Enalosid® forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALOZID® FORTE (ENALOZID FORTE)

Composition:

Active substances: enalapril maleate, hydrochlorothiazide;

One tablet contains enalapril maleate, recalculated to 100% dry substance – 20 mg, hydrochlorothiazide (hydrochlorothiazide), recalculated to 100% dry substance – 12.5 mg;

Excipients: sodium hydrocarbonate; maize starch; pregelatinized starch 1500; lactose monohydrate (200); iron oxide yellow (E 172); magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: yellow, flat cylindrical tablets with beveled edges and a score line. Speckles on the tablet surface are permissible.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors and diuretics. ATC code C09BA02.

Pharmacological properties.

Pharmacodynamics.

Enalozid® Forte is a combination of an angiotensin-converting enzyme (ACE) inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

Enalapril maleate

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE, resulting in increased plasma renin activity (due to inhibition of the negative feedback on renin release) and reduced aldosterone secretion.

ACE is identical to kininase II. Therefore, enalapril may also block the breakdown of bradykinin, a potent vasodilator peptide. However, the role of this effect in the therapeutic action of enalapril remains unclear.

Mechanism of action

Although the mechanism by which enalapril lowers blood pressure is primarily associated with inhibition of the renin-angiotensin-aldosterone system (RAAS), which plays a key role in blood pressure regulation, enalapril may exert an antihypertensive effect even in patients with low-renin hypertension.

Enalapril maleate – hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity. Although enalapril exerts antihypertensive effects even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide results in greater blood pressure reduction in these patients.

Double blockade

Two large randomized controlled trials (ONTARGET [Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial], VA NEPHRON-D [The Department of Veterans Affairs Nephropathy in Diabetes Study]) evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker.

ONTARGET was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was conducted in patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to assess the benefits of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke rates were higher in the aliskiren group than in the placebo group, and adverse reactions and serious adverse reactions (hyperkalemia, hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Pharmacokinetics.

Absorption

After oral administration, enalapril maleate is rapidly absorbed, and peak enalapril concentrations are achieved within one hour. Based on urinary excretion data, the extent of absorption of enalapril maleate is approximately 60%. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent inhibitor of angiotensin-converting enzyme. Peak serum concentrations of enalaprilat are reached 3–4 hours after oral administration of enalapril maleate. The main components excreted in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. Aside from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat is characterized by a prolonged terminal phase, which appears to be associated with binding to ACE. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved by the fourth day of enalapril maleate administration. The presence of food in the gastrointestinal tract does not affect the absorption of enalapril maleate after oral administration. The extent of absorption and hydrolysis of enalapril is similar across different doses within the recommended therapeutic range.

Distribution

Studies in dogs indicate that enalapril does not cross or crosses the blood-brain barrier to a negligible extent; enalaprilat does not enter the brain. Enalapril crosses the placental barrier. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Biotransformation

Aside from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys.

Elimination

Enalaprilat is primarily eliminated via the kidneys. The main components of the drug excreted in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. The effective half-life for accumulation of enalaprilat after repeated oral administration of enalapril maleate is 11 hours. In studies measuring plasma concentrations of hydrochlorothiazide over at least 24 hours, the elimination half-life from plasma ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. After oral administration, at least 61% of the dose is excreted unchanged within 24 hours.

Renal impairment

Enalaprilat is removed from the systemic circulation by hemodialysis.

Lactation

After a single oral dose of 20 mg in five postpartum women, the mean peak concentration of enalapril in breast milk was 1.7 µg/L (range: 0.54–5.9 µg/L) 4–6 hours after administration. The mean peak concentration of enalaprilat was 1.7 µg/L (range: 1.2–2.3 µg/L); peaks were observed at various times within 24 hours. Based on peak milk concentrations, the calculated maximum dose received by a breastfed infant is approximately 0.16% of the maternal dose normalized to body weight. A woman who took enalapril 10 mg daily for 11 months had a peak enalapril concentration in milk of 2 µg/L 4 hours after dosing and a peak enalaprilat concentration of 0.75 µg/L approximately 9 hours after dosing. The total amount of enalapril and enalaprilat detected in breast milk over 24 hours was 1.44 µg/L and 0.63 µg/L of milk, respectively. Enalaprilat concentration in breast milk was not detectable (< 0.2 µg/L) 4 hours after a single 5 mg dose in one woman and 10 mg doses in two women; enalapril levels were not detected.

Clinical characteristics.

Indications.

Enalozid® Forte is indicated for the treatment of mild to moderate hypertension in patients whose condition has been stabilized with the individual components in the same proportions (see sections “Contraindications”, “Special precautions”, “Interaction with other medicinal products and other forms of interaction”, and “Pharmacodynamic properties”).

Contraindications.

• Hypersensitivity to the active substance (active substances) or to any of the excipients listed in the excipients section.
• Severe renal impairment (creatinine clearance ≤ 30 mL/min).
• Anuria.
• Angioedema associated with previous administration of ACE inhibitors, in medical history.
• Hereditary or idiopathic angioedema.
• Hypersensitivity to medicinal products which are sulfonamide derivatives.
• Pregnancy or women who may become pregnant (see section “Use in pregnancy or lactation”).
• Severe hepatic impairment.
• Concomitant use of Enalozid® Forte with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections “Interaction with other medicinal products and other forms of interaction” and “Pharmacodynamic properties”).
• Enalozid® Forte must not be used in combination with a neprilysin inhibitor (e.g., sacubitril/valsartan) due to increased risk of angioedema. Enalozid® Forte must not be administered within 36 hours of switching from sacubitril/valsartan, a medicinal product containing a neprilysin inhibitor, or switching to it from another medicinal product (see sections “Special precautions” and “Interaction with other medicinal products and other forms of interaction”).

Interaction with other medicinal products and other forms of interaction.

Enalapril maleate – hydrochlorothiazide

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

Clinical studies have demonstrated that dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse reactions such as hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to treatment with a single RAAS-blocking medicinal product (see sections “Contraindications”, “Special precautions”, “Pharmacodynamic properties”).

Other antihypertensive agents

Concomitant use of these medicinal products may enhance the hypotensive effect of enalapril and hydrochlorothiazide. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics and ACE inhibitors may further increase lithium levels and increase the risk of lithium toxicity.

Concomitant use of Enalozid® Forte with lithium-containing medicinal products is not recommended; however, if such combination is necessary, serum lithium levels should be closely monitored (see section “Special precautions”).

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

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may attenuate the effects of diuretics and other antihypertensive agents. For this reason, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors, or diuretics may be diminished when NSAIDs, including selective COX-2 inhibitors, are used concomitantly.

Concomitant use of NSAIDs (including COX-2 inhibitors) with angiotensin II receptor antagonists or ACE inhibitors may additionally increase serum potassium levels and may lead to renal dysfunction. These effects are usually reversible. Rarely, renal failure may develop, particularly in patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those receiving diuretics). Therefore, this combination of medicinal products should be prescribed with caution in patients with impaired renal function.

Enalapril maleate

Potassium-sparing diuretics or potassium supplements

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril therapy. Potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels. Caution should also be exercised when Enalozid® Forte is used concomitantly with other medicinal products that may 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 medicinal products is not recommended. If concomitant use of potassium-sparing diuretics, trimethoprim, or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), potassium supplements, or potassium-containing salt substitutes is indicated due to hypokalemia, treatment should be administered with caution and serum potassium levels should be monitored frequently (see section “Special precautions”).

Diuretics (thiazide or loop diuretics)

Prior treatment with high doses of diuretics may lead to dehydration and risk of hypotension at the initiation of enalapril therapy (see sections “Dosage and administration” and “Special precautions”). The hypotensive effect may be attenuated by discontinuation of the diuretic, increasing fluid volume, or increasing salt intake.

Tricyclic antidepressants/neuroleptics/anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may result in additional reduction in blood pressure (see section “Special precautions”).

Gold-containing medicinal products

Rare nitroid reactions (facial flushing, nausea, vomiting, and arterial hypotension) have been reported in patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with an ACE inhibitor, including enalapril.

mTOR (mammalian target of rapamycin) inhibitors

Concomitant use of ACE inhibitors with mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) or vildagliptin may increase the risk of angioedema (see section “Special precautions”).

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

Heparin

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

Neprilysin inhibitors

Concomitant use of ACE inhibitors with neprilysin inhibitors (e.g., sacubitril, racecadotril) may increase the risk of angioedema.

Concomitant use of enalapril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be administered within 36 hours after the last dose of enalapril. Enalapril therapy must not be initiated within 36 hours after the last dose of sacubitril/valsartan (see sections “Contraindications” and “Special precautions”).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors (see section “Interaction with other medicinal products and other forms of interaction”).

Alcohol

Alcohol potentiates the hypotensive effect of ACE inhibitors.

Antidiabetic medicinal products

Results of epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycemic agents) may lead to decreased blood glucose levels with risk of hypoglycemia. This effect is likely to occur during the first weeks of concomitant therapy and in patients with impaired renal function (see sections “Special precautions” and “Adverse reactions”).

Acetylsalicylic acid, thrombolytic agents, and β-blockers

The use of enalapril with acetylsalicylic acid (at cardiologic doses), thrombolytic agents, and β-blockers is safe.

Hydrochlorothiazide

Non-depolarizing muscle relaxants

Thiazides may enhance sensitivity to tubocurarine.

Alcohol, barbiturates, or opioid analgesics

May potentiate orthostatic hypotension.

Antidiabetic medicinal products (oral agents and insulin)

Dosage adjustment of antidiabetic agents may be necessary (see sections “Special precautions” and “Adverse reactions”).

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is reduced in the presence of anion-exchange resins. A single dose of cholestyramine or colestipol resin binds hydrochlorothiazide and reduces its gastrointestinal absorption by 85% and 43%, respectively.

QT interval prolonging agents (e.g., quinidine, procainamide, amiodarone, sotalol)

Increased risk of ventricular arrhythmias, such as torsades de pointes.

Cardiac glycosides (e.g., digoxin)

Hypokalemia may potentiate or exacerbate cardiac reactions to toxic effects of digitalis (e.g., increased ventricular excitability).

Corticosteroids, ACTH

Electrolyte imbalance, particularly hypokalemia, may be exacerbated.

Potassium-depleting diuretics (e.g., furosemide), carbenoxolone, or laxative abuse

Hydrochlorothiazide may increase potassium and/or magnesium losses.

Pressor amines (e.g., adrenaline)

The effect of pressor amines may be reduced (see section “Interaction with other medicinal products and other forms of interaction”).

Cytostatic medicinal products (e.g., cyclophosphamide, methotrexate)

Thiazides may reduce renal excretion of cytotoxic medicinal products and enhance their myelosuppressive effects.

Children

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

Enalapril maleate – hydrochlorothiazide

Hypotension and disturbances of water and electrolyte balance

Symptomatic hypotension rarely occurs in patients with uncomplicated hypertension. In patients with hypertension treated with Enalozid® Forte, symptomatic hypotension is more likely to occur in the presence of reduced circulating blood volume, e.g. due to diuretic therapy, salt-restricted diet, diarrhoea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects"). In such patients, serum electrolyte levels should be monitored regularly at specific intervals. Particular caution is required in treating patients with ischaemic heart disease or cerebrovascular disorders, as excessive reduction in blood pressure may lead to myocardial infarction or stroke. Symptomatic hypotension has been observed in patients with arterial hypertension and heart failure, both with and without renal impairment. It occurs more frequently in patients with more severe degrees of heart failure, as evidenced by the use of high doses of loop diuretics, hyponatraemia or impaired renal function. Treatment of such patients should be initiated under medical supervision, and patients should be closely monitored when adjusting the dose of Enalozid® Forte and/or diuretic. A similar approach may be applied to patients with ischaemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of hypotension, the patient should be placed in a supine position and, if necessary, intravenous administration of physiological saline solution should be used. Transient hypotension upon initiation of treatment is not a contraindication for further use, provided that after normalization of circulating blood volume the blood pressure increases, treatment may be resumed at usual doses.

In some patients with heart failure who have normal or low blood pressure, Enalozid® Forte may cause additional reduction in systemic arterial pressure. This effect is predictable and generally not a reason to discontinue treatment. If hypotension becomes symptomatic, dose reduction and/or discontinuation of the diuretic and/or Enalozid® Forte may be necessary.

Renal impairment

Renal failure has been reported during enalapril therapy, predominantly in patients with severe heart failure or kidney disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, enalapril-associated renal failure is usually reversible.

Enalozid® Forte should not be prescribed to patients with impaired renal function (creatinine clearance < 80 ml/min and >30 ml/min) until enalapril titration reaches the dose of the drug in this dosage form (see section "Dosage and administration").

During enalapril therapy in combination with diuretics, some patients with arterial hypertension without any signs of kidney disease prior to treatment initiation developed increased blood urea and creatinine levels (see section "Special precautions for use. Enalapril maleate: Renal impairment; Hydrochlorothiazide: Renal impairment"). In such cases, treatment with Enalozid® Forte should be discontinued. This situation may indicate the possibility of renal artery stenosis (see section "Special precautions for use. Enalapril maleate: Renovascular hypertension").

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

Evidence exists that concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren in patients increases the risk of arterial hypotension, hyperkalaemia and renal function impairment (including acute renal failure). Therefore, dual blockade of RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamic properties").

If dual blockade is considered absolutely necessary, it should be performed under physician supervision with careful regular monitoring of renal function, water-electrolyte balance and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Hyperkalaemia

Hyperkalaemia cannot be excluded when enalapril and diuretic are used in combination at low doses (see section "Special precautions for use. Enalapril maleate: Hyperkalaemia").

Lithium

Lithium is generally not recommended to be used in combination with enalapril and diuretics (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

The medicinal product Enalozid® Forte contains lactose. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Children

Safety and efficacy of the medicinal product in children have not been established.

Enalapril maleate

Aortic stenosis/hypertrophic cardiomyopathy

Like all other vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and should be avoided in cardiogenic shock and haemodynamically significant obstruction.

Renal impairment

Renal failure associated with enalapril use has been reported, predominantly in patients with severe heart failure or underlying kidney disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, enalapril-associated renal failure is usually reversible (see sections "Dosage and administration", "Special precautions for use. Enalapril maleate: Hydrochlorothiazide, Renal impairment; Hydrochlorothiazide: Renal impairment").

Renovascular hypertension

There is an increased risk of hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney receiving ACE inhibitors. Impaired renal function may occur even with minor changes in serum creatinine levels. For such patients, treatment should be initiated with low doses under close physician supervision, with cautious dose escalation and monitoring of renal function.

Patients on haemodialysis

Enalapril is contraindicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes (e.g. AN 69®) while receiving ACE inhibitors. For such patients, dialysis membranes of another type should be used or antihypertensive agents of other classes should be prescribed.

Kidney transplantation

There is no experience with the use of the medicinal product in patients who have recently undergone kidney transplantation. Therefore, enalapril treatment is not recommended for these patients.

Hepatic impairment

Rarely, use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant necrotic hepatitis, sometimes fatal. The mechanism of this syndrome is unknown. Patients taking ACE inhibitors who develop jaundice or significant elevation of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical supervision (see section "Special precautions for use. Hydrochlorothiazide: Hepatic impairment").

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and without other complicating factors. Enalapril should be used with extreme caution in patients with collagen vascular disease receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if renal impairment already exists. Serious infections have developed in some such patients, which in some cases did not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended when enalapril is prescribed to such patients, and patients should report any signs of infection.

Serum potassium

ACE inhibitors may cause hyperkalaemia as they suppress aldosterone release. The effect is usually mild in patients with normal renal function. Factors contributing to hyperkalaemia include renal failure, impaired renal function, age > 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), dietary supplements or salt substitutes containing potassium (e.g. products containing trimethoprim) or other agents that may increase serum potassium levels (e.g. heparin). Use of potassium supplements, potassium-sparing diuretics, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, or potassium-containing salt substitutes, or other agents that may increase serum potassium levels, particularly in patients with impaired renal function, may lead to significant increase in serum potassium levels. Hyperkalaemia may cause serious and even fatal arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is necessary, these medicinal products should be used with caution and serum potassium levels should be monitored frequently (see sections "Special precautions for use. Enalapril maleate: Hydrochlorothiazide, Hyperkalaemia; Hydrochlorothiazide: Metabolic and endocrine disorders", "Interaction with other medicinal products and other forms of interaction").

Hypoglycaemia

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin and starting ACE inhibitor therapy should be advised to carefully monitor blood glucose levels, especially during the first month of combination therapy (see sections "Special precautions for use. Hydrochlorothiazide: Metabolic and endocrine disorders", "Interaction with other medicinal products and other forms of interaction").

Hypersensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been observed during treatment with ACE inhibitors, including enalapril maleate. These reactions may occur at any time during treatment. In such cases, treatment with Enalozid® Forte should be discontinued immediately and close monitoring of the patient should be established until complete resolution of symptoms before discharge. Even in cases where only tongue swelling is observed without respiratory distress, prolonged monitoring is required, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal cases of angioedema associated with laryngeal or tongue swelling have been reported. Airway obstruction may occur in patients with swelling of the tongue, glottis or larynx, especially in patients with a history of surgical airway procedures. In cases of tongue, glottis or larynx swelling that may lead to airway obstruction, subcutaneous injection of 1:1000 adrenaline solution (0.3 ml – 0.5 ml) should be administered immediately and/or other measures to secure the airway should be performed.

Angioedema occurs more frequently in patients of non-European ancestry taking ACE inhibitors compared to patients of European ancestry. However, overall, it is considered that patients of non-European ancestry have an increased risk of developing angioedema.

Patients who previously experienced angioedema unrelated to ACE inhibitor use may be more prone to developing angioedema during ACE inhibitor therapy (see also section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan may be initiated only 36 hours after the last dose of enalapril. Treatment with enalapril may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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 or tongue swelling, with or without breathing difficulty) (see section "Interaction with other medicinal products and other forms of interaction").

Racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin should be prescribed with caution to patients already taking an ACE inhibitor. Before initiating treatment in patients taking Enalozid® Forte, a careful benefit-risk assessment should be performed.

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 desensitization to hymenoptera venom

Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during desensitization to hymenoptera venom. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before desensitization.

Anaphylactoid reactions during LDL apheresis

In patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate, life-threatening anaphylactoid reactions have rarely occurred. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis session.

Cough

Cough has been observed during ACE inhibitor therapy. The cough is usually non-productive and persistent and resolves after discontinuation of the medicinal product. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/anesthesia

During major surgical procedures or anesthesia with hypotensive agents, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. Hypotension explained by this mechanism can be corrected by increasing fluid volume (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy

ACE inhibitors should not be initiated during pregnancy. If continuation of ACE inhibitor therapy is not considered essential, pregnant women or women planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Ethnic differences

As with other ACE inhibitors, enalapril is less effective in reducing blood pressure in patients of non-European ancestry compared to patients of other ethnicities. This may be explained by the higher prevalence of low-renin system among hypertensive patients of non-European ancestry.

Hydrochlorothiazide

Renal impairment

Thiazides may be insufficiently effective diuretics in patients with impaired renal function and are ineffective at creatinine clearance of 30 ml/min or less (i.e. in moderate or severe renal failure) (see sections "Dosage and administration" and "Special precautions for use. Enalapril maleate – Hydrochlorothiazide: Renal impairment").

Enalozid® Forte should not be prescribed to patients with impaired renal function (creatinine clearance ≤ 80 ml/min) until titration of individual components reaches the dose of the drug in the combined tablet.

Liver disease

Thiazides should be used with caution in patients with impaired or progressive liver function, as hepatic coma may occur even with minor disturbances in water-electrolyte balance (see section "Special precautions for use. Enalapril maleate: Hepatic impairment").

Metabolic and endocrine disorders

Thiazide therapy may reduce glucose tolerance. In some cases, dose adjustment of antidiabetic agents, including insulin, may be required (see section "Special precautions for use. Enalapril maleate: Patients with diabetes").

Thiazides may reduce serum levels of sodium, magnesium and potassium.

Elevated cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, with hydrochlorothiazide 12.5 mg contained in Enalozid® Forte, minimal or no effects have been reported. Furthermore, in clinical studies with hydrochlorothiazide 6 mg, no clinically significant impact on glucose, cholesterol, triglycerides, sodium, magnesium or potassium levels was observed.

Thiazides may reduce calcium excretion in urine and may cause intermittent and slight increase in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcaemia may indicate latent hyperparathyroidism. Thiazide use should be discontinued before assessing parathyroid function.

Thiazide therapy may cause hyperuricaemia and/or exacerbation of gout in some patients. This effect on hyperuricaemia is dose-dependent. Additionally, enalapril may increase uric acid levels in urine and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide. In patients receiving diuretic therapy, serum electrolyte levels should be measured regularly at appropriate intervals. Thiazides (including hydrochlorothiazide) may cause water-electrolyte imbalance (hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of water-electrolyte imbalance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, increased fatigue, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, gastrointestinal disturbances such as nausea and vomiting.

Although hypokalaemia may occur during thiazide diuretic use, combination therapy with enalapril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia may be increased in patients with liver cirrhosis, patients with high diuresis, inadequate oral intake of electrolytes and patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (see section "Interaction with other medicinal products and other forms of interaction"). In hot weather, hyponatraemia may occur in patients prone to oedema. Chloride deficiency is usually mild and does not require treatment.

Thiazides may increase magnesium excretion in urine, which may lead to hypomagnesaemia.

Non-melanoma skin cancer

Epidemiological studies have observed an increased risk of non-melanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) with increasing cumulative dose of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may contribute to the development of non-melanoma skin cancer.

Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer. Such patients should be advised to take preventive measures to reduce exposure to solar and artificial ultraviolet radiation. Patients should regularly check their skin for new lesions and immediately report suspicious skin lesions to their doctor. Use of hydrochlorothiazide may also require review in patients who have previously had non-melanoma skin cancer (see section "Undesirable effects").

Anti-doping test

Hydrochlorothiazide contained in this medicinal product may cause a positive analytical result in anti-doping tests.

Hypersensitivity

Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma during thiazide use. Exacerbation or reactivation of systemic lupus erythematosus has been reported during thiazide use.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within several hours or weeks of starting the medicinal product.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the medicinal product as quickly as possible. If intraocular pressure remains uncontrolled, medical, surgical or other interventions may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamide or penicillin.

Acute respiratory toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide use. Pulmonary oedema usually develops within minutes or hours after hydrochlorothiazide administration. Initial symptoms include dyspnoea, fever, worsening lung condition and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide use.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this product, its use should be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.

Breastfeeding

Enalapril and thiazide diuretics pass into breast milk. Use of Enalozid® Forte during breastfeeding is not recommended.

Ability to affect reaction speed when driving vehicles or operating machinery.

When driving vehicles or operating machinery, it should be considered that dizziness or fatigue may occasionally occur (see section "Undesirable effects").

Dosage and Administration

Arterial Hypertension

Usual dose: ½ tablet. If necessary, the dose may be increased to 1 tablet once daily. Maximum dose is 2 tablets per day.

Previous Diuretic Therapy

Symptomatic arterial hypotension may occur at the beginning of treatment with Enalozid® Forte; hypotension is more frequent in patients with disturbances of water and/or electrolyte balance due to prior diuretic therapy. Diuretic therapy should be discontinued 2–3 days before starting treatment with Enalozid® Forte (see section "Special Precautions").

Dosage in Renal Impairment

Since the initial dose of enalapril in patients with mild renal impairment (creatinine clearance < 80 mL/min and > 30 mL/min) is 5–10 mg, Enalozid® Forte should not be used as initial therapy (see section "Special Precautions"). These patients may receive Enalozid® Forte only after dose titration of each component has been established.

Enalozid® Forte is contraindicated in patients with creatinine clearance ≤ 30 mL/min.

Administration Route

Oral administration.

Children

Safety and efficacy of the drug in children have not been established.

Overdose

Specific information on the treatment of overdose with Enalozid® Forte is lacking. Treatment is symptomatic and supportive. The drug should be discontinued and the patient carefully monitored. Recommended measures include induction of emesis, administration of activated charcoal, and use of laxatives if the drug was recently ingested, as well as correction of dehydration, electrolyte imbalance, and arterial hypotension using standard procedures.

Enalapril Maleate

The main manifestation of overdose is profound arterial hypotension occurring within six hours after tablet ingestion, associated with blockade of the renin-angiotensin system and stupor. Symptoms related to ACE inhibitor overdose may include circulatory shock, disturbances in electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Serum enalaprilat levels 100 and 200 times higher than those observed with therapeutic doses have been reported after ingestion of enalapril maleate at doses of 300 mg and 440 mg, respectively.

Recommended treatment for overdose is intravenous administration of physiological saline. If arterial hypotension occurs, the patient should be placed in a supine position with legs elevated (shock position). Infusion of angiotensin II and/or intravenous administration of catecholamines should be considered if available. If ingestion was recent, measures aimed at removing enalapril maleate from the body should be initiated (e.g., induction of emesis, gastric lavage, use of adsorbents and sodium sulfate). Enalapril can be removed from systemic circulation by hemodialysis (see section "Special Precautions"). In cases of bradycardia resistant to treatment, cardiac pacing is indicated. Vital signs, serum electrolytes, and creatinine levels should be continuously monitored.

Hydrochlorothiazide

The most common signs and symptoms are manifestations of electrolyte imbalance (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. Hypokalemia may potentiate arrhythmias when cardiac glycosides are taken concomitantly.

Adverse Reactions

Enalozid® Forte is generally well tolerated. In clinical studies, adverse reactions were mild, transient, and in most cases did not require discontinuation of therapy.

The most commonly reported adverse reactions observed during clinical trials with Enalozid® Forte were headache and cough.

The following adverse reactions have been reported with the use of Enalozid® Forte, enalapril monotherapy, or hydrochlorothiazide monotherapy in clinical trials or during post-marketing use. All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); unknown (cannot be estimated from available data).

Infections and infestations.

Uncommon: sialadenitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps).

Unknown: non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma).

Blood and lymphatic system disorders.

Uncommon: anemia (including aplastic and hemolytic anemia).

Rare: neutropenia, decreased hemoglobin levels, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, leukopenia, pancytopenia, lymphadenopathy, autoimmune disorders.

Immune system disorders.

Common: anaphylactic reaction.

Endocrine disorders.

Unknown: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolic and nutritional disorders.

Common: hypokalemia, increased cholesterol levels, increased triglyceride levels, hyperuricemia.

Uncommon: hypoglycemia (see section "Special precautions for use"), hypomagnesemia, gout**, electrolyte imbalance (including hyponatremia).

Rare: increased blood glucose levels.

Very rare: hypercalcemia (see section "Special precautions for use").

Nervous system and psychiatric disorders.

Common: headache, depression, syncope, taste disturbance.

Uncommon: confusion, drowsiness, insomnia, nervousness, paresthesia, vertigo, decreased libido**, restlessness.

Rare: pathological dreams, sleep disturbances, paralysis (due to hypokalemia).

Eye disorders.

Very common: blurred vision.

Uncommon: transient blurred vision, xanthopsia.

Unknown: choroidal effusion, acute myopia, acute angle-closure glaucoma.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Cardiac and vascular disorders.

Very common: dizziness.

Common: hypotension, orthostatic hypotension, arrhythmia, angina pectoris, tachycardia.

Uncommon: flushing, palpitations, necrotizing angiitis (vasculitis), myocardial infarction or stroke*, possibly due to excessive hypotension in high-risk patients (see section "Special precautions for use").

Rare: Raynaud's syndrome.

Respiratory, thoracic and mediastinal disorders.

Very common: cough.

Common: dyspnea.

Uncommon: rhinorrhea, sore throat and hoarseness, bronchospasm/asthma.

Rare: pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary edema), rhinitis, allergic alveolitis/eosinophilic pneumonia.

Very rare: acute respiratory distress syndrome (ARDS) (see section "Special precautions for use").

Gastrointestinal disorders.

Very common: nausea.

Common: diarrhea, abdominal pain.

Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers, flatulence**.

Rare: stomatitis/aphthous ulcers, glossitis.

Very rare: intestinal angioedema.

Hepatobiliary disorders.

Rare: liver failure, liver necrosis (may be fatal), hepatitis (hepatocellular or cholestatic), jaundice, cholecystitis (particularly in patients with pre-existing gallstones).

Skin and subcutaneous tissue disorders.

Common: rash (exanthema), hypersensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported.

Uncommon: diaphoresis, pruritus, urticaria, alopecia, photosensitivity.

Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigoid.

Unknown: a syndrome complex has been reported which may include some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated ESR, eosinophilia, and leukocytosis. Skin rash, photosensitivity, or other dermatological manifestations may occur.

Musculoskeletal and connective tissue disorders.

Common: muscle cramps†.

Uncommon: muscle spasms, arthralgia**.

Renal and urinary disorders.

Uncommon: renal dysfunction, renal failure, proteinuria, glycosuria.

Rare: oliguria, interstitial nephritis.

Reproductive system and breast disorders.

Uncommon: impotence.

Rare: gynecomastia.

General disorders and administration site conditions.

Very common: asthenia.

Common: chest pain, fatigue.

Uncommon: malaise, fever.

Investigations.

Common: hyperkalemia, increased serum creatinine.

Uncommon: increased blood urea nitrogen, hyponatremia.

Rare: increased liver enzymes, increased serum bilirubin.

* Frequency rate was comparable to placebo and active control groups in clinical trials.

** Observed only with hydrochlorothiazide at doses of 12.5 mg and 25 mg.

† The frequency of the adverse reaction "muscle cramps" is defined as "common" for hydrochlorothiazide at doses of 12.5 mg and 25 mg, although the frequency for hydrochlorothiazide at a dose of 6 mg is defined as "uncommon".

Non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma).

Based on available epidemiological data, a cumulative dose-dependent association has been observed between hydrochlorothiazide use and the development of non-melanoma skin cancer (BCC and SCC) (see also section "Special precautions for use").

The largest study included 71,553 cases of BCC among 1,430,883 individuals in the control population and 8,629 cases of SCC among 172,462 individuals in the control population. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. In another study, the association between lip cancer (SCC) and hydrochlorothiazide exposure was evaluated: 633 cases of lip cancer were identified among 63,067 individuals in the control population. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6) for any use, increasing to OR 3.9 (95% CI: 3.0–4.9) for greater use (≥25,000 mg) and OR 7.7 (95% CI: 5.7–10.5) for the highest cumulative dose (≥100,000 mg).

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister. 2 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.