Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd (Trading style: Accord) Whiddon Valley, Barnstaple, Devon, EX32 8NS
ATC Code: CO9AA09
Pharmacotherapeutic group: ACE Inhibitors, plain.
Fosinopril is the pro-drug (ester) of the long acting active ACE inhibitor fosinoprilat. After oral administration fosinopril is quickly and fully metabolised to the active fosinoprilat. Fosinopril contains a phosphinic group capable of a specific binding to the active site of the angiotensin converting enzyme, preventing the conversion of angiotensin I in angiotensin II. The reduction in angiotensin II leads to a vasoconstriction reduction and a decrease in aldosterone secretion, which might induce a slight increase in serum potassium and a loss of sodium and fluid.
ACE inhibition also interferes with bradykinin degradation, a potent vasodepressant, contributing to the antihypertensive effect; fosinopril presents a therapeutic action in hypertensive patients with renin low levels.
In patients with cardiac failure, it is assumed that Fosinopril beneficial effects are mainly resultant of a suppression of the renin-angiotensin-aldosterone system; ACE inhibition produces a reduction in pre-load and post-load.
Administration of fosinopril sodium to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate. In hypertension, fosinopril sodium reduces blood pressure within one hour of administration, the maximum effect being observed within 3-6 hours. With the usual daily dosage, the anti-hypertensive effect lasts for 24 hours. In some patients receiving lower dosages the effect may be reduced at the end of the dosage interval. The orthostatic effects and tachycardia are rare but might occur in patients with salt depletion or in hypovolemia (see section 4.4). In some patients the development of optimal blood pressure reduction may require 3-4 weeks of therapy. Fosinopril sodium and thiazide diuretics have additive effects. In heart failure, fosinopril sodium improves symptoms and exercise tolerance and reduces the severity of and frequency of hospitalisation due to cardiac failure. In a study of 8 cirrhotic patients, fosinopril 20 mg/day for one month did not change hepatic (alanine transferase, gamma-glutamyl-transpeptidase, galactose clearance test and antipyrine clearance test) or renal functions.
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.
Reduction of blood pressure with low (0.1mg/kg), medium (0.3mg/kg) and high (0.6mg/kg) target doses of once-daily fosinopril was evaluated in a randomised double-blind study of 252 children and adolescents aged 6 to 16 years of age with hypertension or high-normal blood pressure. At the end of the four weeks of treatment, the mean reduction from baseline in trough systolic blood pressure was similar for children treated with low, medium and high dose fosinopril. No dosage response relationship was demonstrated between the three doses. The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighting less than 50kg.
After oral administration, the extension of the absorption of fosinopril averages 30% to 40%. The absorption of fosinopril is not affected by the presence of food in gastrointestinal tract, however the speed of the absorption might be reduced. Rapid and complete hydrolysis to active fosinoprilat occurs in the gastrointestinal mucosa and liver. The time to reach the maximum plasma concentration is approximately three hours and is independent of administered dose. After multiple or single doses, the pharmacokinetic parameters (Cmax, AUC) are directly proportional to the fosinopril dose that has been taken.
Fosinoprilat is protein bound (>95%), but has a negligible binding to blood cellular components.
One hour after oral administration of fosinopril sodium, less than 1% fosinopril in plasma remains unchanged; 75% is present as active fosinoprilat, 15-20% as fosinoprilat glucuronide (inactive), and the remainder (~5%) as the 4-hydroxy metabolite of fosinoprilat (active).
After intravenous administration, the elimination of fosinopril is by both hepatic and renal routes. In hypertensive patients that receive repeated doses of fosinopril and have normal renal and hepatic functions, the fosinoprilat elimination half-life is 11.5 hours, being of 14 hours in patients with cardiac failure.
In patients with renal failure (creatinine clearance <80 ml/min/1,73 m²), the total fosinoprilat body clearance is approximately half of that observed in patients with normal renal function, while no significant changes are seen in the absorption, the bioavailability and the plasma protein binding. The fosinoprilat clearance does not vary according with the degree of renal failure; the reduction in renal elimination is compensated by the increase in hepato-biliary elimination. A slight increase in AUC values (less than the double of normal values) has been observed in patients with several degrees of renal failure, including terminal renal failure (creatinine clearance <10 ml/min/1.73 m²).
In patients with hepatic failure (alcoholism or biliary cirrhosis), the fosinopril hydrolysis is not significantly reduced, although the rate of the hydrolysis might be reduced; the total fosinoprilat clearance is almost half of the clearance observed in patients with normal hepatic function.
Limited pharmacokinetic data in children and adolescents were provided by a single-dose pharmacokinetic study in 19 hypertensive patients 6 to 16 years of age who received 0.3mg/kg of a solution of fosinopril.
Whether AUC and Cmax values of fosinoprilat (active form of fosinopril) in children from 6 to 16 years of age were comparable to those seen in adults receiving 20mg of fosinopril as a solution, has to be demonstrated.
The terminal elimination half-life for fosinoprilat was 11-13 hours and similar at all stages studied.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that fosinopril has no negative effects on fertility and reproductive performance in rats, and is not teratogenic. ACE inhibitors, as a class, when given in the second or third trimester, have been shown to induce adverse effects on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal reninangiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrient delivery to the foetus. In a study in which female rats were dosed with fosinopril prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The substance has been shown to cross the placenta and is secreted in milk.
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