Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom
Pharmacotherapeutic group: ACE inhibitor
ATC code: C09AA08
Vascace is a specific, long-acting angiotensin-converting enzyme (ACE) inhibitor which suppresses the renin-angiotensin-aldosterone system and thereby the conversion of the inactive angiotensin I to angiotensin II, which is a potent vasoconstrictor. At recommended doses, the effect of Vascace in hypertensive patients and in patients with chronic heart failure is maintained for up to 24 hours.
Vascace induces a reduction of both supine and standing systolic and diastolic blood pressure, usually with no orthostatic component. It is effective in all degrees of essential hypertension as well as in renal hypertension. The antihypertensive effect of Vascace is usually apparent within the first hour after administration, with maximum effect observed between 3 and 7 hours after dosing. In general, the heart rate remains unchanged. Reflex tachycardia is not induced, although small, clinically insignificant alterations of heart rate may occur. In some patients blood pressure reduction may diminish towards the end of the dosage interval.
The antihypertensive effect of Vascace is maintained during long-term therapy. No rapid increase in blood pressure has been observed after abrupt withdrawal of Vascace.
In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate and renal blood flow generally remained unchanged with Vascace, despite a clinically significant blood pressure reduction.
As with other ACE inhibitors, the blood pressure-lowering effect of Vascace in black patients may be less pronounced than in non-blacks. However, racial differences in response are no longer evident when Vascace is administered in combination with hydrochlorothiazide.
No clinical trials have been carried out which prove the effect of cilazapril on morbidity and mortality in heart failure.
In patients with chronic heart failure, the renin-angiotensin-aldosterone and sympathetic nervous systems are generally activated, leading to enhanced systemic vasoconstriction and promotion of sodium and water retention. By suppressing the renin-angiotensin-aldosterone system, Vascace improves loading conditions in the failing heart by reducing systemic vascular resistance (afterload) and pulmonary capillary wedge pressure (preload) in patients on diuretics and/or digitalis. Furthermore, the exercise tolerance of these patients increases significantly. The haemodynamic and clinical effects occur promptly and persist.
Cilazapril is efficiently absorbed and rapidly converted to the active form, cilazaprilat. Ingestion of food immediately prior to Vascace administration delays and reduces absorption to a minor extent which, however, is therapeutically irrelevant. The bioavailability of cilazaprilat from oral cilazapril approximates 60%, based on urinary recovery data. Maximum plasma concentrations are reached within 2 hours after administration and are directly related to dosage.
Cilazaprilat is eliminated unchanged by the kidneys, with an effective half-life of 9 hours after once daily dosing with Vascace.
In patients with renal impairment, higher plasma concentrations of cilazaprilat are observed than in patients with normal renal function, since drug clearance is reduced when creatinine clearance is lower. There is no elimination in patients with complete renal failure, but haemodialysis reduces concentrations of both cilazapril and cilazaprilat to a limited extent.
In elderly patients whose renal function is normal for age, plasma concentrations of cilazaprilat may be up to 40% higher and clearance 20% lower, than in younger patients.
In patients with liver cirrhosis increased plasma concentrations and reduced plasma and renal clearance were observed, with a greater effect on cilazapril than on its active metabolite cilazaprilat.
In patients with chronic heart failure, clearance of cilazaprilat is correlated with creatinine clearance. Thus, dosage adjustments beyond those recommended for patients with impaired renal function (see section 4.2) should not be necessary.
Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Angiotensin converting enzyme inhibitors, as a class, 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 renin-angiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.
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