Enalapril Other names: Enalapril maleate

Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensives. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.

The co-administration of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function (such as the elderly or patients who are volume-depleted, including those on diuretic therapy). Therefore, the combination should be administered with caution in patients with compromised renal function. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

No data is available for treatment of paediatric subjects with liver impairment. Dose adjustment is not considered necessary however such children should only be treated with enalapril under strict monitoring. Treatment of children below the age of 1 month with hepatic impairment is not recommended.

In cases of renal impairment (creatinine clearance <80 ml/min) the initial enalapril dosage should be adjusted according to the patient’s creatinine clearance and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients.

Generally, the intervals between the administration of enalapril should be prolonged and/or the dosage reduced.

Dosage in renal insufficiency:

^* Enalaprilat is dialysable. Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Paediatric population

Special precautions should be followed in patients with impaired renal function:

• Enalapril is contraindicated in paediatric patients with glomerular filtration rate (GFR) <30 ml/min/1.73 m².
• GFR ≥50 ml/min/1.73 m²: Dose adjustment not required.
• GFR ≥30-<50 ml/min/1.73 m²: Start with 50% of the single dose and dose at 12 hour intervals.
• For dialysis: Start with 25% of the normal single dose and dose at 12 hour intervals.

The dose should be increased to the highest possible tolerated dose depending on the effect. Depending on the clinical condition of the patient, the creatinine and potassium concentrations should be checked within 2 weeks after the start of treatment and then at least once a year.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensives.

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetics (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Patients taking concomitant vildagliptin therapy may be at increased risk for angioedema.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Concomitant use of these medicinal products may increase the hypotensive effects of enalapril. Concomitant use with nitroglycerine and other nitrates, or other vasodilators, may further reduce blood pressure.

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril. The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of enalapril.

ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium (e.g., heparin, trimethoprim-containing products such as cotrimoxazole) may lead to significant increases in serum potassium. If concomitant use of enalapril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Blockade of RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and be subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in reduction of blood pressure.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and enhance the risk of lithium toxicity with ACE inhibitors. Use of enalapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

In patients undergoing major surgery or during anaesthesia with medicinal products that produce hypotension, enalapril blocks angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Enalapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If enalapril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

There is no experience regarding the administration of enalapril in patients with a recent kidney transplantation. Treatment with enalapril is therefore not recommended.

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.

Based on human experience ACE inhibitors including enalapril cause congenital malformations (decreased renal function, oligohydramnios, skull ossification retardation, limb contractures, craniofacial deformations and hypoplastic lung development) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) when administered during pregnancy.

Enalapril is contraindicated during the second and third trimester of pregnancy and is not recommended in the first trimester.

Women of childbearing potential must use effective contraception during and up to 1 week after treatment.

Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Enalapril and its metabolites are excreted in human milk to such an extent that effects on the breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from enalapril therapy considering the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of enalapril on fertility are available. In rats, there was no effect on mating or fertility with enalapril treatment.

Enalapril has minor influence on the ability to drive and use machines. Dizziness or weariness may occur which may affect concentration and co-ordination. This may alter the performance at skilled tasks such as driving, riding a bicycle, or using machines.

Summary of safety profile

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%).

Tabulated list of adverse drug reactions

Children

The adverse reaction frequency listed in Table 1 is derived from the clinical studies in children receiving enalapril for heart failure. In total 86 children in these studies received enalapril for up to 1 year; as such the data are limited.

The adverse reactions are listed below by SOC (system organ class) and by frequency, most frequent reactions first, with the following guidelines: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. List of adverse reactions in children with heart failure:

Adults

Enalapril tablets have been evaluated for safety in more than 10 000 adult patients and in controlled clinical studies involving 2 314 hypertensive patients and 363 patients with congestive heart failure. Adverse reactions and frequency in the adult population is listed in Table 2.

Table 2. List of adverse reactions in the adult population:

^* A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.

Paediatric population

Blood pressure and heart rate

Following the first ingestion of enalapril no changes were reported in blood pressure or heart rate in naïve or ACEi pre-treated paediatric heart failure patients during the 8-h observation period. Over the first 8 weeks of treatment, mean values of blood pressure did not change over time. The same trend was observed for heart rate. Mean arterial pressure (MAP), based on systolic and diastolic blood pressure, increased in every age group throughout the duration of the subsequent 10-month study period except for children aged 6-12 months where it showed a minor decrease.

Renal safety parameters

Over the 12-month study period treatment, serum creatinine, blood urea nitrogen (BUN), GFR and potassium levels were generally within normal range and constant in paediatric patients with heart failure. The only difference being in children aged from birth to 3 months where BUN levels were significantly higher at the end of the study compared to the start, mean (± standard deviation (SD)) 4.4 (±1.8) vs 2.8 (±1.4), p=0,0001). In paediatric patients with heart failure, microalbuminuria was consistently reported in only one patient with dilated cardiomyopathy from the first study visit. As this patient prematurely left the study and was lost to follow-up, only limited data are available.

Microalbuminuria was incidentally reported in three other cases, but at other visits microalbumin was within normal range. For the remaining patients values were similar in all age groups throughout the study.