EULEXIN- flutamide capsule
Waylis Therapeutics LLC
There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking Eulexin™. 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 Eulexin™.
Serum transaminase levels should be measured prior to starting treatment with Eulexin™. Eulexin™ 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, Eulexin™ should be immediately discontinued with close follow-up of liver function tests until resolution.
Eulexin™ capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, ,,-trifluoro-2-methyl-4′-nitro-m -propionotoluidide.
Each capsule contains 125 mg flutamide. The compound is a buff to yellow powder with a molecular weight of 276.22 and the following structural formula:
C11 H11 F3 N2 O3
In addition, each capsule contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate. Gelatin capsule shells may contain gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, FDA/E172 Red Iron Oxide, FDA/E172 Yellow Iron Oxide, and black ink containing pharmaceutical glaze (modified) in SD-45, synthetic black iron oxide, N-butyl alcohol, SDA-3A alcohol, FD&C Blue No.2 Aluminum Lake, FD&C Red No.40 Aluminum Lake, FD&C Blue No.1 Aluminum Lake, and D&C Yellow No.10 Aluminum Lake.
In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.
Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled Eulexin™ to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.
In male rats administered an oral 5 mg/kg dose of 14 C-flutamide neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate. 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 Eulexin™ in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma concentrations of Eulexin™ were detected. The plasma half-life for the alpha-hydroxylated metabolite of Eulexin™ is approximately 6 hours. Eulexin™, 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 Eulexin™, in vivo , at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins.
The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled Eulexin™ to normal adult volunteers, showed that Eulexin™ is rapidly and extensively metabolized, with Eulexin™ comprising only 2.5% of plasma radioactivity 1 hour after administration. At least six 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-5nitro-4-(trifluoromethyl)phenol.
Eulexin™ and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours.
|Single Dose flutamide||Hydroxyflutamide||Steady-State flutamide||Hydroxyflutamide|
|Cmax (ng/mL)||25.2 ± 34.2||894 ± 406||113 ± 213||1629 ± 586|
|Elimination half-life (hr)||—||8.1 ± 1.3||7.8||9.6 ± 2.5|
|Tmax (hr)||1.9 ± 0.7||2.7 ± 1.0||1.3 ± 0.7||1.9 ± 0.6|
|Cmin (ng/mL)||—||—||—||673 ± 316|
Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, Eulexin™ and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth Eulexin™ dose. The half-life of the active metabolite in geriatric volunteers after a single Eulexin™ dose is about 8 hours and at steady-state in 9.6 hours.
There are no known alterations in Eulexin™ absorption, distribution, metabolism, or excretion due to race.
Following a single 250 mg dose of Eulexin™ administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of Eulexin™. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of Eulexin™. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Eulexin™ and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.
No information on the pharmacokinetics of Eulexin™ in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury).
Eulexin™ has not been studied in women or pediatric subjects.
Interactions between Eulexin™ capsules and LHRH-agonists have not occurred. Increases in prothrombin time have been noted in patients receiving warfarin therapy (see PRECAUTIONS).
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