Enap® 20 hl

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Enap® 20 HL (Enap® 20 HL)

Composition:

Active ingredients: 1 tablet contains enalapril maleate 20 mg and hydrochlorothiazide 12.5 mg;

Excipients: sodium hydrocarbonate, lactose monohydrate, maize starch, pregelatinized starch, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round, flat tablets with beveled edges and a score line on one side.

Pharmacotherapeutic group. Combined preparations of ACE inhibitors. Enalapril and diuretics. ATC code C09BA02.

Pharmacological properties.

Pharmacodynamics.

Enap® 20 HL is a combination of an angiotensin-converting enzyme (ACE) inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

Enalapril maleate

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. Inhibition of ACE leads to a reduction in plasma levels of angiotensin II, resulting in increased plasma renin activity (due to inhibition of the negative feedback mechanism on renin release) and reduced aldosterone secretion.

ACE is identical to kininase II. Enalapril may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role of this effect in the therapeutic actions of enalapril remains unclear. While the mechanism by which enalapril lowers blood pressure is primarily attributed to 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.

Two large randomized controlled trials (ONTARGET [Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and 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 relevant to other ACE inhibitors and angiotensin II receptor blockers.

Therefore, 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 Endpoints) was designed to evaluate 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 were higher in the aliskiren group compared to placebo, and adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity.

Non-melanoma skin cancer (NMSC)

Based on available epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population of 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), compared with 1,430,833 and 172,426 individuals in the respective control populations. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study suggested a possible link between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer were compared with 63,067 individuals in the control population using a random sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) for high doses (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Enalapril maleate – hydrochlorothiazide

The antihypertensive effects of the two components are additive and typically last for 24 hours. Although enalapril alone exerts a hypotensive effect even in patients with low-renin hypertension, concomitant administration with hydrochlorothiazide in such patients results in a greater reduction in blood pressure.

The enalapril component in the combination product generally attenuates the potassium-lowering effect caused by hydrochlorothiazide.

Pharmacokinetics.

Enalapril maleate

After oral administration, enalapril is rapidly absorbed, reaching peak serum concentration (Cmax) within 1 hour. Based on urinary excretion data, the extent of absorption of enalapril after oral administration is approximately 60–70%.

Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Cmax of enalaprilat in serum is reached within 3–4 hours after oral administration of enalapril maleate. Enalapril is primarily eliminated by the kidneys. The main components in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. Apart from conversion to enalaprilat, no significant metabolism of enalapril occurs. The serum concentration profile of enalaprilat is characterized by a prolonged terminal phase, likely due to binding to ACE. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved by day 4 of oral enalapril administration. The effective accumulation half-life of enalaprilat after multiple oral doses of enalapril is 11 hours. Food intake does not affect the gastrointestinal absorption of enalapril. The extent of absorption and hydrolysis of enalapril is similar across different doses within the recommended therapeutic range.

Hydrochlorothiazide

When plasma levels of hydrochlorothiazide were monitored for at least 24 hours, the elimination half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. After oral administration, at least 61% of the dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Enalapril maleate/hydrochlorothiazide

Repeated concomitant administration of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The combined tablet is bioequivalent to the individual components administered simultaneously.

Clinical characteristics.

Indications.

Arterial hypertension in patients who require combination therapy.

Contraindications.

• Hypersensitivity to any component of the medicinal product or to other sulfonamide-derived drugs.
• History of angioedema associated with previous treatment with ACE inhibitors, or hereditary or idiopathic angioedema.
• Severe hepatic impairment.
• Renal artery stenosis.
• Severe renal impairment (creatinine clearance ≤30 mL/min).
• Anuria.
• Refractory hypokalemia or hyperkalemia.
• Refractory hyponatremia.
• Symptomatic hyperuricemia (gout).
• Pregnancy or women planning to become pregnant (see section "Use in pregnancy or lactation").
• Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Special precautions").
• Concomitant use with sacubitril/valsartan due to increased risk of angioedema. Enap® 20 HL must not be administered within 36 hours after the last dose of sacubitril/valsartan, a drug containing a neprilysin inhibitor, or after switching from it to another drug (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Enalapril maleate – hydrochlorothiazide

Dual blockade of the RAAS

Clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse events such as hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to treatment with a single RAAS-blocking agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions").

Other antihypertensive agents

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

Combination of enalapril maleate with beta-blockers, methyldopa, or calcium channel blockers improves antihypertensive efficacy.

Ganglionic blockers or adrenergic blockers used in combination with enalapril should be administered only under careful patient monitoring.

Lithium

Reversible increases in serum lithium concentration 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 this medicinal product with lithium-containing drugs is not recommended; however, if such combination is necessary, serum lithium levels must be carefully monitored (see section "Special precautions").

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid > 3 g/day, and non-selective NSAIDs

NSAIDs, including selective COX-2 inhibitors, may attenuate the effects of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors, or diuretics may be reduced when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs (including COX-2 inhibitors) and 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, such drug combinations should be prescribed with caution in patients with compromised renal function.

Enalapril

Potassium-sparing diuretics or potassium supplements or potassium-containing salt substitutes

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

Diuretics (thiazide or loop diuretics)

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

Tricyclic antidepressants/neuroleptics/anesthetics/sedatives

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

Gold preparations

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

mTOR inhibitors (mammalian target of rapamycin inhibitors)

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

Neprilysin inhibitors

Concomitant use with neprilysin inhibitors (e.g., sacubitril, racecadotril) may increase the risk of angioedema. Initiation of sacubitril/valsartan therapy must not occur within 36 hours after the last dose of enalapril therapy. Enalapril therapy must not be initiated within 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

Cyclosporine

Concomitant use of cyclosporine may enhance hyperuricemia, potentially triggering gout attacks in patients with asymptomatic disease.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol

Alcohol potentiates the hypotensive effect of ACE inhibitors.

Antidiabetic agents (oral hypoglycemic agents and insulin)

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 effect is likely to occur during the first weeks of concomitant therapy and in patients with renal impairment (see sections "Special precautions" and "Adverse reactions").

Acetylsalicylic acid, thrombolytics, and β-blockers

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

Hydrochlorothiazide

Non-depolarizing muscle relaxants

Thiazides may enhance sensitivity to tubocurarine.

Alcohol, barbiturates, or narcotic analgesics may potentiate orthostatic hypotension.

Anticholinergic agents (e.g., atropine, biperiden)

Due to reduced gastrointestinal motility and delayed gastric emptying, the bioavailability of thiazide diuretics increases.

Carbamazepine

Due to the risk of symptomatic hyponatremia, clinical and biological monitoring is required.

Antidiabetic agents (oral hypoglycemic agents and insulin)

Thiazide treatment may reduce glucose tolerance. When antidiabetic agents and thiazide diuretics are used concomitantly, dosage adjustment of the antidiabetic agent may be necessary. Metformin should be used with caution due to the risk of lactic acidosis associated with potential functional renal impairment caused by hydrochlorothiazide.

Antigout agents (probenecid, sulfinpyrazone, allopurinol)

Dosage adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

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.

Prostaglandin synthase inhibitors – in some patients, their use may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

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

Increase the risk of torsades de pointes tachycardia.

Medicinal products causing changes in serum potassium levels

Periodic monitoring of serum potassium levels and ECG examination are recommended if hydrochlorothiazide is used concomitantly with medicinal products that cause changes in serum potassium levels (e.g., cardiac glycosides and antiarrhythmic agents) and agents that may induce polymorphic ventricular tachycardia (torsades de pointes), since hypokalemia is a factor predisposing to the development of torsades de pointes:

• Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide);
• Some neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

Cardiac glycosides

Hypokalemia or hypomagnesemia may potentiate or enhance cardiac response to the toxic effects of digitalis (e.g., increased ventricular excitability).

Corticosteroids, ACTH

Exacerbation of electrolyte imbalance, particularly hypokalemia.

Potassium-wasting 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").

Antineoplastic agents (e.g., cyclophosphamide, methotrexate)

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

Salicylates

When high doses of salicylates are used, hydrochlorothiazide may potentiate their toxic effects on the central nervous system.

Methyldopa

Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

Calcium salts

Thiazide diuretics increase serum calcium levels by reducing calcium excretion. If calcium-containing dietary supplements are required, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Iodine-containing contrast agents

In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high doses of iodine-containing contrast agents. Patients require rehydration before administration of iodine-containing agents.

Amphotericin B (parenteral), stimulant laxatives

Hydrochlorothiazide exacerbates electrolyte imbalance, particularly hypokalemia.

β-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

Children

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

Enalapril maleate – hydrochlorothiazide

Dual blockade of the RAAS

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be restricted to selected cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent acting on the RAAS. Do not use enalapril with aliskiren in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Arterial hypotension and fluid/electrolyte imbalance

As with other antihypertensive agents, symptomatic arterial hypotension may occur in some patients. Symptomatic hypotension has been observed in patients with heart failure, with or without concomitant renal insufficiency. 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 be initiated on therapy under medical supervision.

Patients should be evaluated for clinical signs of fluid and electrolyte imbalance such as dehydration, hyponatremia, hypochloremic alkalosis (which may induce hepatic encephalopathy or hepatic coma), hypomagnesemia, or hypokalemia (which may occur due to diarrhea or vomiting). Serum electrolyte levels should be periodically monitored in such patients.

Particular caution is required when treating patients with ischemic heart disease or cerebrovascular disease, as excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of developing arterial hypotension, the patient should be placed in a supine position and, if necessary, administered 0.9% sodium chloride solution intravenously. Transient arterial hypotension is not a contraindication to subsequent dosing. Treatment may be initiated only after effective normalization of circulating blood volume and arterial pressure; therapy may be resumed at reduced doses or with each component administered separately.

In some patients with heart failure and normal or low blood pressure, Enap® 20 HL may further reduce blood pressure. This reaction is expected and usually not a reason to discontinue treatment. If arterial hypotension becomes refractory to treatment, the dose should be reduced and/or diuretic and/or the drug therapy discontinued.

Renal impairment

Renal dysfunction has been reported with enalapril, particularly in patients with severe heart failure or kidney disease, including renal artery stenosis. If diagnosed promptly and treated appropriately, enalapril-associated renal failure is usually reversible.

In some patients with hypertension without pre-existing renal impairment, administration of enalapril with a diuretic may result in increased serum urea and creatinine. Dose reduction of enalapril and/or discontinuation of the diuretic may be required. In such cases, the possibility of renal artery stenosis should be considered.

Hyperkalemia

Hyperkalemia cannot be excluded when enalapril is used concomitantly with low-dose diuretics.

Lithium

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

Children

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

Enalapril maleate

Aortic stenosis/hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction or obstructive outflow pathways. They should be avoided in cardiogenic shock and hemodynamically significant obstruction.

Renal impairment

Renal failure associated with enalapril use has been reported, primarily 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 section "Dosage and administration").

Renovascular hypertension

In some patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney, administration of ACE inhibitors has been associated with increased blood urea nitrogen and serum creatinine, which are usually reversible upon discontinuation of the drug. Therapy in such patients should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Patients undergoing hemodialysis

Use of enalapril is contraindicated in patients requiring dialysis due to 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, alternative dialysis membranes or antihypertensive agents from other classes should be used.

Kidney transplantation

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

Hepatic impairment

Rarely, ACE inhibitors have 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 marked increases in liver enzymes should discontinue the ACE inhibitor and receive appropriate medical monitoring.

Neutropenia/agranulocytosis

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 complicating factors. Enalapril should be used with extreme caution in patients with collagen vascular diseases receiving immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially if renal function is already impaired. Serious infections, sometimes unresponsive to intensive antibiotic therapy, have occurred in some such patients. Periodic monitoring of white blood cell counts is recommended when prescribing enalapril to such patients, and patients should be instructed to report any signs of infection.

Hyperkalemia

Elevated serum potassium levels have been observed in some patients receiving ACE inhibitors, including enalapril. Risk factors for hyperkalemia include renal failure, reduced renal function, age >70 years, diabetes mellitus, intercurrent illness (e.g., dehydration, acute heart decompensation, metabolic acidosis), and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements or salt substitutes, or other drugs that may increase serum potassium (e.g., heparin, trimethoprim or co-trimoxazole [trimethoprim/sulfamethoxazole], and particularly aldosterone antagonists or angiotensin receptor blockers). Use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase serum potassium, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, even fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is considered necessary, they should be used with caution, with careful monitoring of renal function and plasma potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia

Patients with diabetes receiving oral antidiabetic agents or insulin who start taking an ACE inhibitor should be advised to closely monitor their blood glucose, especially during the first month of combination therapy (see section "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. These reactions may occur at any time during treatment. In such cases, treatment with Enap® 20 HL should be discontinued immediately, and the patient should be closely monitored until complete resolution of symptoms before discharge. Even in cases of isolated tongue swelling without respiratory distress, prolonged monitoring is required, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases of angioedema associated with laryngeal or tongue swelling have been very rarely reported. Patients with swelling of the tongue, glottis, or larynx may develop airway obstruction, particularly if they have a history of airway surgery. In cases of tongue, glottis, or laryngeal swelling that may lead to airway obstruction, immediate subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) and/or other measures to secure the airway should be performed.

Angioedema occurs more frequently in Black patients taking ACE inhibitors compared to other patients.

Patients with a history of angioedema unrelated to ACE inhibitor use may be more susceptible to developing angioedema during ACE inhibitor therapy (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated until 36 hours after the last dose of enalapril. Enalapril therapy should not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

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

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 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 low-density lipoprotein (LDL) apheresis

Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis session.

Cough

Cough has been observed during therapy with ACE inhibitors. The cough is usually non-productive and persistent and resolves after discontinuation of the drug. Cough due to ACE inhibitors 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

Initiation of ACE inhibitor therapy during pregnancy is not recommended. 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 alternative therapy should be initiated if necessary (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 Black patients compared to patients of other races. This may be explained by the higher prevalence of low-renin hypertension in Black patients.

Hydrochlorothiazide

Renal impairment

Thiazides may be insufficiently effective as diuretics in patients with impaired renal function and are ineffective when creatinine clearance is ≤30 mL/min, i.e., in moderate to severe renal failure (see section "Dosage and administration").

Enap® 20 HL should not be prescribed to patients with impaired renal function (creatinine clearance ≤80 mL/min) until individual component titration reaches the dose contained in the combined tablet.

Hepatic disorders

Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as these drugs may cause intrahepatic cholestasis, and even minor fluid and electrolyte imbalances may precipitate hepatic coma. Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment.

Metabolic and endocrine disturbances

Thiazide therapy may reduce glucose tolerance. In some cases, adjustment of antidiabetic agents, including insulin, may be required.

Latent diabetes mellitus may become apparent during thiazide therapy.

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

Elevations in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, with hydrochlorothiazide 12.5 mg (the dose in Enap® 20 HL), minimal or no effects have been reported. Furthermore, in clinical studies with hydrochlorothiazide 6 mg, no clinically significant effects on glucose, cholesterol, triglycerides, sodium, magnesium, or potassium were observed.

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

Thiazide therapy may cause hyperuricemia and/or exacerbate gout in some patients. This effect on hyperuricemia is dose-dependent. Additionally, enalapril may increase urinary uric acid levels and thereby attenuate the hyperuricemic effect of hydrochlorothiazide.

Patients receiving diuretic therapy should have serum electrolyte levels monitored regularly at appropriate intervals.

Thiazides (including hydrochlorothiazide) may cause fluid and electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Warning signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, somnolence, fatigue, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Although hypokalemia may occur during thiazide diuretic therapy, concomitant therapy with enalapril may reduce diuretic-induced hypokalemia. The risk of hypokalemia may be increased in patients with liver cirrhosis, those with high diuresis, inadequate oral electrolyte intake, or those receiving concomitant corticosteroid or adrenocorticotropic hormone therapy (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatremia may occur in hot weather in patients prone to edema. Chloride deficiency is usually mild and does not require treatment.

Thiazides may increase urinary magnesium excretion, potentially leading to hypomagnesemia.

Hydrochlorothiazide may affect laboratory test results:

• the drug may reduce iodine binding to plasma proteins;
• treatment should be discontinued before laboratory tests assessing parathyroid function;
• the drug may increase serum free bilirubin levels;
• hydrochlorothiazide may yield a positive analytical result in anti-doping tests.

Hypersensitivity

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

Non-melanoma skin cancer (NMSC)

In two epidemiological studies based on the Danish National Cancer Registry, an increased risk of NMSC (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) was observed with increasing cumulative doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. Preventive measures such as limiting exposure to sunlight and ultraviolet radiation are recommended, and patients should be advised to take appropriate protective measures when exposed. Suspicious skin lesions should be promptly investigated, including histological examination by biopsy. The continued use of hydrochlorothiazide should also be re-evaluated in patients with a history of NMSC (see section "Adverse reactions").

Idiopathic uveitis, acute myopia, and secondary angle-closure glaucoma

Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to idiopathic uveitis, transient myopia, and acute angle-closure glaucoma. Symptoms include decreased visual acuity or eye pain, usually occurring within hours or weeks of drug intake. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, rapid medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

Acute respiratory toxicity

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

Special warnings regarding inactive ingredients

The drug contains lactose; therefore, it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment, the drug should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Period of breastfeeding

Enalapril and thiazide diuretics pass into breast milk. Use of the drug during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

Arterial Hypertension

Treatment of hypertension is never initiated with combination drugs. Adequate doses of individual components should first be established. The dose is prescribed by a physician individually for each patient depending on the patient's condition.

Administer 1 tablet once daily. The maximum dose is 2 tablets once daily.

The tablets should be taken whole, orally, during or after meals, with liquid. The medication should be taken at the same time each day. If a dose is missed, it should be taken as soon as possible, but not if only a few hours remain before the next scheduled dose. In this case, the patient should wait and take only the next scheduled dose. Two doses must not be taken simultaneously.

For most patients, 20 mg (exceptionally 40 mg) of enalapril or 50 mg of hydrochlorothiazide daily is sufficient to control hypertension; therefore, it is not recommended to take more than 2 tablets of Enap® 20 HL per day. If an adequate response is not achieved, adding a third agent or changing the therapy is recommended.

Previous Diuretic Therapy

Symptomatic hypotension may occur at the beginning of treatment, particularly in patients with disturbances in fluid or electrolyte balance due to prior diuretic therapy. Diuretic therapy should be discontinued 2–3 days before starting Enap® 20 HL.

The duration of treatment is not time-limited.

Dosage in Renal Impairment

Thiazides may be less effective in patients with impaired renal function and are ineffective when creatinine clearance is below 30 mL/min or serum creatinine levels exceed 265 µmol/L (3 mg/100 mL) (i.e., in moderate to severe renal impairment).

Enap® 20 HL may be used in patients with creatinine clearance ranging from >30 to <80 mL/min only after prior dose titration of each individual component.
The recommended initial dose of enalapril maleate used alone in mild renal impairment is 5–10 mg.

Children

The safety and efficacy of Enap® 20 HL in children have not been established.

Overdose

Specific information regarding the treatment of Enap® 20 HL overdose is lacking. Treatment is symptomatic and supportive. Administration of the drug should be discontinued and the patient should be carefully monitored. Recommended measures include: inducing vomiting if the drug was recently ingested, and correcting dehydration, electrolyte imbalances, and arterial hypotension using standard procedures.

Enalapril Maleate

The main manifestation of overdose is marked arterial hypotension occurring within 6 hours after drug intake, accompanied by RAAS blockade and stupor. Symptoms associated with ACE inhibitor overdose may include circulatory shock, electrolyte imbalance, pulmonary hyperventilation, tachycardia, palpitations, dizziness, anxiety, and cough. Plasma enalaprilat levels 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. After ingestion of a larger number of tablets, treatment should be discontinued, vital signs should be monitored in a medical facility, gastric lavage, activated charcoal, and a laxative should be administered. Treatment is symptomatic. In case of arterial hypotension, intravenous administration of physiological saline is recommended. Usually, placing the patient in a supine position with a low pillow is sufficient. In more severe cases, infusion of physiological saline should be administered, and if possible, infusion of angiotensin II and/or intravenous catecholamines should be considered.

Arterial pressure, pulse, respiration, serum electrolytes, serum creatinine levels, and diuresis should be continuously monitored.

In more severe cases, toxic amounts of enalapril and/or enalaprilat should be removed from the circulation by hemodialysis (see section "Special Instructions"). In cases of bradycardia resistant to treatment, cardiac pacing is indicated. Vital signs, serum electrolytes, and serum creatinine levels should be continuously monitored.

Hydrochlorothiazide

The most common signs and symptoms observed are depletion of electrolytes (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If digoxin is also administered, hypokalemia may exacerbate cardiac arrhythmias. Other manifestations of overdose may include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, fatigue, disturbances of consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen (primarily due to renal failure).

Vital signs, electrolyte concentrations, and serum creatinine levels should be continuously monitored.

Adverse reactions.

Enap® 20 HL is generally well tolerated. The most common adverse reactions were headache and cough, which were transient in nature and did not require discontinuation of therapy.

The following adverse reactions have been reported during use of the drug, enalapril monotherapy, or hydrochlorothiazide.

Side effects

System organ class / disorder	Very common (≥1/10)	Common (from ≥1/100 to <1/10)	Uncommon (from ≥1/1000 to <1/100)	Rare (from ≥1/10000 to <1/1000)	Very rare (<1/10000)	Frequency not known (cannot be calculated from available data)
Blood and lymphatic system disorders			Anaemia (including aplastic and haemolytic anaemia)	Neutropenia, decreased haemoglobin, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, leucopenia, pancytopenia, lymphadenopathy, autoimmune disorders
Endocrine disorders						Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		Hypokalaemia, increased cholesterol, increased triglycerides, hyperuricaemia	Hypoglycaemia1), hypomagnesaemia, gout2)	Increased blood glucose	Hypercalcaemia1)
Nervous system and psychiatric disorders		Headache, depression, syncope, taste disturbances	Confusion, drowsiness, insomnia, restlessness, fatigue, paraesthesia, vertigo, decreased libido2)	Nightmares, sleep disorders, paresis (due to hypokalaemia)
Eye disorders	Blurred vision					Choroidal effusion
Ear and labyrinth disorders			Tinnitus
Cardiac and vascular disorders	Dizziness	Hypotension, orthostatic hypotension, arrhythmia, angina pectoris, tachycardia	Flushing, palpitations, myocardial infarction or stroke3), possibly due to excessive hypotension in high-risk patients1)	Raynaud's syndrome		Chest pain
Respiratory, thoracic and mediastinal disorders	Cough	Dyspnoea	Rhinorrhoea, throat pain and hoarseness, bronchospasm/ asthma	Lung infiltrates, respiratory distress (including pneumonitis and pulmonary oedema), rhinitis, allergic alveolitis/ eosinophilic pneumonia	Acute respiratory distress syndrome (ARDS)1)
Gastrointestinal disorders	Nausea	Diarrhoea, abdominal pain	Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers, flatulence2)	Stomatitis/ aphthous ulcers, glossitis	Angioneurotic intestinal oedema
Hepatobiliary disorders				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		Rash (exanthema), hypersensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported	Diaphoresis, pruritus, urticaria, alopecia	Multiform erythema, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigoid		A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/ arthritis, positive antinuclear factor test, elevated ESR, eosinophilia and leukocytosis. Skin rashes, photosensitivity or other dermatological manifestations may also occur
Benign, malignant and unspecified neoplasms (including cysts and polyps)						NMSC (BCC and SCC)4)
Musculoskeletal and connective tissue disorders		Muscle cramps5)	Arthralgia2)
Renal and urinary disorders			Renal dysfunction, renal failure, proteinuria	Oliguria, interstitial nephritis
Reproductive system and breast disorders			Impotence	Gynaecomastia
Laboratory investigations		Hyperkalaemia, increased serum creatinine	Increased blood urea nitrogen, hyponatraemia	Elevated liver enzymes, increased serum bilirubin	Hypochloraemic alkalosis

1. See section "Special precautions".
2. Observed only with administration of hydrochlorothiazide at doses of 12.5 and 25 mg.
3. The frequency rate was comparable to that in placebo and active control groups in clinical studies.
4. Non-melanoma skin cancer: based on available epidemiological study data, a cumulative dose-dependent association between hydrochlorothiazide use and NMSC has been observed (see sections "Pharmacodynamics" and "Special precautions").
5. The frequency of the adverse reaction "muscle cramps" is defined as "common" for hydrochlorothiazide at doses of 12.5 and 25 mg, although the frequency of this reaction for hydrochlorothiazide at a dose of 6 mg is defined as "uncommon".

Additional adverse reactions observed with individual components:

Enalapril. Anaphylactic shock, asthenia, cholestasis.

Hydrochlorothiazide. Arrhythmia, cholestasis, sialadenitis, xanthopsia, necrotizing angiitis (vasculitis), anaphylactic reaction, restlessness, muscle spasms, disorientation, mood changes, transient visual disturbances; thirst, glucosuria, reduced glucose tolerance which may lead to manifestation of latent diabetes mellitus, sexual dysfunction, exhaustion; hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma; hyperuricemia, which may provoke gout attacks in patients with asymptomatic disease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 5 years.

Storage conditions. No special temperature storage conditions are required for this medicinal product. Store in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 2, 3, 6, or 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and site of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.