Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Menarini International Operations Luxembourg S.A., 1 Avenue de la Gare, 1611 Luxembourg
Pharmacotherapeutic group: ACE inhibitor
ATC code: C09AA15
The beneficial effects of ZOFENIL in hypertension and acute myocardial infarctionappear to result primarily from the suppression of the plasma renin-angiotensin aldosterone system. Inhibition of ACE (Ki 0.4 nM in rabbit lung for arginine salt of zofenoprilat) results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity.The plasma ACE activity is suppressed by 53.4% and 74.4% at 24 hours after administration of single oral doses of 30 mg and 60 mg zofenopril calcium respectively.
Inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin-system, which contributes to peripheral vasodilatation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effect of zofenopril calcium and is responsible for certain side effects.
In patients with hypertension, administration of ZOFENIL results in a reduction of supine and standing blood pressure to about the same extent, with no compensatory increase of the heart rate. Mean systemic vascular resistance tends to decline after ZOFENIL administration.
Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy.
Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure.Currently there are no data regarding the effects of ZOFENIL on morbidity and mortality in hypertensive patients.
Although antihypertensive effects have been found in all races studied, black hypertensive patients (usually a low-renin hypertensive population) has a smaller average response to ACE inhibitor monotherapy than non-black patients. This difference disappears when a diuretic is added.
The clinical effect resulting from the early use of ZOFENIL following myocardial infarction may be linked to many factors such as the reduction in plasma levels of angiotensin II (in this way limiting the process of ventricular remodelling which can negatively influence the quod vitam prognosis of the infarction patient), and the increase in plasma/tissue concentrations of vasodilator substances (prostaglandins-kinin system)
A randomised, placebo-controlled clinical trial of zofenopril was performed in 1,556 patients with anterior myocardial infarction who had not received thrombolytic therapy. Treatment was begun within 24 hours and continued for 6 weeks. The incidence of the primary combined endpoint (severe heart failure and/or death at 6 weeks) was reduced in zofenopril-treated patients (zofenopril 7.1%, placebo 10.6%). At one year, the survival rate was improved in the ZOFENILgroup.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of 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. CV 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.
Zofenopril calcium is a prodrug, since the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from thio-ester hydrolysis.
Zofenopril calcium is rapidly and completely absorbed by the oral route and undergoes nearly complete conversion to zofenoprilat, which reaches peak blood levels after 1.5 h following an oral dose of ZOFENIL. Single dose kinetics are linear over a dose-range of 10-80 mg of zofenopril calcium and no accumulation occurs after the administration of 15-60mg of zofenopril calcium for 3 weeks. The presence of food in the gastrointestinal tract reduces the rate but not the extent of absorption and the AUCs of zofenoprilat are nearly identical in the fasted or fed state.
Approximately 88% of the circulating radioactivity measured ex-vivo following a radiolabelled dose of zofenopril calcium is bound to plasma protein and the steady state volume of distribution is 96 litres.
Eight metabolites, accounting for 76% of the urinary radioactivity, were identified in human urine following a radiolabelled dose of zofenopril calcium. The main metabolite is zofenoprilat (22%), which is then metabolized through several pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), cysteine conjugation (9%) and S-methylation of the thiol group (8%). Half-life of zofenoprilat is 5.5 h and its total body clearance is 1300 ml/min following oral zofenopril calcium.
Radiolabelled zofenoprilat administered intravenously is eliminated in urine (76%) and faeces (16%) while following an oral dose of radiolabelled zofenopril calcium, 69% and 26% of the radioactivity is recovered in urine and faeces respectively, indicating a dual route of elimination (kidney and liver).
In the elderly, no dose adjustment is required when the renal function is normal. Pharmacokinetics in renal dysfunction: Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled zofenopril calcium, patients with mild renal impairment (creatinine clearance >45 and <90 ml/min) eliminate zofenopril from the body at the same rate as normal subjects (creatinine clearance >90 ml/min).
In patients with moderate to severe renal impairment (7-44 ml/min), the rate of elimination is reduced to about 50% of normal. This indicates that these patients should be given half the usual starting dose of ZOFENIL.
In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the rate of elimination is reduced to 25% of normal. This indicates that these patients should be given a quarter of the usual starting dose of ZOFENIL.
In patients with mild to moderate hepatic dysfunction given single doses of radiolabelled zofenopril calcium, the Cmax and Tmax values for zofenoprilat were similar to those in normal subjects. However, AUC values in cirrhotic patients were about twice those obtained for normal subjects, indicating that the initial dose of ZOFENIL for patients with mild to moderate hepatic dysfunction should be half of that for patients with normal hepatic function.
There are no pharmacokinetic data of zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.
In repeat oral dose toxicity studies conducted in three mammalian species most of the treatment related effects where those usually reported for ACE inhibitors. These changes included a decrease in erythrocytic parameters, an increase in serum urea nitrogen, a decrease in heart weight and hyperplasia of the juxta-glomerular cells which occurred at dose levels much higher than the maximum recommended human dose. In a repeat dose oral toxicity study in the dog, species-specific immunologically-mediated blood dyscrasias occurred at high dose levels.
No significant changes in cytochrome P450 enzyme activities have been observed in a 1 year repeated oral toxicity study in the monkey.
In reproductive toxicity studies, zofenopril caused a dose related reduction in growth rate in offspring and also nephrotoxicity and reduced postnatal viability at dose levels of 90 and 270 mg/kg in the F1 generation. Treatment with zofenopril during pregnancy caused foetal and developmental toxicity in offspring in the rat and also embryo- and feto-toxicity in the rabbit but only at maternally toxic dose levels.
Genotoxicity studies showed that zofenopril was not mutagenic or clastogenic.
Carcinogenicity studies conducted in mice and rats revealed no evidence of carcinogenicity. An increased incidence of testicular atrophy occurred only in the mouse study, the clinical significance of which is unknown.
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