Pharmacokinetics in children

Enalaprilat t½ = 14-16 hours (study in children aged 1 month-16 years)
enalaprilat t½ = 11±5 hours (study in children aged < 1 year)

enalaprilat after a single dose tmax = 4-8 hours
enalaprilat after repeated doses tmax = 3-4 hours
enalapril tmax = 1 hour

From a study of 10 children aged under 1 year:
children aged under 20 days convert enalapril into enalaprilat more slowly. The AUC per dose, normalized per kg or for body surface area, is conversely a factor of 5-6 times higher than in children aged > 20 days.

	Enalapril	Enalaprilat
Dilated cardiomyopathy patients
Tmax (hours)	1,7	4,6
Cmax (ng/ml/mg)	203	155
Congestive heart failure patients
Tmax (hours)	1,8	6,3
Cmax (ng/ml/mg)	274	178

Source: SmPC Aqumeldi

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Hypertension, proteinuria

Oral Term neonate [1] [2] [5] [7] Initial dose: Enalaprilmaleate: 0.01 mg/kg/day in 2 doses. Maintenance dose: Depending on the effect and side effects, increase to 0.01 - 0.1 mg/kg/day in 2 doses. Caution is needed in neonates because they can be very sensitive to this medicine. Be aware of the possibility of hypotension 1 month up to 18 years and < 20 kg [1] [2] [3] [4] [8] [9] Enalaprilmaleate: 0.1 mg/kg/day in 2 doses. Max: 1 mg/kg/day. 1 month up to 18 years and 20 up to 50 kg [1] [2] [3] [4] [6] [8] [9] Initial dose: Enalaprilmaleate: 0.1 mg/kg/day in 2 doses. Maintenance dose: 0.1 - 0.5 mg/kg/day in 2 doses. Max: 20 mg/day. 1 month up to 18 years and ≥ 50 kg [1] [2] [3] [4] [6] [8] [9] Initial dose: Enalaprilmaleate: 0.1 mg/kg/day in 2 doses. Maintenance dose: 0.1 - 0.5 mg/kg/day in 2 doses. Max: 40 mg/day.

Cardiac failure

Oral Term neonate [16] Starting (test) dose 0,01-0,04 mg/kg/dose, max 2 mg. Monitor bloodpressure every 1-2hours.  If well tolerated continue treatment after 8 hours.   0.15 - 0.3 mg/kg/day in 1 - 2 doses. Max: 20 mg/day. 1 month up to 18 years [16] Starting (test) dose 0,01-0,04 mg/kg/dose, max 2 mg. Monitor bloodpressure every 1-2hours.  If well tolerated continue treatment after 8 hours.   0.15 - 0.3 mg/kg/day in 1 - 2 doses. Max: 20 mg/day.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Dose adjustment is not required

GFR 30-50 ml/min/1.73 m2

50 percentage of single dose and dosing interval : 12 uur
. Then set the dose depending on the effect to the highest possible tolerated dose. The concentrations of creatinine and potassium must be checked within 2 weeks of commencing the treatment and then at least once a year, depending on the clinical condition of the patient.

GFR 10-30 ml/min/1.73 m2

25 percentage of single dose and dosing interval : 12 uur
. Then set the dose depending on the effect to the highest possible tolerated dose. The concentrations of creatinine and potassium must be checked within 2 weeks of commencing the treatment and then at least once a year, depending on the clinical condition of the patient.

GFR < 10 ml/min/1.73 m2

Generalized recommendations cannot be given.

Clinical consequences

ACE inhibitors lower the intraglomerular filtration pressure and reduce proteinuria. This means that they probably have a protective effect on renal function in the longer term. For this reason, the highest possible tolerated dose is often given in secondary care in cases of reduced renal function. When commencing an ACE inhibitor, the serum creatinine concentration can rise as a result of a decrease in the intraglomerular filtration pressure.

Patients on dialysis

25% of the normal dose each time and the interval between two doses: 12 hours. Then set the dose depending on the effect to the highest possible tolerated dose.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

The most frequent drug related adverse reactions reported in children were cough (5.7%), vomiting (3.1%), microalbuminuria (3.1%), hyperkalaemia (2.9%), hypotension (1.4%), and postural dizziness (1.2%). (SmPC Aqumeldi)

Also reported:  Taste loss, exanthema, leukopenia.

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications in children

There is no data known about application after a kidney transplant.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Only give with sufficient hydration. Be careful in combination with diuretics. Monitor the renal function and potassium.

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

References

1. Wells T, et al, The pharmacokinetics of enalapril in children and infants with hypertension, J Clin Pharmacol, 2001, Oct;41(10), 1064-74
2. Nakamura H, et al, The kinetic profiles of enalapril and enalaprilat and their possible developmental changes in pediatric patients with congestive heart failure, Clin Pharmacol Ther, 1994, Aug;56(2), 160-8
3. Wells T, et al, A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension, J Clin Pharmacol, 2002, Aug;42(8):, 870-80
4. Rouine-Rapp K, et al, Effect of enalaprilat on postoperative hypertension after surgical repair of coarctation of the aorta, Pediatr Crit Care Med, 2003, Jul;4(3), 327-32
5. Hsu DT, et al , Enalapril in infants with single ventricle: results of a multicenter randomized trial, Circulation, 2010, Jul 27;122(4):, 333-40
6. MSD BV, SPC Renitec (RVG 10575) 06-08-2015, www.geneesmiddeleninformatiebank.nl
7. Lindle KA, et al., Angiotensin-converting enzyme inhibitor nephrotoxicity in neonates with cardiac disease, Pediatr Cardiol, 2014, Mar;35(3), 499-506
8. Lurbe E, et al., Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension, J Hypertens, 2009, Sep;27(9), 1719-42
9. Di Salvo G, et al. , Atenolol vs enalapril in young hypertensive patients after successful repair of aortic coarctation, J Hum Hypertens, 2016, 30, 363-7
10. TAD Pharma GmbH, SmPC, Corvo 2,5/5/10/20 mg Tabletten (42698.00.00), 09/14
11. Hexal AG, SmPC, Enalapril Sandoz 30/40 mg Tabletten (67838.00.00/67839.00.00), 06/17
12. BERLIN-CHEMIE AG, SmPC, Benalapril 5/10/20 mg Tabletten (3001069.00.00), 03/19
13. Hexal AG, SmPC, EnaHEXAL® i.v. 1,25 mg Injektionslösung (26672.01.00), 06/17
14. MSD SHARP & DOHME GMBH, SmPC, Xanef® 2,5/5/10/20 mg Tabletten (30056.00.00), 09/18
15. Uptodate, Pediatric drug information: Enalapril Topic 83360 Version 217.0, accessed 03/19
16. Proveca Pharma Limited, SmPC Aqumeldi (EU/1/23/1717/001-003) 22-11-2023, www.ema.europa.eu

Changes