Pharmacology: Pharmacodynamics: Serum Lipid-lowering Effect: This drug significantly lowers serum total cholesterol and serum triglyceride in patients with hyperlipidemia.
This drug lowers blood lipid level in animals with hyperlipidemia induced by high-cholesterol diet (rats and rabbits), rats with hyperlipidemia induced by casein-containing diet or Triton and animals fed with normal feed (rats and hamsters).
In oral administration in rats, EPA content of lipoprotein is increased and elimination of lipoprotein from blood is promoted.
The effects such as inhibition of absorption of cholesterol from intestine, inhibition of activity of its biosynthesis in liver and promotion of its catabolism and excretion into bile are shown (rats).
The effects such as inhibition of absorption of triglyceride from intestine, inhibition of activity of its biosynthesis in liver and inhibition of its secretion from liver, and increase in plasma lipoprotein lipase (LPL) activity are shown (rats).
Antiplatelet Effect: This drug inhibits platelet aggregation by various aggregating agents and similarly reduces platelet adhesiveness in patients with various thrombotic and atherosclerotic diseases.
This drug is considered to increase EPA content of mainly platelet membrane phospholipid and competitively inhibit the metabolism of arachidonic acid from platelet membrane, thereby inhibiting the production of thromboxane A2 and inhibiting platelet aggregation.
This drug inhibits platelet aggregation by collagen (rabbits, ex vivo).
This drug inhibits platelet aggregation by collagen, ADP and arachidonic acid in rats, rabbits and humans (in vitro).
Production of prostacyclin-like substance in the wall of thoracic aorta in rats was not changed or increased.
Maintenance of Arterial Distensibility: This drug inhibits the decrease in distensibility of isolated aorta of rabbits fed with high-cholesterol feed and maintains the distensibility comparable to that of aorta of rabbits fed with normal feed.
This drug inhibits the increase in pulse wave velocity (PWV) in thoracic aorta and femoral artery of rabbits fed with high-cholesterol feed. The PWV values are largely at the same level as those in rabbits fed with normal feed.
This drug inhibits the reduction of density and elastin content of vascular smooth muscle cells and accumulation of free cholesterol in smooth muscles and inhibits the growth of intimal smooth muscle cells in aorta of rabbits fed with high-cholesterol feed.
Effects in Various Arterial Occlusive Disease Models: Oral administration inhibits sudden death associated with thrombus formation caused by intravenous injection of arachidonic acid (rats) and inhibits thrombus formation in thrombotic obstruction of arteriovenous shunt (rats) and ellagic acid-induced thrombus (rabbits). This drug also inhibits the progression of lauric acid-induced peripheral gangrene (rats).
Clinical Studies: Data of EPADEL 300mg and 600mg: "Moderate" or better global improvement was achieved in 47.5% (19/40) of the subjects in a clinical study in patients with hyperlipidemia.
Data of EPADEL 300mg (for reference).
Hyperlipidemia: In clinical studies including double-blind controlled studies, "improved" or better and "mild" or better global improvement of hyperlipidemia were achieved in 43.8% (163/372) and 68.0% (253/372) of the subjects, respectively.
In long-term studies (24 to 52 weeks), serum total cholesterol (values before administration were 220 mg/dL or higher in 137 subjects) decreased by 3% to 6% and serum triglyceride (values before administration were 150 mg/dL or higher in 97 subjects) by 14% to 20%. These effects were stable.
When EPADEL 300mg were administered immediately after meals at a dose of 900 mg twice daily (morning and evening) or at a dose of 600 mg thrice daily (morning, noon and evening) for 12 weeks in a double-blind controlled study in patients with high serum triglyceride (TG) values, the rates of change in serum TG at the last evaluation in the twice-daily administration (230 subjects; serum TG before administration, 256.7 mg/dL) and in the thrice-daily administration (224 subjects; serum TG before administration, 249.4 mg/dL) were -12.62% and -10.65%, respectively, showing the value below the predetermined non-inferiority margin of 10%, which confirmed the non-inferiority of efficacy (in rate of change in serum TG) of twice-daily administration to that of thrice-daily administration.
Post-marketing Survey: JELIS: Patients with hyperlipidemia who had already received dietary instruction, have 250 mg/dL or higher serum total cholesterol values and were considered to require treatment with HMG-CoA reductase inhibitors (including patients with accompanying stable ischemic heart disease) were randomly allocated to the combined use of HMG-CoA reductase inhibitor (10 mg/day of pravastatin or 5 mg/day of simvastatin) and 1800 mg/day of EPADEL or the treatment only with HMG-CoA reductase inhibitor (control group). In 18,645 patients (9326 in the EPADEL and 9319 in the control group) included in efficacy evaluation who were followed up for 4.6 years on average in un-blinded manner, cardiovascular events (sudden cardiac death, fatal or nonfatal myocardial infarction, angina unstable and cardiovascular reconstruction) were observed in 262 patients (2.8%) in the EPADEL group and 324 patients (3.5%) in the control group. Hazard ratio was 0.81 (95% confidence interval, 0.69 to 0.95, the same applies hereinafter), indicating a significant reduction in the EPADEL group. Cardiovascular death (sudden cardiac death or fatal myocardial infarction) was observed in 29 patients (0.3%) in the EPADEL group and 31 patients (0.3%) in the control group. Hazard ratio was 0.94 (0.57 to 1.56). All deaths were observed in 286 patients (3.1%) in the EPADEL group and 265 patients (2.8%) in the control group. Hazard ratio was 1.09 (0.92 to 1.28). No significant difference was observed in either event.
Pharmacokinetics: Plasma Concentration: In single-dose oral administration of 2700 mg* of EPADEL immediately after a meal in healthy adult males, the maximum plasma concentration was achieved approximately 6 hours after the administration.
In oral administration of EPADEL at a dose of 600 mg or 900 mg 3 times a day, immediately after every meal, on consecutive days for 4 weeks, plasma concentration reached a steady state about 1 week after the start of the administration.
The pharmacokinetics was similar in 8-day repeated oral administration of EPADEL immediately after meals at a dose of 900 mg twice daily (morning and evening) and at a dose of 600 mg thrice daily (morning, noon and evening). The plasma concentration was gradually increased with the number of days of administration and reached a steady state on Day 5 to Day 6 in both groups.
*: The approved maximum dose of EPADEL is 900 mg per time.
Excretion (for reference): When 14C-labeled EPA-E was orally administered in male rats, 2.7% was excreted in urine and 16.7% in feces within 168 hours after the administration.
Forty-four point four percent of radioactivity was excreted in exhaled air.
Toxicology: Preclinical Safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, and safety pharmacology.