INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Enap® (Enap®)

Composition:

Active substance: enalaprilat;

1 ml of injection solution contains 1.25 mg of enalaprilat;

Excipients: benzyl alcohol, sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless solution free from visible mechanical impurities.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme inhibitors.

ATC code C09A A02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Enalaprilat inhibits angiotensin-converting enzyme, which catalyzes the conversion of angiotensin I to angiotensin II. Inhibition of angiotensin-converting enzyme leads to a decrease in angiotensin II concentration, an increase in plasma renin activity, and a reduction in aldosterone secretion.

Pharmacodynamic effect

The antihypertensive and hemodynamic effects of enalaprilat in patients with elevated blood pressure result from the dilation of resistance vessels and a reduction in total peripheral resistance, leading to a gradual decrease in arterial pressure. Systolic and diastolic pressures, as well as pulmonary artery pressure, are reduced, while coronary blood flow increases, and cardiac index and stroke volume increase (with unchanged heart rate).

After intravenous injection, the effect of the drug begins within 5–15 minutes, maximum effect occurs within 1–4 hours, and the duration of action lasts approximately 6 hours.

Enalaprilat does not affect glucose, lipoprotein, uric acid, or cholesterol metabolism. The drug can be administered to patients with diabetes, chronic obstructive pulmonary disease, angina pectoris, or congestive heart failure.

Pharmacokinetics.

Absorption

After oral administration, enalaprilat is poorly absorbed and is nearly inactive; therefore, it should be administered only intravenously.

Distribution

After intravenous injection, the drug rapidly distributes into most body tissues, with the highest concentrations found in the lungs, kidneys, and blood vessels. The elimination half-life is 4 hours. Between 50 and 60% of enalaprilat is bound to plasma proteins.

Metabolism

Enalaprilat is not metabolized; 100% of enalaprilat is excreted unchanged in urine.

Excretion

Enalaprilat is primarily eliminated by the kidneys via glomerular filtration and tubular secretion. Excretion occurs in several phases, explained by the strong binding to serum angiotensin-converting enzyme. The half-life during the initial phase is approximately 11 hours, and during the terminal phase – 35 hours.

Renal impairment

In patients with renal insufficiency, exposure to enalapril and enalaprilat is increased. Elimination is slowed; therefore, dose adjustment should be made according to renal function.

Enalaprilat can be removed from systemic circulation by hemodialysis. The clearance of enalaprilat during dialysis is 1.03 mL/sec (62 mL/min).

Clinical characteristics.

Indications

Hypertension, hypertensive crisis.

Enalaprilat is indicated for the treatment of arterial hypertension in cases when oral therapy is not feasible.

Contraindications

Hypersensitivity to enalapril, enalaprilat, other angiotensin-converting enzyme (ACE) inhibitors, or to any excipients of the medicinal product.
History of angioedema associated with previous treatment with ACE inhibitors.
Hereditary or idiopathic angioedema.
Contraindicated in pregnancy and in women who are planning to become pregnant (see section "Use in pregnancy or lactation").
Concomitant use of Enap® with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (eGFR [estimated glomerular filtration rate] < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use with a neprilysin inhibitor (e.g., sacubitril) is contraindicated due to increased risk of angioedema. Therapy should not be initiated earlier than 36 hours after discontinuation of sacubitril/valsartan—a medicinal product containing a neprilysin inhibitor. Sacubitril/valsartan may be initiated no earlier than 36 hours after discontinuation of Enap® (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction

Potassium-sparing diuretics, potassium-containing dietary supplements

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes containing potassium may lead to a significant increase in serum potassium levels. Caution should also be exercised when enalapril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of enalapril with the above-mentioned agents is not recommended. If these agents are indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special precautions for use").

Diuretics (thiazide or loop diuretics)

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

Other antihypertensive agents

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

Antidiabetic agents

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may reduce blood glucose levels and increase the risk of hypoglycemia. This phenomenon is most likely during the first weeks of concomitant therapy and in patients with renal impairment (see sections "Special precautions for use", "Adverse reactions").

Lithium preparations

Concomitant use of ACE inhibitors and lithium has been associated with reversible increases in serum lithium levels and lithium toxicity. Concomitant use of ACE inhibitors with thiazide diuretics may further increase serum lithium levels and increase the risk of lithium intoxication. Concomitant use of enalapril with lithium is not recommended; however, if such combination is necessary for a patient, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives

Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to additional reduction in blood pressure (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (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 NSAIDs, 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 levels and may lead to impaired renal function. These effects are usually reversible.

Acute renal failure may rarely occur, particularly in certain patients with impaired renal function (e.g., elderly patients or patients with reduced intravascular volume, including those taking diuretics). Therefore, such combination should be used with caution in patients with renal impairment. Patients should maintain adequate fluid intake; renal function should be closely monitored at the start of concomitant therapy and periodically during 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 restricted to specific cases 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 worsening renal function (including acute renal failure) compared to treatment with a single agent acting on the RAAS. Concomitant use of Enap® with aliskiren is not recommended in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

Gold preparations

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and arterial hypotension) have been rarely reported in patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with ACE inhibitors, including enalapril.

Medicinal products increasing the risk of angioedema

Concomitant use with neprilysin inhibitors (e.g., sacubitril) is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

mTOR inhibitors

Concomitant use of ACE inhibitors with racadotril, mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus), and vildagliptin increases the risk of angioedema (see section "Special precautions for use").

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

Enalapril can be safely used concomitantly with acetylsalicylic acid (in cardiologic doses), thrombolytics, and β-blockers.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly have an increased risk of developing hyperkalemia (see section "Special precautions for use").

Cyclosporine

Hyperkalemia may occur during concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur during concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.

Special precautions for use.

Enalaprilat for parenteral administration rapidly reduces elevated arterial pressure and improves cardiac function.

Symptomatic hypotension

Patients with arterial hypotension due to severe heart failure, hyponatremia and/or hypovolemia caused by diuretic therapy, salt-free diet, dialysis, or due to diarrhea and vomiting represent a subgroup of patients in whom arterial pressure depends on renin and activation of the renin-angiotensin system (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects"). Symptomatic hypotension has also been observed in patients with heart failure, with or without renal impairment. Symptomatic hypotension occurred more frequently in patients with more severe forms of heart failure who were receiving higher doses of loop diuretics, had hyponatremia, or had impaired renal function. Such patients should start treatment under medical supervision, and close monitoring is required when adjusting the dose of the drug and/or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disease should be monitored carefully, as excessive reduction in arterial pressure may lead to myocardial infarction or stroke.

Arterial hypotension and its serious consequences are rare and reversible events. They can be avoided by discontinuing diuretic therapy and low-salt diet before initiating treatment with Enap**®**, if possible.

If discontinuation of diuretic therapy in all such patients is not feasible, cautious initiation of treatment with a lower dose (½ ampoule) of enalaprilat is recommended.

In case of developing arterial hypotension, the patient should be placed in a horizontal position and, if necessary, 0.9% sodium chloride solution should be administered intravenously to expand plasma volume. Transient hypotension is not a contraindication to enalapril treatment. After normalization of arterial pressure and plasma volume, patients usually tolerate subsequent doses well.

Aortic or mitral valve stenosis / hypertrophic cardiomyopathy

The drug should be used cautiously in patients with aortic stenosis, idiopathic hypertrophic subaortic stenosis, and generalized atherosclerosis. Arterial hypotension in such patients may lead to hypoperfusion and ischemia of the heart, brain, and kidneys. Patients with peripheral vascular disease or generalized atherosclerosis may have clinically silent renal vascular disease. Therapy with enalaprilat in such patients should be initiated very cautiously with a lower dose (0.625 mg).

ACE inhibitors should be administered cautiously to patients with left ventricular outflow tract obstruction and avoided in cases of cardiogenic shock and hemodynamically significant left ventricular outflow tract obstruction.

Renal function impairment

Patients with impaired renal function (creatinine clearance < 80 mL/min) require dose adjustment according to creatinine clearance (see section "Dosage and administration") and subsequent response to treatment. Serum creatinine and potassium levels should be monitored regularly.

In some patients with arterial hypertension, who had no evidence of renal disease prior to starting treatment, enalapril combined with diuretics has usually caused slight and transient increases in blood urea nitrogen and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation increases the likelihood of existing renal artery stenosis (see section "Special precautions for use": Renovascular hypertension).

Renovascular hypertension

There is an increased risk of arterial hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney are treated with ACE inhibitors. In patients with stenosis of a single kidney, transient impairment of renal function or even acute renal failure of the affected kidney may occur. Loss of renal function may occur even with minimal changes in serum creatinine levels. Such patients should start treatment with low doses under strict medical supervision, with careful titration and monitoring of renal function.

Kidney transplantation

There are insufficient data on enalapril treatment in patients with recent kidney transplantation; therefore, enalapril treatment in such patients is not recommended.

Hepatic impairment

Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome remains unclear. Patients taking ACE inhibitors who develop jaundice or marked elevation of liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical supervision.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. Neutropenia occurred rarely in patients with normal renal function and in the absence of other complicating factors. Enalapril should be prescribed very cautiously to patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) who are undergoing immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if renal function is already impaired. Serious infections resistant to intensive antibiotic therapy have developed in some of these patients. Periodic monitoring of white blood cell count is recommended when prescribing enalapril/enalaprilat to such patients, and patients should be instructed to report any signs of infection.

Hypersensitivity and angioedema

In isolated cases, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx may occur during enalaprilat treatment. This may occur at any time during treatment. In such cases, treatment should be completely discontinued, antihistamines should be administered, and appropriate monitoring should be initiated to ensure complete resolution of all hypersensitivity symptoms. In cases of angioedema of the tongue without respiratory distress, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal outcomes due to laryngeal angioedema or tongue swelling have been reported. When swelling is localized in the tongue, glottis, or larynx, especially in patients with a history of surgical procedures on the airways, airway obstruction may develop. When the tongue, pharynx, or larynx are involved in the process, potentially causing airway obstruction, immediate appropriate therapy should be initiated, 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 African descent taking ACE inhibitors compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing it during ACE inhibitor treatment (see section "Contraindications"). Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Therapy should not be initiated earlier than 36 hours after discontinuation of sacubitril/valsartan. Sacubitril/valsartan therapy may be initiated no earlier than 36 hours after discontinuation of Enap® (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR (mammalian target of rapamycin) inhibitors (e.g., temsirolimus, sirolimus, everolimus), and vildagliptin increases the risk of angioedema (swelling of the airways or tongue, with or without respiratory dysfunction) (see section "Interaction with other medicinal products and other forms of interaction").

Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already taking ACE inhibitors.

Anaphylactoid reactions during desensitization

Patients receiving ACE inhibitors undergoing desensitization to wasp or bee venom may rarely experience life-threatening reactions resembling allergic (pseudoanaphylactic) reactions. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each desensitization session.

Anaphylactoid reactions during low-density lipoprotein apheresis

Patients receiving ACE inhibitors undergoing low-density lipoprotein apheresis with dextrin sulfate may rarely experience life-threatening reactions resembling allergic (pseudoanaphylactic) reactions. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Patients undergoing hemodialysis sessions

Hypersensitivity reactions resembling allergic (pseudoanaphylactic) reactions have been reported in patients undergoing dialysis sessions using polyacrylonitrile membranes (e.g., AN 69) while concurrently taking an ACE inhibitor. Therefore, for such patients, consideration should be given to using dialysis membranes of another type or an antihypertensive agent from another class.

Hypoglycemia

Patients with diabetes mellitus who are taking oral antidiabetic agents or insulin and initiating ACE inhibitor therapy should be advised to closely monitor blood glucose levels, especially during the first few months of concomitant use (see section "Interaction with other medicinal products and other forms of interaction").

Cough

Cough has been reported during treatment with ACE inhibitors. The cough is usually dry 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/anesthesia

During major surgical procedures or anesthesia with agents causing arterial hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension develops that can be explained by these interaction mechanisms, it is corrected by increasing fluid volume.

Hyperkalemia

ACE inhibitors may cause hyperkalemia because they suppress aldosterone release. In patients with normal renal function, this effect is usually mild. The risk of hyperkalemia is increased in patients with renal impairment, impaired renal function, hypoaldosteronism, age > 70 years, diabetes mellitus, transient conditions such as dehydration, acute heart decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of potassium-containing dietary supplements or salt substitutes; and in patients taking other drugs that may increase serum potassium levels (e.g., heparin, trimethoprim, or co-trimoxazole [trimethoprim/sulfamethoxazole], and especially aldosterone antagonists or angiotensin receptor blockers). In particular, the use of potassium-sparing diuretics, dietary supplements, or salt substitutes containing potassium in patients with impaired renal function may lead to significant increases in serum potassium levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

Generally, the combination of lithium and enalapril is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy or breastfeeding

ACE inhibitors are contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

If pregnancy is confirmed, enalapril treatment should be discontinued immediately (see section "Use during pregnancy or breastfeeding").

Enalapril is not recommended during breastfeeding (see sections "Contraindications", "Use during pregnancy or breastfeeding").

Ethnic characteristics

Enalapril, like other ACE inhibitors, is less effective in lowering arterial pressure in patients of African descent with arterial hypertension compared to individuals of other races, possibly due to low plasma renin levels in these patients.

Special warnings regarding excipients

The preparation contains benzyl alcohol (E 1510), which may cause toxic and anaphylactoid reactions in infants and children under 3 years of age; therefore, it is contraindicated in premature infants and newborns.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

Epidemiological data on the teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

In cases where ACE inhibitors were taken during pregnancy, periodic ultrasound examinations should be performed to assess the intra-amniotic space. However, both physicians and patients should be aware that oligohydramnios may develop after irreversible fetal damage has already occurred.

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound evaluation of fetal renal and skull function is recommended.

Newborns whose mothers took ACE inhibitors should be carefully monitored for arterial hypotension, oliguria, and hyperkalemia. Enalapril, which can cross the placenta, may be partially removed from the newborn's body by peritoneal dialysis and theoretically by exchange transfusion, although there is no experience with the latter procedure (see sections "Contraindications", "Special precautions for use").

Breastfeeding

Enalapril and enalaprilat pass into breast milk, but their effect on the breastfed infant remains uncertain. Breastfeeding is not recommended during treatment with ACE inhibitors.

Ability to affect reaction speed when driving or operating machinery.

Patients are not recommended to use or operate vehicles and machinery until their response to treatment is known. When switching to enalapril therapy, the possible development of dizziness or increased fatigue, which may impair the ability to drive or operate machinery, should be considered.

Method of Administration and Dosage

For use in adults.

Enap®, injection solution, should be administered intravenously as a slow bolus injection over at least 5 minutes. It may also be administered diluted in 50 mL of 5% glucose, 0.9% sodium chloride solution (physiological saline), 5% glucose in 0.9% sodium chloride solution, or 5% glucose in lactated Ringer's solution.

The usual recommended dose for the treatment of arterial hypertension and hypertensive crises (acute elevation of arterial pressure) is 1 ampoule (1.25 mg), administered by slow intravenous injection or infusion over at least 5 minutes every 6 hours.

When switching from enalapril therapy to enalaprilat therapy, the usual dose is 1 ampoule (1.25 mg) every 6 hours.

Treatment with enalaprilat usually lasts 48 hours. After this period, patients should be switched to enalapril tablet therapy. When transitioning from parenteral enalaprilat to oral enalapril, the recommended initial dose is 5 mg once daily for patients who have previously received 1 ampoule (1.25 mg) of enalaprilat every 6 hours. The dose may be increased if necessary. For patients initially treated with half the usual dose of enalaprilat (0.625 mg), the recommended dose when switching to oral therapy is 2.5 mg of enalapril per day.

Dosage in patients receiving diuretics

For patients receiving diuretics, the recommended initial dose is ½ ampoule (0.625 mg). If the clinical effect is inadequate after 1 hour, the same dose may be repeated, and treatment continued with the full dose (1 ampoule every 6 hours) after 6 hours.

Dosage in renal impairment

Enalaprilat dosage in patients with chronic renal impairment depends on creatinine clearance. Patients with creatinine clearance > 0.5 mL/sec (serum creatinine up to 265 µmol/L) should receive the usual enalaprilat dose of 1 ampoule (1.25 mg) every 6 hours. Patients with creatinine clearance < 0.5 mL/sec (serum creatinine exceeding 265 µmol/L) should receive an initial dose of ½ ampoule (0.625 mg). If the clinical effect is inadequate after one hour, the same dose should be repeated. Treatment should then continue at the full dose of 1.25 mg (1 ampoule) every 6 hours.

Dosage during hemodialysis

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

The recommended dose for patients undergoing hemodialysis is 0.625 mg (½ ampoule) every 6 hours.

Elderly patients

Enalaprilat dosage should be adjusted according to renal function (see section "Special Warnings and Precautions for Use").

Children

Enap®, injection solution, should not be used in children due to insufficient data on efficacy and safety.

Overdose

The most likely manifestation of overdose is arterial hypotension. If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, plasma volume should be corrected by intravenous infusion of 0.9% sodium chloride solution. In severe cases, angiotensin II administration is recommended.

During treatment of overdose, arterial pressure, respiratory rate, serum potassium concentration, and diuresis should be monitored.

Transient arterial hypotension is not a contraindication for enalaprilat therapy. After stabilization of arterial pressure and plasma volume, patients usually tolerate the standard dose of the drug (1 mg/1.25 mg) well. Enalaprilat can be removed from systemic circulation by hemodialysis. During hemodialysis, enalaprilat clearance ranges from 38 to 62 mL/min; after a four-hour hemodialysis session, serum enalaprilat concentrations decrease by 45–57%.

Side effects

Enalaprilat is a metabolite of enalapril. Therefore, when treating with Enap® injection solution, the same adverse effects may occur as with Enap® tablets or other ACE inhibitors.

In controlled clinical trials of enalaprilat, the most common adverse effect in sensitive patients was arterial hypotension (1.8%). Adverse effects occurring in over 1% of patients also included headache (2.9%) and nausea (1.1%). Infrequent adverse effects occurring in 0.5–1% of patients included myocardial infarction, fatigue, dizziness, fever, skin rash, and constipation.

Adverse reactions are listed by system organ class and frequency: very common > 1/10; common > 1/100, < 1/10; uncommon > 1/1000, < 1/100; rare > 1/10000, < 1/1000; very rare < 1/10000; frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

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:
not known: syndrome of inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders:
uncommon: hypoglycaemia (see section "Special warnings and precautions for use").
Psychiatric disorders:
common: depression;
uncommon: confusion, insomnia, nervousness;
rare: dream abnormalities, sleep disorders.
Nervous system disorders:
very common: dizziness;
common: headache, syncope, taste disturbance;
uncommon: somnolence, paraesthesia, vertigo.
Eye disorders:
very common: blurred vision.
Ear and labyrinth disorders:
uncommon: tinnitus.
Cardiac disorders:
common: chest pain, cardiac arrhythmia, angina pectoris, tachycardia;
uncommon: palpitations, myocardial infarction or cerebrovascular accident*, possibly due to excessive hypotension in high-risk patients (see section "Special warnings and precautions for use").
Vascular disorders:
common: hypotension (including orthostatic hypotension);
uncommon: flushing, orthostatic hypotension;
rare: Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders:
very common: cough;
- common: dyspnoea;
- uncommon: rhinorrhoea, throat inflammation, dysphonia, pharyngitis, bronchospasm/asthma;
- rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal disorders:
very common: nausea;
common: diarrhoea, abdominal pain, taste distortion;
uncommon: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers;
rare: stomatitis/aphthous ulcers, glossitis;
very rare: oedema.
Hepatobiliary disorders:
rare: liver failure, hepatitis — hepatocellular or cholestatic, including necrosis; cholestasis, including jaundice.
Skin and subcutaneous tissue disorders:
common: rash, increased sensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section "Special warnings and precautions for use");
uncommon: increased sweating, pruritus, urticaria, alopecia;
rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A syndrome complex has been reported: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibodies, elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Exanthema, photosensitivity, and other skin changes may also occur.

Musculoskeletal and connective tissue disorders:
uncommon: muscle cramps.
Renal and urinary disorders:
uncommon: renal dysfunction, renal failure, proteinuria;
rare: oliguria.
Reproductive system and breast disorders:
uncommon: impotence;
rare: gynaecomastia.
General disorders:
very common: asthenia;
common: fatigue;
uncommon: fever.
Laboratory findings:
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.

If severe adverse effects occur, treatment should be discontinued.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25°C. Keep out of the reach of children.

Incompatibilities. The medicinal product must not be mixed with amphotericin B and phenytoin due to clouding of the solution and precipitate formation.

Packaging. 1 ml of solution for injection in a vial; 5 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.