Aqumeldi · 4.8 Undesirable effects · 1

HOS-288475 · has-adverse-reaction-information · PDF-Seite 11

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 AQUMELDI 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. Adverse reactions Frequency Nervous system disorders Dizziness postural Common Vascular disorders Hypotension Common Respiratory, thoracic and mediastinal disorders Cough Common Gastrointestinal disorders Vomiting Common Investigations Hyperkalaemia Common Microalbuminuria Common 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 Adverse reactions Frequency Blood and lymphatic system disorders Aplastic anaemia Uncommon Haemolytic anaemia Uncommon Anaemia Uncommon Bone marrow depression Rare Neutropenia

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HOS-288471 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or any other angiotensin converting enzyme inhibitor (ACEi). • History of angioedema associated with previous ACE inhibitor therapy. • Hereditary or idiopathic angioedema. • Second and third trimesters of pregnancy (see sections 4.4 and 4.6). • The concomitant use of AQUMELDI with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). • Combination with sacubitril/valsartan (a medicinal product containing a neprilysin inhibitor) due to the increased risk of angioedema. AQUMELDI is not to be administered within 36 hours of switching to or from sacubitril/valsartan (see sections 4.4 and 4.5). • Paediatric patients with severe renal impairment (GFR <30 ml/min/1.73 m2) (see section 4.2).

HOS-288470 · has-indication-information · PDF-Seite 2

AQUMELDI is indicated for the treatment of heart failure in children from birth to less than 18 years.

HOS-288473 · has-interaction-information · PDF-Seite 8

No interaction studies have been performed with AQUMELDI in the adult or paediatric population. Interaction studies with enalapril have only been performed in adults. Blockade of the renin-angiotensin-aldosterone system (RAAS) Clinical study data have shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium sparing diuretics, potassium supplements, or other medicinal products that may increase serum potassium 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 (see section 4.4). Diuretics (thiazide or loop diuretics) Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril (see section 4.4). 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. Antihypertensives 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. Lithium 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 (see section 4.4). Tricyclic antidepressants/antipsychotics/anaesthetics/narcotics Concomitan

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HOS-288474 · has-pregnancy-information · PDF-Seite 10

Pregnancy 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. AQUMELDI is contraindicated during the second and third trimester of pregnancy and is not recommended in the first trimester (see section 4.3 and 4.4). 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 (see sections 4.3 and 4.4). Breast-feeding AQUMELDI and its metabolites are excreted in human milk to such an extent that effects on the breastfed newborns/infants cannot be excluded (see section 5.2). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from AQUMELDI 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 (see section 5.3).

HOS-288472 · has-warning-information · PDF-Seite 4

Symptomatic hypotension In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of AQUMELDI and/or diuretic is adjusted. Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with AQUMELDI. This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or AQUMELDI may be necessary. If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution for injection. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion. Aortic or mitral valve stenosis/hypertrophic cardiomyopathy 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. Renal impairment Renal failure has been reported in association with enalapril and has been seen mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with enalapril therapy is usually reversible (see section 4.8). Some hypertensive patients, with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic. Dose reduction of enalapril and/or discontinuation of the diuretic may be required (see section 4.2). This situation should raise the possibility of underlying renal artery stenosis (see renovascular hypertension

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