Enalapril-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL-TEVA (Enalapril-Teva)

Composition:

Active substance: enalapril maleate;

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

Excipients:

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

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

Pharmaceutical form. Tablets.

Main physico-chemical properties:

2.5 mg tablets: white, round, biconvex tablets;

5 mg tablets: white, round, biconvex snap tab tablets with a score line on one side;

10 mg tablets: red-brown with specks, round, biconvex snap tab tablets with a score line on one side;

20 mg tablets: pale-orange with specks, round, biconvex snap tab tablets with a score line on one side.

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 angiotensin II levels in plasma, resulting in increased plasma renin activity (due to removal of negative feedback on renin release) and decreased aldosterone secretion.

ACE is identical to kininase II. Thus, enalapril may also block the breakdown of bradykinin, a potent vasodepressor 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 (RAAS). Enalapril may exert antihypertensive effects 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 a significant increase in heart rate.

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

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

In hemodynamic studies in patients with arterial hypertension, blood pressure reduction was accompanied by decreased peripheral arterial resistance and increased cardiac output, with minimal or no increase in heart rate. After enalapril administration, renal blood flow increased; glomerular filtration rate (GFR) remained unchanged. No signs of sodium or water retention were observed. However, in patients with low baseline glomerular filtration rate, this rate 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 at least complement the effects of diuretics. Enalapril may reduce or prevent thiazide-induced hypokalemia. In patients with heart failure receiving cardiac glycosides and diuretics, enalapril administration reduced peripheral resistance and blood pressure. Cardiac output increased, and heart rate (usually elevated in heart failure patients) decreased. Pulmonary capillary wedge pressure was reduced. Enalapril treatment improved exercise tolerance and reduced the severity of heart failure according to New York Heart Association criteria. These effects persisted throughout long-term enalapril therapy. In patients with mild to moderate heart failure, enalapril slowed the progression of myocardial dilation and heart failure, as evidenced by reduced left ventricular end-diastolic and end-systolic volumes and improved ejection fraction.

In a multicenter, randomized, double-blind, placebo-controlled study (SOLVD Prevention), a population with asymptomatic left ventricular dysfunction (left ventricular ejection fraction <35%) was evaluated. A total of 4228 patients were randomized to receive placebo (n=2117) or enalapril (n=2111). In the placebo group, heart failure or death occurred in 818 patients (38.6%) compared to 630 patients (29.8%) in the enalapril group (29% risk reduction, 95% CI, 21–36%, p<0.001). Death or hospitalization due to development or worsening of heart failure occurred in 518 patients (24.5%) in the placebo group and 434 patients (20.6%) in the enalapril group (20% risk reduction, 95% CI, 9–30%, p<0.001). In a multicenter, randomized, double-blind, placebo-controlled study (SOLVD Treatment), a population with symptomatic congestive heart failure due to systolic dysfunction (ejection fraction <35%) was evaluated. A total of 2569 patients receiving standard heart failure therapy were randomized to placebo (n=1284) or enalapril (n=1285). In the placebo group, 510 deaths (39.7%) occurred compared to 452 deaths (35.2%) in the enalapril group (16% risk reduction, 95% CI, 5–26%, p=0.0036). Cardiovascular mortality was 461 in the placebo group versus 399 in the enalapril group (18% risk reduction, 95% CI, 6–28%, p<0.002), primarily due to reduced mortality from progressive heart failure (251 in placebo group vs. 209 in enalapril group, 22% risk reduction, 95% CI, 6–35%). Fewer patients died or were hospitalized due to worsening heart failure (736 in placebo group vs. 613 in enalapril group, 26% risk reduction, 95% CI, 18–34%, p<0.0001). Overall, in the SOLVD studies in patients with left ventricular dysfunction, enalapril reduced the risk of myocardial infarction by 23% (95% CI, 11–34%, p<0.001) and reduced the risk of hospitalization for unstable angina by 20% (95% CI, 9–29%, p<0.001).

Clinical Pharmacology in Children
Experience with enalapril in children with arterial hypertension aged 6 years and older is limited. A clinical study included 110 children aged 6 to 16 years with arterial hypertension, body weight ≥20 kg, and GFR >0.5 ml/s/1.73 m². Children with body weight <50 kg received 0.625 mg, 2.5 mg, or 20 mg of enalapril once daily, while children with body weight ≥50 kg received 1.25 mg, 5 mg, or 40 mg of enalapril once daily. Blood pressure reduction was dose-dependent; the effect was consistent across all dose subgroups (by age, Tanner stage, sex, race). Study results indicate that the lowest doses (0.625 mg and 1.25 mg), equivalent to an average dose of 0.02 mg/kg/day, did not provide sustained antihypertensive effect. The maximum studied dose was 0.58 mg/kg (40 mg) once daily. The adverse reaction profile in children was similar to that in adults.

Pharmacokinetics

Absorption
Enalapril is rapidly absorbed from the gastrointestinal tract, with peak serum concentration reached within 1 hour. Bioavailability is approximately 60%, and food intake does not affect absorption. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentration of enalaprilat is reached 4 hours after oral administration of enalapril. The elimination half-life of enalaprilat after multiple enalapril doses is 11 hours.

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

Metabolism
Apart from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.

Excretion
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 insufficiency (creatinine clearance 40–60 ml/min), the steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after 5 mg once daily. In severe renal impairment (creatinine clearance ≤30 ml/min), AUC increases approximately 8-fold. After repeated administration of enalapril maleate, the effective elimination half-life of enalaprilat is prolonged, and the time to reach steady state is increased (see section "Dosage and Administration").

Enalaprilat can be removed from the systemic circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 ml/min.

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 excipient of the medicinal product, or to other ACE inhibitors.
• History of angioedema associated with previous treatment with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breast-feeding").
• Concomitant use of enalapril with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).
• Concomitant use with sacubitril/valsartan. Enalapril must not be used in combination with sacubitril/valsartan, as this combination increases the risk of angioedema. Enalapril should not be administered within 36 hours before or after switching to or from sacubitril/valsartan, a medicinal product containing a neprilysin inhibitor (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.

Medicinal products that increase the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Concomitant use of ACE inhibitors with racecadotril (an antidiarrheal agent), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (see section "Special precautions for use").

Potassium-sparing diuretics, potassium-containing dietary supplements, or other medicinal products that may increase serum potassium levels. ACE inhibitors reduce diuretic-induced potassium loss. Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product. Potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution should also be exercised when enalapril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of enalapril with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, treatment should be administered with caution and serum potassium levels should be monitored frequently (see section "Special precautions for use").

Cyclosporine. Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin. Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

Other antihypertensive medicinal products. 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.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced circulating blood volume and excessive hypotension at the start of enalapril therapy. The hypotensive effect can be minimized by discontinuing the diuretic, increasing salt and fluid intake, or initiating therapy with a low dose of enalapril.

Lithium. Concomitant use of ACE inhibitors and lithium may cause reversible 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, careful monitoring of serum lithium levels is required.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors. NSAIDs, including selective COX-2 inhibitors, may reduce the effect 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 and may lead to renal impairment. 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 circulating blood volume, including those taking diuretics). Therefore, such combinations should be used with caution in patients with renal impairment. Patients should maintain adequate fluid intake and be closely monitored for renal function at the start of concomitant therapy and periodically during treatment.

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

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic medicinal products. Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may reduce blood glucose levels, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.

Alcohol. Alcohol enhances the hypotensive effect of ACE inhibitors.

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

Dual blockade of the RAS. Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited 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 RAS 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 RAS. Enalapril must not be used concomitantly with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²) (see sections "Contraindications" and "Special precautions for use").

Special precautions for use.

Symptomatic hypotension. Symptomatic hypotension rarely occurs in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving enalapril, symptomatic hypotension is more likely in the presence of hypovolemia, for example due to diuretic therapy, dietary salt restriction, in patients undergoing hemodialysis, as well as in patients with diarrhea or vomiting. Symptomatic hypotension has also been observed in patients with heart failure, with or without concomitant renal impairment. Symptomatic hypotension occurs more frequently in patients with more severe forms of heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should begin enalapril therapy under medical supervision. Particular caution is required when adjusting the dose of enalapril and/or diuretic. This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, intravenous physiological saline should be administered. Transient arterial hypotension during enalapril therapy is not a contraindication for continued use, which can usually be resumed without complications after blood pressure normalization through fluid volume restoration.

In some patients with heart failure and normal or low blood pressure, further reduction in blood pressure may occur during enalapril therapy. This effect is expected and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, it may be necessary to reduce or discontinue the doses of diuretics and/or enalapril.

Stenosis of aortic or mitral heart valves/hypertrophic cardiomyopathy. As with all vasodilating agents, ACE inhibitors should be used with extreme caution in patients with left ventricular outflow tract obstruction or obstructive pathway, and should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

Renal function impairment. Patients with impaired renal function (creatinine clearance <80 mL/min) require dose adjustment according to creatinine clearance, followed by adjustment based on treatment response. Serum creatinine and potassium levels should be monitored regularly.

Renal function impairment has been reported in association with enalapril use, predominantly in patients with severe heart failure or kidney disease, including renal artery stenosis. When detected early and managed appropriately, renal failure associated with enalapril therapy is usually reversible.

In some patients with hypertension who had no pre-existing kidney disease, enalapril therapy combined with diuretics has led to increased blood urea nitrogen and serum creatinine levels. In such cases, it may be necessary to reduce the enalapril dose and/or discontinue the diuretic. This condition may indicate the possibility of renal artery stenosis.

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney who are taking ACE inhibitors have an increased risk of arterial hypotension and renal failure. Loss of kidney function may occur with only minor changes in serum creatinine. Such patients should start treatment under medical supervision with low doses; careful dose titration and monitoring of renal function are required during therapy.

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. Rarely, ACE inhibitors may cause a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes resulting in death. The mechanism of this syndrome is not understood. If jaundice or a marked increase in liver enzymes occurs during ACE inhibitor therapy, the ACE inhibitor should be discontinued, close monitoring should be instituted, and treatment should be initiated as necessary.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complications. Enalapril should be used with extreme caution in patients with collagen vascular diseases, concomitant therapy with immunosuppressants, allopurinol, or procainamide, or in combination of these factors, especially if renal function is already impaired. Serious infections, sometimes unresponsive to intensive antibiotic therapy, may develop in some of these patients. If enalapril is administered to such patients, periodic monitoring of white blood cell count is recommended. Patients should immediately report any signs of infection.

Hypersensitivity/angioedema. Cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported with ACE inhibitors, including enalapril, occurring at various times during treatment. In such cases, enalapril therapy should be discontinued immediately and the patient should be closely observed until complete resolution of symptoms. Observation may only be discontinued after this. Even if only tongue swelling occurs without respiratory tract involvement, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal cases of angioedema of the larynx and tongue have been reported. In cases of angioedema of the tongue, glottis, or larynx that may cause airway obstruction, especially in patients with a history of surgery, appropriate therapy should be initiated immediately, which may include administration of adrenaline (0.3–0.5 mL of 1:1000 adrenaline solution for subcutaneous injection) and/or measures to ensure airway patency.

Angioedema occurs more frequently in patients of African descent receiving 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.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy may only be initiated 36 hours after the last dose of enalapril. Enalapril therapy may only be initiated 36 hours after the last dose of sacubitril/valsartan (see sections «Contraindications» and «Interaction with other medicinal products and other types of interactions»).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway swelling or tongue swelling with or without respiratory distress) (see section «Interaction with other medicinal products and other types of interactions»). Caution is required when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during allergen desensitization with Hymenoptera venom. Rarely, patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom have developed anaphylactoid reactions that could be life-threatening. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis. Rarely, patients receiving ACE inhibitors undergoing low-density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. Such reactions can be avoided by temporarily discontinuing ACE inhibitors before each apheresis session.

Patients undergoing hemodialysis. In patients undergoing dialysis with high-flux membranes (e.g., AN69®) and concomitantly receiving an ACE inhibitor, anaphylactoid reactions have occasionally occurred. 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 who are taking oral antidiabetic agents or insulin and start ACE inhibitor therapy should be advised to closely monitor blood glucose levels, especially during the first few months of concomitant therapy (see section «Interaction with other medicinal products and other types of interactions»).

Cough. Cough has been reported during ACE inhibitor therapy. 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 that cause arterial hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension develops due to this interaction mechanism, it can be corrected by increasing fluid volume.

Hyperkalemia/serum potassium levels. During therapy with ACE inhibitors, including enalapril, increased serum potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal impairment, impaired renal function, age >70 years, diabetes mellitus, hypoaldosteronism, transient conditions such as dehydration, acute heart decompensation, or metabolic acidosis. ACE inhibitors may cause hyperkalemia because they inhibit aldosterone release. This effect is usually minor in patients with normal renal function. However, in patients with renal impairment and/or those taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), or other agents that increase serum potassium levels (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor antagonists, hyperkalemia may occur. Caution is required when using potassium-sparing diuretics and angiotensin receptor antagonists in patients taking ACE inhibitors. Serum potassium levels and renal function should be monitored in such patients (see section «Interaction with other medicinal products and other types of interactions»). Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is considered necessary, they should be used with caution, with regular monitoring of serum potassium levels (see section «Interaction with other medicinal products and other types of interactions»).

Lithium. Combination of lithium and enalapril is generally not recommended (see section «Interaction with other medicinal products and other types of interactions»).

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, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections «Pharmacological properties» and «Interaction with other medicinal products and other types of interactions»). If dual blockade is necessary, therapy should be conducted under specialist supervision with continuous monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy (see section «Interaction with other medicinal products and other types of interactions»).

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 «Pharmacological properties» and «Dosage and administration»). Enalapril is not recommended for treating children with conditions other than arterial hypertension. Enalapril is not recommended for newborns and children with glomerular filtration rate <30 mL/min/1.73 m² due to lack of data (see section «Dosage and administration»).

Ethnic characteristics. As with all ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of African descent compared to other ethnic groups, possibly due to a higher prevalence of low-renin states among hypertensive patients of African descent.

Lactose. The medicinal product Enalapril-Teva contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Sodium. The medicinal product Enalapril-Teva contains less than 1 mmol sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. ACE inhibitors are contraindicated in pregnant women or women planning pregnancy (see section «Contraindications»). Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy should be initiated.

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy may cause fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). Oligohydramnios likely indicates impaired fetal renal function and may lead to limb contractures, craniofacial deformities, and pulmonary hypoplasia.

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound assessment of renal and skull function is recommended. Newborns whose mothers took ACE inhibitors should be closely monitored for arterial hypotension.

Breastfeeding. Limited pharmacokinetic data indicate very low concentrations in breast milk. Although these concentrations are considered clinically insignificant, use of Enalapril-Teva is not recommended during breastfeeding of preterm infants and newborns in the first weeks of life due to a theoretical risk of cardiovascular and renal effects and insufficient experience with such use. For older infants, use of Enalapril-Teva in breastfeeding women may be considered if treatment is necessary for the mother and the infant is monitored for any adverse reactions.

Ability to affect reaction speed when driving or operating machinery.

When driving or operating machinery, consider the possible development of dizziness or fatigue.

Dosage and Administration

The Enalapril-Teva medicinal product is administered orally. Food intake does not affect the absorption of Enalapril-Teva tablets.

Dosage must be individually adjusted according to each patient's condition (see section "Special Warnings and Precautions for Use") and the blood pressure response.

If tablet splitting is necessary, it is best performed as follows:

Place the tablet on a hard, flat surface with the score line facing upwards (on a table or plate), press down firmly and sharply with both index fingers on either side of the break line simultaneously (as shown in the image below):

Children

There is limited experience from clinical studies on the use of enalapril in the treatment of arterial hypertension in children (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Arterial Hypertension

The enalapril dosage 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). The Enalapril-Teva medicinal product is taken once daily. For mild arterial hypertension, the recommended initial dose of enalapril is 5–10 mg.

In patients with highly activated renin-angiotensin-aldosterone system (RAAS) (e.g., those with renovascular hypertension, disturbances in salt and/or fluid balance, decompensated cardiac function, or severe arterial hypertension), excessive reduction in blood pressure may occur after the initial dose. Such patients should be started on a 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 5 mg or lower is recommended. Whenever possible, diuretic treatment should be discontinued 2–3 days before starting Enalapril-Teva. Kidney 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, the Enalapril-Teva medicinal product is used concomitantly with diuretics and, if necessary, cardiac glycosides or beta-blockers. The initial dose of Enalapril-Teva for patients with clinically manifest heart failure or asymptomatic left ventricular dysfunction is 2.5 mg. Treatment must be initiated under close medical supervision to monitor the initial effects of the drug on blood pressure. If no adverse effects occur, or after appropriate management of symptomatic hypotension that may arise at the beginning of Enalapril-Teva treatment for heart failure, the dose should be gradually increased to the usual maintenance dose of 20 mg, administered either once daily 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, given in two divided doses.

Table 1

Proposed dose titration of Enalapril-Teva for patients with heart failure/asymptomatic left ventricular dysfunction

Week	Dose, mg/day
Week 1	Days 1 to 3: 2.5 mg/day* once daily Days 4 to 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 should be performed both before and during treatment with Enalapril-Teva (see section "Special precautions"), as cases of hypotension and (less frequently) subsequent renal failure have been reported. In patients receiving diuretics, the diuretic dose should be reduced, if possible, prior to initiating Enalapril-Teva. The development of hypotension after the initial dose of Enalapril-Teva does not necessarily predict that hypotension will persist during continued therapy and is not an indication to discontinue the drug. Serum potassium levels and renal function should also be monitored.

Dosing in renal impairment

Generally, the dosing interval of enalapril should be prolonged and/or the dose of the drug reduced.

Table 2

Dosing in renal impairment

Renal status	Creatinine clearance (CrCL), ml/min	Initial dose, mg/day
Mild impairment	30 < CrCL < 80 ml/min	5-10 mg
Moderate impairment	10 < CrCL ≤ 30 ml/min	2.5 mg
Severe impairment, such patients are usually on hemodialysis	CrCL ≤ 10 ml/min	2.5 mg on dialysis days*

*See section "Special precautions. Patients undergoing hemodialysis". Enalapril is removed by hemodialysis. Dose 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 precautions").

Children with hypertension aged 6 years and older

For children who can swallow tablets, the dose should be individually prescribed depending on the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients with body weight from 20 to 50 kg and 5 mg for patients with body weight ≥50 kg. Enalapril-Teva should be taken once daily. Dosage should be adjusted according to need up to a maximum of 20 mg per day for patients with body weight from 20 to 50 kg and 40 mg per day for patients with body weight ≥50 kg.

Children.

The drug is indicated for use in children aged 6 years and older.

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.

Overdose.

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

For the treatment of overdose, intravenous infusion of isotonic saline solution is 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 undertaken (such as induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from systemic circulation by hemodialysis (see section "Special precautions. Patients undergoing hemodialysis"). In cases of bradycardia resistant to therapeutic interventions, treatment with a cardiac pacemaker is indicated. Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Side effects.

The adverse reactions listed below have been observed during clinical trials and post-marketing surveillance with enalapril at the following frequencies: 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).

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 disorders: frequency not known – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: uncommon – hypoglycaemia (see section "Special precautions").

Nervous and psychiatric disorders: common – headache, depression; uncommon – confusion, drowsiness, insomnia, nervousness, paraesthesia, vertigo; rare – abnormal dreams, sleep disturbances.

Eye disorders: very common – blurred vision.

Cardiac and vascular disorders: very common – dizziness; common – hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia; uncommon – orthostatic hypotension, palpitations, myocardial infarction or stroke*, possibly due to excessive hypotension in patients with high risk (see section "Special precautions"); rare – Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders: very common – cough; common – dyspnoea; uncommon – rhinorrhoea, sore throat, dysphonia, 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 ulcers; rare – stomatitis/aphthous ulcers, glossitis; very rare – angioneurotic oedema of the intestine.

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

Skin and subcutaneous tissue disorders: common – rash, hypersensitivity/angioedema of face, limbs, lips, tongue, glottis and/or larynx; uncommon – increased sweating, pruritus, urticaria, alopecia; rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma; frequency not known – a symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis; skin rashes, photosensitivity or other dermatological manifestations may also occur.

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 – increased fatigue; uncommon – muscle cramps, hot flushes, tinnitus, discomfort, fever.

Laboratory findings: common – hyperkalaemia, increased serum creatinine; uncommon – increased blood urea, hyponatraemia; rare – increased liver enzymes, increased serum bilirubin.

*The incidence of these events was comparable between placebo and active control groups during clinical trials.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

Tablets 2.5 mg: 10 tablets in a blister; 3 blisters in a cardboard box.

Tablets 5 mg, 10 mg or 20 mg: 10 tablets in a blister; 3, 6 or 9 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Teva Operations Poland Sp. z o.o.

Manufacturer's address and place of business.

80 Mogilska Street, 31-546 Kraków, Poland.