Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Generics [UK] Limited t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL
Pharmacotherapeutic group: Angiotensin II antagonists, plain
ATC code: C09CA02
Eprosartan is a potent, synthetic, orally active non-biphenyl non-tetrazole angiotensin II receptor antagonist, which binds selectively to the AT1 receptor.
Angiotensin II is a potent vasoconstrictor and the primary active hormone of the renin-angiotensin-aldosterone system, playing a major part in the pathophysiology of hypertension.
Eprosartan antagonised the effect of angiotensin II on blood pressure, renal blood flow and aldosterone secretion in normal volunteers. Blood pressure control is maintained over a 24 hour period with no first dose postural hypotension or reflex tachycardia. Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.
Eprosartan was evaluated in mild to moderate hypertensive patients (sitting DBP≥95 mmHg and <115 mmHg) and severe hypertensive patients (sitting DBP≥115 mmHg and ≤125 mmHg).
Doses up to 1200 mg per day, for 8 weeks, have been shown in clinical trials to be effective with no apparent dose relationship in the incidence of adverse events reported.
In patients with hypertension, blood pressure reduction did not produce a change in heart rate.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
Eprosartan does not compromise renal autoregulatory mechanisms. In normal adult males eprosartan has been shown to increase mean effective renal plasma flow. Eprosartan has no deleterious effects on renal function in patients with essential hypertension and patients with renal insufficiency. Eprosartan does not reduce glomerular filtration rate in normal males, in patients with hypertension or in patients with varying degrees of renal insufficiency. Eprosartan has a natriuretic effect in normal subjects on a salt restricted diet. Eprosartan may be safely administered to patients with essential hypertension and to patients with varying degrees of renal insufficiency without causing sodium retention or a deterioration of renal function.
Eprosartan does not significantly affect the excretion of urinary uric acid.
Eprosartan does not potentiate effects relating to bradykinin (ACE-mediated), e.g. cough. In a study specifically designed to compare the incidence of cough in patients treated with eprosartan and an angiotensin converting enzyme inhibitor, the incidence of dry persistent cough in patients treated with eprosartan (1.5%) was significantly lower (p<0.05) than that observed in patients treated with an angiotensin converting enzyme inhibitor (5.4%). In a further study investigating the incidence of cough in patients who had previously coughed while taking an angiotensin converting enzyme inhibitor, the incidence of dry, persistent cough was 2.6% on eprosartan, 2.7% on placebo, and 25.0% on an angiotensin converting enzyme inhibitor (p<0.01, eprosartan versus angiotensin converting enzyme inhibitor).
In three clinical studies (n=791) the blood pressure lowering effect of eprosartan has been shown to be at least as great as the ACE inhibitor enalapril, with one study in severe hypertensives showing a statistically significantly greater decrease in sitting and standing systolic blood pressure for eprosartan over enalapril.
Angiotensin II binds to the AT1 receptor in many tissues (e.g. smooth vascular musculature, suprarenals, kidney, heart) and produces important biological effects such as vasoconstriction, sodium retention and release of aldosterone. More recently, angiotensin II has been implicated in the genesis of cardiac and vascular hypertrophy through its effect on cardiac and smooth muscle cell growth.
In hypertensive patients eprosartan does not affect fasting triglycerides, total cholesterol, or LDL (low density lipoprotein) cholesterol levels. In addition, eprosartan has no effect on fasting blood sugar levels.
Absolute bioavailability following a single 300 mg oral dose of eprosartan is about 13%, due to limited oral absorption. Eprosartan plasma concentrations peak at one to two hours after an oral dose in the fasted state. Plasma concentrations are dose proportional from 100 to 200 mg, but less than proportional for 400 and 800 mg doses. A slight accumulation (14%) is seen with chronic use of eprosartan. Administration of eprosartan with food delays absorption with minor increases (<25%) observed in Cmax and AUC.
The volume of distribution of eprosartan is about 13 litres. Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. The extent of plasma protein binding is not influenced by gender, age, hepatic dysfunction or mild-moderate renal impairment but has shown to be decreased in a small number of patients with severe renal impairment.
Following intravenous [14C] eprosartan, about 61% of radioactivity is recovered in the faeces and about 37% in the urine. Following an oral dose of [14C] eprosartan, about 90% of radioactivity is recovered in the faeces and about 7% in the urine.
Following oral and intravenous dosing with [14C] eprosartan in human subjects, eprosartan was the only drug-related compound found in the plasma and faeces. In the urine, approximately 20% of the radioactivity excreted was an acyl glucuronide of eprosartan with the remaining 80% being unchanged eprosartan.
The terminal elimination half-life of eprosartan following oral administration is typically five to nine hours. Total plasma clearance is about 130 ml/min. Biliary and renal excretion contribute to the elimination of eprosartan.
Both AUC and Cmax values of eprosartan are increased in the elderly (on average, approximately two-fold), but this does not necessitate alterations in dosing.
Following administration of a single 100 mg dose of eprosartan, AUC values of eprosartan (but not Cmax) are increased, on average, by approximately 40% in patients with hepatic impairment.
Compared to subjects with normal renal function (n=7), mean AUC and Cmax values were approximately 30% higher in patients with creatinine clearance 30-59 ml/min (n=11) and approximately 50% higher in patients with creatinine clearance 5-29 ml/min (n=3).
In a separate investigation, mean AUC was approximately 60% higher in patients undergoing dialysis (n=9) compared to subjects with normal renal function (n=10).
There is no difference in the pharmacokinetics of eprosartan between males and females.
There were no mortalities in rats and mice dosed at up to 3000 mg/kg BW and in dogs given up to 1000 mg/kg BW.
In chronic toxicity studies eprosartan did not produce any toxic effects in rats (after oral administration of doses of up to 1000 mg/kg/day for up to six months). In dogs, eprosartan caused a reduction in red cell parameters (erythrocytes, haemoglobin, haematocrit) at doses of 30 mg/kg BW/day or more after oral administration for up to six months, but red cell parameters returned to normal values at 1 year despite continuous drug administration.
In pregnant rabbits, eprosartan has been shown to produce maternal and foetal mortality at 10 mg/kg BW per day during late pregnancy only. Maternal toxicity but no foetal effects were observed at 3 mg/kg BW per day.
Genotoxicity was not observed in a battery of in vitro and in vivo tests
Carcinogenicity was not observed in rats and mice given up to 600 or 2000 mg/kg BW per day respectively for 2 years.
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