Enalapril krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL KRKA (ENALAPRIL KRKA)

Composition:

Active substance: enalapril maleate;

1 tablet contains 2.5 mg or 5 mg or 10 mg or 20 mg of enalapril maleate;

Excipients:

tablets of 2.5 mg and 5 mg: sodium hydrogencarbonate, lactose monohydrate, maize starch, hydroxypropylcellulose, talc, magnesium stearate;

tablets of 10 mg and 20 mg: sodium hydrogencarbonate, lactose monohydrate, maize starch, talc, magnesium stearate, iron oxide red (E 172), iron oxide yellow (E 172) – only for 20 mg tablets.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2.5 mg tablets: white, round, biconvex tablets with beveled edges;

5 mg tablets: white, round, flat tablets with beveled edges and a notch on one side;

10 mg tablets: reddish-brown, round, flat tablets with beveled edges and a notch on one side, with white specks on the surface and throughout the tablet mass;

20 mg tablets: light orange, round, flat tablets with beveled edges and a notch on one side, with white specks on the surface and throughout the tablet mass.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors, single component. ATC code C09A A02.

Pharmacological Properties.

Pharmacodynamics.

Enalapril maleate is the maleic acid salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to suppression of the negative feedback of angiotensin II on renin release) and decreased aldosterone secretion.

ACE is identical to kininase II. Thus, enalapril may also block the degradation of bradykinin, a potent vasodilator peptide. However, the significance of this effect for the therapeutic action of enalapril remains unclear.

The mechanism by which enalapril lowers blood pressure is primarily related to inhibition of the renin-angiotensin-aldosterone system. Enalapril can exert an antihypertensive effect even in patients with low-renin hypertension.

Administration of enalapril to patients with arterial hypertension results in reduction of blood pressure in both supine and upright positions without significant increase in heart rate.

Symptomatic postural hypotension is infrequent. In some patients, optimal blood pressure reduction may require several weeks of therapy. Abrupt discontinuation of enalapril has not been associated with rapid rebound increase in blood pressure.

Effective inhibition of ACE activity usually occurs 2–4 hours after oral administration of a single dose of enalapril. Antihypertensive activity typically begins within 1 hour, with peak blood pressure reduction achieved 4–6 hours after dosing. The duration of effect is dose-dependent. However, with recommended doses, antihypertensive and hemodynamic effects have been shown to be maintained for at least 24 hours.

In hemodynamic studies in patients with arterial hypertension, the reduction in blood pressure was accompanied by decreased peripheral arterial resistance, increased cardiac output, and little or no change in heart rate. Renal blood flow increased after enalapril administration; glomerular filtration rate remained unchanged. There was no evidence of sodium or water retention. However, in patients with low baseline glomerular filtration rates, these values usually increased.

In short-term clinical studies in patients with or without diabetes and kidney disease, enalapril administration was associated with reduced albuminuria, urinary excretion of IgG, and total urinary protein.

When used concomitantly with thiazide-like diuretics, the blood pressure-lowering effects of enalapril are at least additive to those of diuretics. Enalapril may reduce or prevent thiazide-induced hypokalemia. In patients with heart failure receiving cardiac glycosides and diuretics, enalapril reduces peripheral resistance and blood pressure, increases cardiac output, and decreases heart rate (which is typically elevated in heart failure patients). Pulmonary capillary wedge pressure is reduced. Enalapril therapy improves exercise tolerance and reduces severity of heart failure as assessed by New York Heart Association criteria. These benefits are maintained throughout long-term enalapril therapy.

In patients with mild to moderate heart failure, enalapril slows the progression of myocardial dilation and heart failure, as evidenced by reduced left ventricular end-diastolic and end-systolic volumes and improved ejection fraction.

There is limited experience regarding the efficacy and safety of enalapril use in children aged 6 years and older with arterial hypertension. A clinical study included 110 children aged 6 to 16 years with arterial hypertension, body weight ≥ 20 kg, and glomerular filtration rate > 30 mL/min/1.73 m². Patients with body weight < 50 kg received 0.625 mg, 2.5 mg, or 20 mg of enalapril daily, while patients with body weight ≥ 50 kg received 1.25 mg, 5 mg, or 40 mg of enalapril daily. Once-daily enalapril reduced diastolic blood pressure in a dose-dependent manner.

The dose-dependent antihypertensive effect of enalapril was consistent across all subgroups (age, Tanner stage, sex, race). Study results indicate that the lowest doses, 0.625 mg and 1.25 mg (corresponding to an average dose of 0.02 mg/kg/day), did not provide therapeutic efficacy. The maximum dose was 0.58 mg/kg (40 mg) once daily. The adverse event profile in children was similar to that observed in adult patients.

Pharmacokinetics.

Absorption

Enalapril is rapidly absorbed from the gastrointestinal tract, with peak serum concentrations reached within 1 hour. The extent of absorption is approximately 60%, and food intake does not affect absorption. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Maximum serum concentrations of enalaprilat are reached 4 hours after oral administration of enalapril. The elimination half-life of enalaprilat after multiple doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved within 4 days of treatment.

Distribution

Over the entire therapeutic concentration range, 60% of enalaprilat is protein-bound in plasma.

Metabolism

After absorption, enalapril is rapidly hydrolyzed to form the active metabolite enalaprilat, a potent inhibitor of ACE.

Elimination

Enalaprilat is primarily eliminated by the kidneys. The main components in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

Renal Impairment

In patients with renal impairment, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal impairment (creatinine clearance 0.6–1 mL/s), steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after 5 mg once daily. In patients with severe renal impairment (creatinine clearance 0.5 mL/s), AUC increases approximately 8-fold. At these levels of renal impairment, the effective elimination half-life of enalaprilat is prolonged and the time to reach steady state is increased (see "Dosage and Administration").

Enalaprilat can be removed from the systemic circulation by hemodialysis. The dialysis clearance of enalaprilat is 1.03 mL/s.

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.
• Treatment of clinically manifest heart failure.
• Prevention of clinically manifest heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction < 35%).

Contraindications.

• Hypersensitivity to enalapril, to any other ingredient of the medicinal product, or to other angiotensin-converting enzyme (ACE) inhibitors.
• History of angioedema associated with previous treatment with ACE inhibitors.
• Pregnancy or planning pregnancy (see sections "Special warnings and precautions for use", "Use during pregnancy or lactation").
• Hereditary or idiopathic angioedema.

Enalapril must not be used concomitantly with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Concomitant use with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Enalapril CRKA must not be administered within 36 hours after the last dose of sacubitril/valsartan – a medicinal product containing a neprilysin inhibitor – or after switching from it to another medicinal product (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive therapy

Concomitant use of antihypertensive agents may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may additionally reduce blood pressure.

Potassium-sparing diuretics, potassium supplements, or other medicinal products that may increase serum potassium levels

ACE inhibitors enhance diuretic-induced potassium loss. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), dietary supplements, salt substitutes containing potassium, or other medicinal products that may increase serum potassium levels (e.g., trimethoprim-containing preparations), especially in patients with renal impairment, may lead to significant increases in serum potassium levels. If concomitant use of enalapril with the above-mentioned agents is considered appropriate, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special warnings and precautions for use").

Diuretics (thiazide or loop diuretics)

Prior treatment with high-dose diuretics may lead to reduced blood volume and increase the risk of arterial hypotension at the start of enalapril therapy (see section "Special warnings and precautions for use"). Hypotensive effects may be minimized by discontinuing the diuretic, increasing salt intake, or initiating therapy with a low dose of enalapril.

Other antihypertensive agents

Concomitant use of enalapril with other antihypertensive agents may increase the antihypertensive effect of enalapril. Enalapril may be used together with any other agents for the treatment of arterial hypertension. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may additionally reduce blood pressure.

Lithium

Concomitant use of ACE inhibitors and lithium may lead to transient increases in serum lithium levels and lithium toxicity. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. Concomitant use of enalapril with lithium is not recommended. If such a combination is necessary for a patient, serum lithium levels should be closely monitored.

Tricyclic antidepressants/neuroleptics/anesthetics/narcotics

Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to additional blood pressure reduction.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors

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

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors may have an additive effect on increasing serum potassium and may lead to renal impairment. These effects are usually reversible.

Acute renal failure is rarely possible, particularly in certain patients with impaired renal function (e.g., elderly patients or patients with reduced circulating blood volume, including those taking diuretics). Therefore, such combinations should be used cautiously in patients with renal impairment. Patients should maintain adequate fluid intake and be under close monitoring of renal function at the start of concomitant therapy and periodically during such treatment.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to specific cases only, with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and renal impairment (including acute renal failure) compared to treatment with a single agent acting on the RAAS.

The medicinal product must not be used with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special warnings and precautions for use").

Gold preparations

Rarely, nitrite-like reactions (symptoms include facial flushing, nausea, vomiting, and arterial hypotension) have been reported in patients receiving gold injections (sodium aurothiomalate) concomitantly with ACE inhibitors, including enalapril.

mTOR inhibitors (mammalian target of rapamycin inhibitors)

Concomitant use with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section "Special warnings and precautions for use").

Neprilysin inhibitors

Concomitant use with neprilysin inhibitors (such as sacubitril, racecadotril) may increase the risk of angioedema. Initiation of sacubitril/valsartan therapy is not permitted within 36 hours after the last dose of enalapril. Initiation of enalapril therapy is not permitted within 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special warnings and precautions for use").

Antidiabetic agents

Results of epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycemic agents) may lead to reduced blood glucose levels with a risk of hypoglycemia. This effect may occur during the first weeks of concomitant therapy and in patients with renal insufficiency (see sections "Special warnings and precautions for use" and "Undesirable effects").

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

Enalapril may be safely used concomitantly with acetylsalicylic acid (at cardiologically indicated doses), thrombolytics, and β-blockers.

Special precautions for use.

Symptomatic arterial hypotension

Symptomatic hypotension is very rare in patients with uncomplicated arterial hypertension. It is more likely to occur in patients with arterial hypertension who have reduced blood volume, for example due to diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Symptomatic arterial hypotension may occur in patients with heart failure, with or without concomitant renal impairment. It is more likely to occur in patients with more severe forms of heart failure due to high-dose loop diuretic therapy, hyponatraemia or impaired renal function. Such patients should be treated under medical supervision, and monitoring should be especially careful when changing the dose of enalapril and/or diuretic. This also applies to patients with ischaemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If hypotension develops, the patient should be placed in a supine position and, if necessary, plasma volume should be increased by infusion of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for enalapril treatment. After normalization of blood pressure and plasma volume, patients usually tolerate subsequent doses well.

In some patients with heart failure and normal or low blood pressure, enalapril may cause additional reduction in blood pressure. This effect is expected and usually not a reason to discontinue treatment. If arterial hypotension becomes symptomatic, the dose should be reduced or diuretic and/or enalapril therapy discontinued.

Stenosis of the aortic or mitral valve of the heart / hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be used with caution in patients with obstruction of the left ventricular outflow tract or outflow obstruction; they should be avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Renal function impairment

Patients with impaired renal function (creatinine clearance < 1.33 ml/s (< 80 ml/min)) require dose adjustment according to creatinine clearance, and subsequently according to response to treatment. Serum creatinine and potassium levels should be monitored regularly.

In patients with severe heart failure or kidney disease, including renal artery stenosis, treatment with enalapril may lead to renal failure. When detected early and treated appropriately, it is usually reversible.

In some patients without prior kidney disease, Enalapril KRKA in combination with diuretics has caused slight and transient increases in blood urea nitrogen and serum creatinine. In such cases, the dose should be reduced and/or the diuretic and/or Enalapril KRKA discontinued. This condition may indicate possible renal artery stenosis.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney who are taking angiotensin-converting enzyme inhibitors, transient hypotension or renal failure may occur. Loss of kidney function may occur even with minor changes in serum creatinine. Such patients should start treatment under physician supervision with low doses; careful titration and monitoring of renal function are necessary during treatment.

Kidney transplantation

There is no experience with enalapril use in patients who have recently undergone kidney transplantation; therefore, enalapril is not recommended for such patients.

Hepatic impairment

During treatment with ACE inhibitors, a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes leading to death, may rarely occur. The mechanism of this syndrome is unclear. If jaundice or marked elevation of liver enzymes occurs during treatment with ACE inhibitors, treatment should be immediately discontinued, the patient should be closely monitored, and treatment initiated as necessary.

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and without other complications. Enalapril should be used with extreme caution in patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) who are receiving concomitant therapy with antidepressants, allopurinol or procainamide, or a combination of these factors, especially if renal function is impaired. Serious infections, which sometimes do not respond to intensive antibiotic therapy, may develop in some of these patients. Periodic monitoring of white blood cell count is recommended in such patients. Patients should immediately report any signs of infection.

Hypersensitivity / angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx rarely occurs during treatment with ACE inhibitors, including enalapril. This may occur at any time during treatment. In such cases, treatment should be completely discontinued and appropriate monitoring initiated to ensure all symptoms have completely resolved.

Even if only tongue swelling without respiratory tract involvement is observed, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases due to angioedema of the larynx and tongue have been very rarely reported.

Angioedema of the tongue, glottis or larynx, which may cause airway obstruction, particularly in patients with a history of surgery, may lead to airway obstruction. When the tongue, pharynx or larynx are involved and airway obstruction may occur, appropriate therapy should be initiated immediately, which may include subcutaneous administration of 1:1000 adrenaline solution (0.3 – 0.5 ml) and/or measures to ensure airway patency.

Angioedema occurs more frequently in patients of non-Caucasian race taking ACE inhibitors compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor therapy have an increased risk of developing angioedema during ACE inhibitor treatment (see also section "Contraindications").

Concomitant use of ACE inhibitors with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema.

Concomitant use of ACE inhibitors and neprilysin inhibitors may increase the risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Anaphylactoid reactions during allergen immunotherapy with insect venom

Rarely, anaphylactoid reactions, which may be life-threatening, have occurred in patients receiving ACE inhibitors during allergen immunotherapy with insect venom. Such reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before starting immunotherapy.

Anaphylactoid reactions during low-density lipoprotein apheresis

In patients taking ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate, rare life-threatening reactions similar to allergic (pseudoallergic) reactions may occur. Such reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis.

Patients undergoing haemodialysis sessions

Cases of hypersensitivity, allergic-like (pseudoallergic) reactions, have been reported in patients undergoing dialysis sessions with polyacrylonitrile membranes (e.g., AN 69) and concomitantly taking ACE inhibitors. For such patients, consideration should be given to using other types of dialysis membranes or another class of antihypertensive agents.

Hypoglycaemia

Patients with diabetes mellitus taking oral antidiabetic agents or insulin require careful glycaemic monitoring, especially during the first few months of concomitant treatment with ACE inhibitors.

Cough

Cough has been reported during treatment with ACE inhibitors. The cough is usually non-productive and persistent and resolves after discontinuation of the drug. Cough due to ACE inhibitor therapy should be considered in the differential diagnosis of cough.

Surgery/anaesthesia

In patients undergoing major surgery or anaesthesia with agents causing arterial hypotension, enalapril may block the formation of angiotensin II due to compensatory renin release. If hypotension occurs and is considered to have developed via this mechanism, correction should be performed by increasing fluid volume.

Hyperkalaemia

During treatment with ACE inhibitors, including enalapril, elevated serum potassium levels have been observed in some patients. The risk of hyperkalaemia is increased in patients with renal impairment, impaired renal function, age > 70 years, diabetes mellitus, transient conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium-containing dietary supplements, salt substitutes containing potassium, or other drugs associated with increased serum potassium levels (such as heparin, trimethoprim-containing preparations). Concomitant use of potassium-containing dietary supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase serum potassium levels, particularly in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution and regular monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

Combination of lithium and enalapril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade is necessary, therapy should be conducted under specialist supervision and with continuous monitoring of renal function, electrolyte levels and blood pressure parameters. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Children

There is limited experience with effective and safe use in children aged 6 years and older with arterial hypertension, but no experience with other indications. There are also limited data on pharmacokinetics in children aged 2 months and older (see sections "Dosage and administration" and "Pharmacological properties"). Enalapril is not recommended for treating children with conditions other than arterial hypertension.

Enalapril is not recommended for use in neonates and children with glomerular filtration rate <30 ml/min/1.73 m² due to lack of data (see section "Dosage and administration").

Pregnancy

The medicinal product is contraindicated in pregnant women and women planning pregnancy.

If continued therapy with ACE inhibitors is not considered essential, women planning pregnancy should be switched to alternative antihypertensive treatment with an established safety profile during pregnancy. If pregnancy is detected, ACE inhibitor therapy should be immediately discontinued and, if possible, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or lactation").

Ethnic characteristics

Like other angiotensin-converting enzyme inhibitors, enalapril is less effective in lowering blood pressure in patients of non-Caucasian race compared to other racial groups, possibly because low renin levels are more frequently found in this population of patients with arterial hypertension.

Special warnings regarding inactive ingredients

Enalapril KRKA contains lactose. The product should not be administered to patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy or lactation.

Pregnancy

ACE inhibitors are contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

Women planning pregnancy should be switched to alternative antihypertensive treatment with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be immediately discontinued and, if possible, alternative therapy initiated.

Use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

If ACE inhibitors are used during the second trimester of pregnancy, ultrasound assessment of kidney and skull function is recommended.

Newborns whose mothers took ACE inhibitors should be closely monitored for arterial hypotension (see sections "Contraindications", "Special precautions for use").

Lactation

Limited pharmacokinetic data show very low concentrations in breast milk. Although such concentrations are considered clinically insignificant, use of Enalapril KRKA is not recommended during breastfeeding of preterm infants and infants in the first weeks of life due to a hypothetical risk of cardiovascular and renal effects, and due to insufficient experience with such use. Use of Enalapril KRKA during breastfeeding of older infants may be considered if treatment is necessary for the mother and the infant is monitored for any adverse effects.

Ability to affect reaction speed when driving or operating machinery.

Due to the possible occurrence of side effects such as dizziness, fainting, arterial hypotension, muscle cramps, confusion, drowsiness, blurred vision, driving vehicles or operating machinery should be avoided.

Dosage and Administration

Tablets should be taken whole, with a small amount of water, independent of food intake. The medication should be taken at the same time each day. Two doses must not be taken at the same time.

The initial dose ranges from 2.5 mg to 20 mg, depending on the severity of hypertension and the patient's condition. The drug should be taken once daily. Dose adjustment depends on the achieved reduction in arterial pressure.

Arterial Hypertension

The dose of enalapril ranges from an initial dose of 5 mg to a maximum of 20 mg, depending on the degree of arterial hypertension and the patient's condition (see below). Enalapril Krka should be taken once daily. For mild arterial hypertension, the recommended initial dose is 5–10 mg.

In patients with a highly activated renin-angiotensin-aldosterone system (e.g., renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction in arterial pressure may occur after the initial dose. Such patients should be started on an initial dose of 5 mg or lower, and treatment initiation should be under medical supervision.

Prior treatment with high doses of diuretics may lead to fluid depletion and an increased risk of arterial hypotension at the start of enalapril therapy. For such patients, an initial dose of 2.5 mg to 5 mg is recommended. If possible, diuretic treatment should be discontinued 2–3 days before starting Enalapril Krka. Renal function and serum potassium levels should be monitored.

The usual maintenance dose is 20 mg once daily. The maximum maintenance dose is 40 mg per day.

Heart Failure / Asymptomatic Left Ventricular Dysfunction

For the treatment of clinically manifest heart failure, enalapril maleate is used in combination with diuretics and, if necessary, cardiac glycosides or β-blockers. The initial dose of enalapril for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. Treatment should be initiated under close medical supervision to assess the initial effect of the drug on arterial pressure. In the absence of adverse effects, or after appropriate management of symptomatic hypotension occurring at the beginning of enalapril treatment for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered as a single dose or divided into two doses, depending on patient tolerance.

Dose titration should be performed over 2–4 weeks. This therapeutic regimen has been shown to effectively reduce mortality in patients with clinically manifest heart failure. The maximum dose is 40 mg per day, divided into two doses.

Proposed titration regimen of enalapril maleate for patients with heart failure / asymptomatic left ventricular dysfunction

Week	Dose, mg/day
Week 1	days 1–3: 2.5 mg/day* once daily days 4–7: 5 mg/day in two divided doses
Week 2	10 mg/day in one or two divided doses
Weeks 3 and 4	20 mg/day in one or two divided doses

* The drug should be used with caution in patients with impaired renal function or those receiving diuretics (see section "Special precautions").

Careful monitoring of blood pressure and renal function is required both before and during treatment with enalapril maleate in patients with heart failure (see section "Special precautions"), as cases of hypotension and (less frequently) subsequent renal failure have been reported. Whenever possible, the dose of diuretics should be reduced prior to initiating therapy with Enalapril KRKA. The development of hypotension after the initial dose of enalapril does not necessarily indicate that hypotension will persist during long-term treatment and is not an indication to discontinue the drug. During enalapril therapy, serum potassium levels should also be monitored (see section "Interaction with other medicinal products").

Dosing in renal impairment

For patients with renal impairment, the dosing intervals of enalapril should be prolonged and/or the dose reduced.

Renal status	Creatinine clearance	Initial dose in mg/day
Mild impairment	30–80 mL/min	5–10 mg
Moderate impairment	10–30 mL/min	2.5 mg
Severe impairment. Such patients are usually on hemodialysis*	< 10 mL/min	2.5 mg on dialysis days**

*See section "Special instructions – Patients undergoing hemodialysis".

** Enalapril is removed by hemodialysis. Dosage adjustment on days when hemodialysis is not performed should be based on blood pressure levels.

Use in elderly patients

Dosage should be adjusted according to renal function (see section "Special instructions").

Use in children

There is limited experience with clinical studies of enalapril for the treatment of hypertension in children (see sections "Pharmacological properties", "Special instructions").

Children with hypertension aged 6 years and older

Enalapril KRKA can be used in children aged 6 years and older. Dosage depends on the child's body weight.

The dose should be individually adjusted according to the patient's condition, blood pressure response to treatment, and body weight.

For patients with body weight of 20–50 kg, the recommended initial dose is 2.5 mg once daily. The recommended initial dose for patients with body weight of 50 kg or more is 5 mg once daily. The dose should be adjusted according to the patient's needs. The maximum recommended dose is 20 mg daily for patients with body weight of 20–50 kg and 40 mg/day for patients with body weight > 50 kg, respectively (see section "Special instructions").

Children

Use in children aged 6 years and older.

Enalapril KRKA is not recommended for use in neonates and children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of data.

Overdose.

Data on overdose are limited. The main signs of overdose, according to available data, are profound arterial hypotension starting approximately 6 hours after drug intake, associated with blockade of the renin-angiotensin system, and stupor. Symptoms related to overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma enalaprilat levels reported to exceed 100 and 200 times the maximum levels achieved with therapeutic doses were observed after ingestion of 300 mg and 440 mg of enalapril, respectively.

For treatment of overdose, intravenous infusions of isotonic solution are recommended. If arterial hypotension occurs, the patient should be placed in a supine position. Administration of angiotensin II and/or intravenous catecholamines may be considered. If the drug was recently ingested, measures to eliminate enalapril maleate should be initiated (e.g., vomiting, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special instructions"). In cases of bradycardia resistant to therapeutic measures, treatment with a cardiac pacemaker is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse Reactions

The undesirable effects listed below have been reported during clinical trials and post-marketing surveillance with enalapril, with the following frequencies: very common (≥ 1/10), common (≥ 1/100 < 1/10), uncommon (≥ 1/1000 < 1/100), rare (≥ 1/10,000 < 1/1000), very rare (< 1/10,000), unknown (cannot be estimated from available data).

Blood and lymphatic system disorders:
Uncommon – anaemia (including aplastic and haemolytic);
Rare – neutropenia, decreased haemoglobin, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine system disorders:
Unknown – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders:
Uncommon – hypoglycaemia in diabetic patients treated with oral antidiabetic agents or insulin (see section "Special warnings and precautions for use").

Nervous system and psychiatric disorders:
Common – depression, headache;
Uncommon – confusion, drowsiness, insomnia, nervousness, paraesthesia, vertigo;
Rare – sleep disorders, abnormal dreams.

Eye disorders:
Very common – blurred vision.

Cardiovascular system disorders:
Very common – dizziness;
Common – hypotension (including orthostatic hypotension), syncope, chest pain, cardiac arrhythmia, angina pectoris, tachycardia;
Uncommon – orthostatic hypotension, palpitations, myocardial infarction or stroke*, possibly due to excessive hypotension in high-risk patients (see section "Special warnings and precautions for use");
Rare – Raynaud's phenomenon.

Respiratory system disorders:
Very common – cough;
Common – dyspnoea;
Uncommon – rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma;
Rare – pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia, pharyngitis.

Gastrointestinal disorders:
Very common – nausea;
Common – diarrhoea, abdominal pain, taste disturbances;
Uncommon – intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer;
Rare – stomatitis/aphthous ulcers, glossitis;
Very rare – angioedema of the gastrointestinal tract with concomitant use of ACE inhibitors, including enalapril.

Hepatobiliary disorders:
Rare – hepatic failure, hepatocellular or cholestatic hepatitis, hepatitis including necrosis, cholestasis (including jaundice).

Skin and subcutaneous tissue disorders:
Common – rash, hypersensitivity/angioedema of the face, limbs, lips, tongue, glottis and/or larynx (see section "Special warnings and precautions for use");
Uncommon – increased sweating, pruritus, urticaria, alopecia, facial flushing;
Rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A complex syndrome has been reported, comprising some or all of the following manifestations: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis. Skin rashes, photosensitivity and other skin reactions may also occur as adverse reactions.

Renal and urinary disorders:
Uncommon – renal dysfunction, renal failure, proteinuria;
Rare – oliguria.

Reproductive system disorders:
Uncommon – impotence;
Rare – gynaecomastia.

General disorders and administration site conditions:
Very common – asthenia;
Common – fatigue;
Uncommon – muscle cramps, flushing, tinnitus, discomfort, fever.

Laboratory test abnormalities:
Common – hyperkalaemia, increased serum creatinine;
Uncommon – increased blood urea, hyponatraemia;
Rare – increased liver enzymes, increased serum bilirubin.

* Incidence rates were comparable to those in placebo and active control groups in clinical trials.

Treatment should be discontinued in the event of severe adverse reactions.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25°C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging. 10 tablets in a blister; 2, 6, or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.