Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Proveca Pharma Limited, 2 Dublin Landings, North Wall Quay, Dublin 1, Ireland
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitors, plain
ATC code: C09AA02
Enalapril maleate is the maleate salt of enalapril, a derivative of two amino-acids, L-alanine and Lproline.
After oral administration in adults, enalapril is hydrolysed via hepatic CES 1 to the active metabolite enalaprilat, which acts as an ACE inhibitor. ACE is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and hence inhibition of ACE results in decreased plasma angiotensin II. This also leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion. The mechanism of action of enalapril is therefore primarily via the suppression of the RAAS. However, ACE is identical to kininase II, and so enalapril may also exert its effects by blocking the degradation of bradykinin, a potent vasodepressor peptide. Questions remain regarding the differential effects of ACE inhibition on RAA axis depending on the paediatric age range in question.
Exploratory pharmacodynamics for brain natriuretic peptides (Nt-proBNP), shortening fraction and RAAS associated with enalapril orodispersible tablets in children with heart failure were studied in two clinical studies; 32 children aged 1 month to <12 years with heart failure due to dilated cardio myopathy (DCM) (WP08) and 70 children aged birth to 6 years with heart failure due to congenital heart disease (CHD) (WP09). Mean age 555 days, mean weight 8.92 kg and height 74.01 cm. 46% were females and 54% were males. The data are presented below.
In children with DCM, Nt-proBNP median values (range) did not change from 32 (5 to 1 777) pmol/l at the start to 35 (3 to 1 302) pmol/l (p=ns) at the end of the study. Only 10% of patients in this cohort were ACEi naïve. In children with CHD, Nt-proBNP levels were lower at the end of the study compared to the beginning. The median Nt-proBNP value at the start of the study were 171 (1 to 2 789) pmol/l and 73 (5 to 2 165) pmol/l (p=ns) at the end. In this cohort 44% of patients were naïve to ACEi treatment.
In patients with DCM, echocardiography (shortening fraction) mean values (±SD)) slightly, but significantly increased in all patients from 22.3% (SD 7.3) to 25.1% (SD 7.8) (p<0.05, t-test) reflecting an improvement of the cardiac conditions of the patients in all age groups. In patients with CHD, shortening fraction remained almost the same during the study period. Mean values (±SD) at the screening and end of study visits were 38.7% (SD 8.6) and 38.5% (SD 6.2) respectively.
In terms of effects on the RAAS, renin, plasma renin activity and angiotensin I, all increased at the end of the two studies compared to pre-dose values. Aldosterone concentrations had decreased at 4 hours after administration of enalapril orodispersible tablets as well as at the end of the study. The observed changes were unlikely to be a consequence of the natural course of disease or maturation-dependent changes of the RAAS system. A comparable trend for the 4 parameters of the RAAS system was observed in ACEi naïve and ACEi pre-treated cohorts, with the main difference being in the baseline pre-dose values. The observed changes in markers of the RAAS during the course of enalapril orodispersible tablets treatment lie within the expected pattern of ACE inhibition.
Data on the use of Aqumeldi in children below 1 month of age in the clinical studies is scarce (n=4).
Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril tablet is approximately 60%. Enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin converting enzyme inhibitor.
The absorption of AQUMELDI orodispersible tablets is not expected to be affected by food.
As described in the adult population, over the range of concentrations, which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60%. In adults, the apparent volume of distribution (V/F) of enalapril from AQUMELDI was 93.15 L (SD 33.23 L).
Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril.
Excretion of enalaprilat is primarily renal. In adults, after a single oral dose of enalapril (10 mg), 18% of the administered dose was found in urine and 6% in faeces as unchanged enalapril compared with 43% of enalaprilat in urine and 27% in faeces. Elimination kinetics of enalaprilat is biphasic, with an initial phase reflecting renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (terminal elimination half-life 36 hours) which is assumed to represent drug equilibration from ACE enzyme binding sites.
Steady state concentrations of enalaprilat are achieved after 3 or 4 doses of enalapril. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril (about 20%). The elimination half-life for enalapril from AQUMELDI in adults was 0.77 h (SD 0.11 h) and oral clearance (CL/F) 87.54 l/h (SD 33.45 l/h).
The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤30 ml/min), AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (see section 4.2). Enalaprilat may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min.
After a single 20 mg oral dose in five postpartum women the average peak enalapril milk level was 1.7 µg/l (range 0.54 to 5.9 µg/l) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7 µg/l (range 1.2 to 2.3 µg/l); peaks occurred at various times over the 24 hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dose.
A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 µg/l 4 hours after a dose and peak enalaprilat levels of 0.75 µg/l about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44 µg/l and 0.63 µg/l of milk respectively.
Enalaprilat milk levels were undetectable (<0.2 µg/l) 4 hours after a single dose of enalapril 5 mg in one mother and 10 mg in two mothers; enalapril levels were not determined.
In children with DCM, dose and weight normalised maximum plasma concentrations (Cmax) were 203 ng/ml/mg × kg for enalapril and 155 ng/ml/mg × kg for enalaprilat, with high coefficients of variation of 73% for enalapril and 61% for enalaprilat. Maximum plasma concentrations (Tmax) were of 1.7 hours for enalapril and 4.6 hours for enalaprilat, after administration of enalapril orodispersible tablet (ODT). In children with CHD, dose and weight normalised maximum plasma concentrations (Cmax) were 274 ng/ml/mg × kg for enalapril and 178 ng/ml/mg × kg for enalaprilat, with high coefficients of variation of 58% for enalapril and 82% for enalaprilat. Maximum plasma concentrations (Tmax) were of 1.8 hours for enalapril and 6.3 hours for enalaprilat, after administration of enalapril ODT.
Data from clinical studies in children with heart failure receiving AQUMELDI allow comparison of the pharmacokinetic parameters in children with DCM and CHD in patients aged 1 month to under 6 years of age (see table below). In this age group, DCM patients showed a 50% lower exposure (AUC) to enalapril, compared to CHD patients. The metabolism of the active metabolite enalaprilat, however, was the same for both groups. The time to achieve maximal concentrations Tmax of enalapril were similar.
| Enalapril | Enalaprilat | Enalapril | Enalaprilat | Enalapril | Enalaprilat | ||
|---|---|---|---|---|---|---|---|
| n | AUCtau,ss,norm (ng/ml·h/mg·kg) | Cmax,ss,norm (ng/ml/mg·kg) | tmax or tmax,ss (h) | ||||
| DCM 1 month to <6 years | 20 | 428.3 (235.5–1338.2) | 1040.1 (0–4468.2) | 136.4 (44–760.8) | 120.4 (0–516.3) | 1.99 (0.93–4.17) | 5.37 (0–12.02) |
| CHF 1 month to <6 years | 60 | 785.1 | 1166.3 | 261.0 | 142.1 | 1.98 | 6.0 |
| p DCM versus CHD | 0.0025 | 0.4517 | 0.051 | 0.9543 | 0.7632 | 0.0095 | |
The elimination half life (T½) for enalapril from AQUMELDI in children was 1.67 h and for enalaprilat was 21.66 h.
Although no published results are available describing the PK of enalapril in children with renal impairment, since the drug and its active metabolite are predominantly renally excreted, impaired renal function is expected to result in elevated levels of enalapril and enalaprilat. Thus, the dose of enalapril should be adjusted accordingly and renal function monitored (see section 4.2).
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 enalapril has no effects on fertility and reproductive performance in rats and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is secreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester.
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