythema, ulcerations, bullous eruptions, and epidermal necrolysis—and change in urine color to an amber or yellow-green appearance, which can be attributed to flutamide and/or its metabolites. Also observed were cholestatic jaundice, hepatic encephalopathy and hepatic necrosis. The hepatic conditions were usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide. Hyperglycemia and aggravated diabetes mellitus have been reported very rarely.

Two reports of malignant male breast neoplasms in patients being dosed with flutamide have been reported. One involved aggravation of a preexisting nodule which was first detected 3 to 4 months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma. The other report involved gynecomastia and a nodule noted 2 and 6 months respectively, after initiation of flutamide monotherapy for treatment of advanced prostatic carcinoma. Nine months after the initiation of therapy, the nodule was excised and diagnosed as a moderately differentiated invasive ductal tumor staged T4N0M0, G3, no metastases had advanced.

Anemia occurred in 6% of patients, leukopenia 3%, thrombocytopenia 1%.

Clinically evident hepatitis and jaundice occurred in <1% of patients.

CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients. Rarely insomnia, tiredness, headache, dizziness, weakness, malaise, blurred vision and decreased libido have been reported.

Pruritus, ecchymosis, herpes zoster, thirst, lymphedema, lupus-like syndrome, hematuria, reduced sperm counts have been reported rarely in long-term treatment. Edema occurred in 4% of patients; neuromuscular, genitourinary symptoms occurred in 2% of patients. Pulmonary symptoms occurred in <1% of patients.

As shown in Table 1, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, loss of libido, impotence) were those known to be associated with low serum androgen levels and known to occur with LHRH-agonists alone.

The only notable difference between these treatment groups was the higher incidence of diarrhea in the flutamide+LHRH-agonist group (12%; severe in 5%) as compared to the placebo+LHRH-agonist group (4%; severe in less than 1%).

In addition, the following adverse reactions were reported during treatment with flutamide+LHRH-agonist. No causal relatedness of these reactions to drug treatment has been made, and some of the adverse experiences reported are those that commonly occur in elderly patients.

gynecomastia in 9% of patients. Rarely breast tenderness sometimes accompanied by galactorrhea.

Irritation at the injection site and rash occurred in 3% of patients. Photosensitivity reactions have been reported in 5 patients.

Reported abnormal laboratory test results include elevated AST, ALT; elevated blood urea nitrogen (BUN) and bilirubin levels; less frequently, elevated serum creatinine levels and elevated gamma-glutamyl transferase levels have been reported.

hypertension in 1% of patients. Rarely thrombophlebitis, pulmonary embolism, myocardial infarction.

In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquillization, emesis and methemoglobinemia.

Clinical trials have been conducted with flutamide in doses up to 1500 mg/day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness and some increases in AST. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established.

Since flutamide is highly protein bound, dialysis may not be of any use as treatment for overdose. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. Gastric lavage may be considered. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.