Enap®-n

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Enap®-HL Enap®-H

Composition:

Active substances: 1 tablet contains enalapril maleate 10 mg and hydrochlorothiazide 12.5 mg, or enalapril maleate 10 mg and hydrochlorothiazide 25 mg;

Excipients: sodium hydrocarbonate, lactose monohydrate, corn starch, pregelatinized starch, talc, magnesium stearate, quinoline yellow dye (E 104) – only in Enap®-H.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Enap®-HL: white, round, flat tablets with a bevelled edge and a notch on one side.

Enap®-H: yellow, round, flat tablets with a bevelled edge and a notch on one side.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. ATC code C09BA02.

Pharmacological Properties.

Pharmacodynamics.

The medicinal product is a combination of an ACE inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

ACE is peptidyl dipeptidase, which 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 loop on renin release) and decreased aldosterone secretion.

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

Mechanism of action

Although the mechanism by which enalapril lowers arterial 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 antihypertensive effects 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 contributes to greater blood pressure reduction in these patients.

Dual blockade

Two large randomized controlled trials (ONTARGET – Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial, VA NEPHRON-D – Veterans Affairs Nephropathy in Diabetes study) investigated the use of a combination of ACE inhibitors with angiotensin receptor blockers (ARBs) II.

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

These studies did not demonstrate significant benefits regarding renal or cardiovascular outcomes or mortality reduction; however, an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings may also apply to other ACE inhibitors and ARBs II.

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

The ALTITUDE trial (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 ARBs II in patients with type 2 diabetes and chronic kidney disease, 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 events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Non-melanoma skin cancer

Epidemiological studies have established a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer (NMSC). One study included 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), with 1,430,883 and 172,462 control patients, respectively. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear relationship between cumulative dose and incidence of BCC and SCC was observed. Another study suggested a possible association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer were identified in a control group of 63,067 individuals using a random sampling strategy. A clear dose-response relationship was demonstrated, with an adjusted RR of 2.1 (95% CI: 1.7–2.6), RR 3.9 (3.0–4.9) for high cumulative dose (at least 25,000 mg), and RR 7.7 (5.7–10.5) for the highest cumulative dose (at least 100,000 mg) (see section "Special precautions for use").

Pharmacokinetics.

Enalapril

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

Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat are reached 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. 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, likely due to binding to ACE. In individuals with normal renal function, steady-state concentrations of enalaprilat in serum are achieved by day 4 of oral enalapril administration. Food intake does not affect gastrointestinal absorption of enalapril. 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 only to a minimal extent; enalaprilat does not reach 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 by the kidneys. The main components of the drug in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. The effective half-life for accumulation of enalaprilat after multiple oral doses of enalapril maleate is 11 hours. In studies measuring plasma concentrations of hydrochlorothiazide over at least 24 hours, the plasma elimination half-life 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 to 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 received enalapril 10 mg daily for 11 months had a peak milk concentration of enalapril of 2 µg/L at 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 undetectable (< 0.2 µg/L) 4 hours after a single 5 mg dose of enalapril in one woman and 10 mg in two women; enalapril levels were not detected.

Clinical characteristics.

Indications.

Arterial hypertension in patients indicated for combination therapy.

Contraindications.

• Hypersensitivity to enalapril and other ACE inhibitors, hydrochlorothiazide and other sulfonamide derivatives, or to any other components of Enap®-H or Enap®-HL.
• History of angioedema associated with previous treatment with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Severe renal impairment [creatinine clearance less than 30 mL/min or serum creatinine levels exceeding 265 µmol/L (3 mg/100 mL)].
• Renal artery stenosis.
• During hemodialysis.
• Clinical condition following kidney transplantation.
• Severe hepatic impairment.
• Anuria, primary hyperaldosteronism.
• Refractory hypokalemia or hyperkalemia.
• Refractory hyponatremia.
• Symptomatic hyperuricemia (gout).
• Pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").
  • Do not use enalapril with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Special precautions").
  • Concomitant use with sacubitril/valsartan therapy – due to increased risk of angioedema. The medicinal product should 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 agent (see sections "Interaction with other medicinal products and other forms of interactions" and "Special precautions").

Interaction with other medicinal products and other forms of interactions.

Enalapril maleate and hydrochlorothiazide

Other antihypertensive agents

Concomitant use of these medicinal products may potentiate the antihypertensive effect. Simultaneous administration of nitroglycerin and other nitrates or vasodilators may further reduce blood pressure.

Lithium

Concomitant use of lithium and ACE inhibitors may reversibly increase serum lithium concentrations and enhance its toxicity. Concurrent use of thiazide diuretics and ACE inhibitors may further increase lithium levels and increase the risk of lithium toxicity. Concomitant use of enalapril/hydrochlorothiazide with lithium is not recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and non-selective NSAIDs, may attenuate the antihypertensive effects of ACE inhibitors, diuretics, or other antihypertensive agents. In some patients with impaired renal function (e.g., elderly patients or those with dehydration, including those receiving diuretic therapy), concomitant use of NSAIDs, including COX-2 inhibitors, with angiotensin receptor antagonists (ARA II) and ACE inhibitors may have additive effects on increasing serum potassium and further worsening renal function, including possible acute renal failure. These effects are usually reversible. Therefore, such combinations should be initiated with caution in patients with renal impairment. Patients should consume adequate fluid and require close monitoring of renal function at the start of concomitant therapy and regularly during treatment.

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

Clinical studies have shown that dual blockade of RAAS with concomitant use of ACE inhibitors, ARA II, 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 "Pharmacodynamic properties", "Contraindications", "Special precautions").

Enalapril

Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium 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 salt substitutes may lead to a significant increase in serum potassium levels. Caution should also be exercised when combining enalapril with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of enalapril with the above-mentioned agents is not recommended. If these agents are indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special precautions").

Agents increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions").

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

Co-trimoxazole (trimethoprim/sulfamethoxazole)

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

Cyclosporine

Concomitant use of cyclosporine may enhance hyperkalemia, which may trigger gout attacks in patients with asymptomatic disease.

Heparin

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

Diuretics (thiazide or loop diuretics)

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

Tricyclic antidepressants / antipsychotics / narcotics

Concomitant use of anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure.

Gold preparations

Rare reactions similar to nitrite reactions (symptoms of vasodilation, including flushing, facial swelling, dizziness, nausea, vomiting, and arterial hypotension) have been observed in patients treated with injectable gold preparations (sodium aurothiomalate) and concomitantly with ACE inhibitors, including enalapril.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Antidiabetic agents

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects with a risk of hypoglycemia. This effect is likely to occur during the first weeks of concomitant therapy and in patients with impaired renal function (see section "Adverse reactions").

Acetylsalicylic acid, thrombolytics, beta-blockers

Enalapril may be used cautiously concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytic agents, and beta-blockers.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist

It has been reported that in patients with confirmed atherosclerotic disease, heart failure, or diabetes with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist (ARA) is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to therapy with a single RAAS-blocking agent. Dual blockade (e.g., combining an ACE inhibitor with an ARA II) should be limited to individually defined cases and accompanied by careful monitoring of renal function, potassium levels, and blood pressure.

Hydrochlorothiazide

Non-depolarizing muscle relaxants

Possible potentiation of sensitivity to muscle relaxants.

Alcohol, barbiturates, narcotic analgesics

May potentiate orthostatic hypotension.

Antidiabetic agents (oral antidiabetics and insulin)

Thiazide therapy may reduce glucose tolerance. Dose adjustments may be required. Metformin should be used with caution due to the risk of lactic acidosis associated with possible renal impairment caused by hydrochlorothiazide.

Other antihypertensive agents

Additive effect.

Cholestyramine and colestipol resins

Anion-exchange resins may reduce hydrochlorothiazide absorption. Single doses of cholestyramine or colestipol resins reduce gastrointestinal absorption of hydrochlorothiazide by 85% and 43%, respectively.

Prolongation of QT interval (e.g., procainamide, amiodarone, sotalol)

Increased risk of torsades de pointes tachycardia.

Cardiac glycosides

Hypokalemia may increase cardiac sensitivity or enhance clinical response to digoxin toxicity (e.g., increased ventricular excitability).

Corticosteroids, adrenocorticotropic hormone (ACTH)

Hydrochlorothiazide may potentiate electrolyte imbalance, primarily hypokalemia.

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

Hydrochlorothiazide may increase potassium and/or magnesium loss.

Medicinal products used for gout treatment (probenecid, sulfinpyrazone, and allopurinol)

Dose adjustments of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid concentration. Dose increases of probenecid or sulfinpyrazone may be necessary. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Pressor amines (e.g., adrenaline)

Thiazides may reduce the response to pressor amines, but not sufficiently to preclude concomitant use.

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

Increase bioavailability of thiazide diuretics due to reduced gastrointestinal motility and delayed gastric emptying.

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

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Prolonged use of NSAIDs may reduce diuretic, natriuretic, and antihypertensive effects of diuretics.

Salicylates

In case of high-dose salicylate intake, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Methyldopa

There are isolated reports of hemolytic anemia with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant use of cyclosporine may enhance hyperuricemia and increase the risk of complications such as gout.

Medicinal products affected by changes in serum potassium levels

Periodic monitoring of serum potassium levels and ECG is recommended when enalapril/hydrochlorothiazide is used concomitantly with medicinal products affected by changes in serum potassium levels (e.g., digitalis glycosides and antiarrhythmic agents), as well as with the following agents (including antiarrhythmics) that may cause torsades de pointes tachycardia, where hypokalemia is a favorable factor for this arrhythmia (ventricular tachycardia):

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);

• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);

• Some antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);

• Other agents (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinca alkaloids).

Calcium salts

Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium supplementation is required, dosage should be adjusted under control of serum calcium levels.

Effect on laboratory test results

Due to their effect on calcium metabolism, thiazides may influence assessment of parathyroid gland function (see section "Special precautions").

Carbamazepine

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

Iodine-containing contrast agents

In cases of diuretic-induced dehydration, the risk of acute renal failure increases, particularly with high-dose contrast agents. Patients require rehydration prior to administration of iodine-containing agents.

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormones (ACTH), or stimulant laxatives

Hydrochlorothiazide may potentiate electrolyte imbalance, especially hypokalemia.

Beta-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

Amantadine

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

Special precautions for use.

Enalapril and hydrochlorothiazide

Arterial hypotension and disturbances of water-electrolyte balance

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving Enap®-H or Enap®-HL, arterial hypotension occurs more frequently in the presence of salt/volume depletion, for example due to diuretic therapy, dietary salt restriction, dialysis, or presence of diarrhea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Side effects"). In such patients, regular monitoring of serum electrolyte levels is required. Symptomatic arterial hypotension occurred more frequently in patients with more severe forms of heart failure, reflected by the use of high doses of loop diuretics, hyponatremia, or impaired renal function. Treatment of such patients should be initiated under medical supervision, and patients should strictly adhere to adjusted doses of the drug and/or diuretic. Similar attention should be paid to the treatment of patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction of 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, administered intravenous physiological saline. Transient hypotension upon initiation of the drug is not a contraindication for further use; if blood pressure increases after normalization of circulating blood volume, therapy may be resumed at usual doses.

In some patients with heart failure and normal or low blood pressure, the drug may cause additional reduction in systemic arterial pressure. This reaction to the drug intake is expected and should not be considered a reason to discontinue treatment. If hypotension becomes symptomatic, dose reduction and/or discontinuation of the diuretic and/or enalapril/hydrochlorothiazide-containing drug may be necessary.

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

Evidence indicates that concomitant use of ACE inhibitors, ARAs II, or aliskiren in patients increases the risk of developing arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, ARAs II, 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 medical supervision with careful monitoring of renal function, water-electrolyte balance, and blood pressure.

Concomitant use of ACE inhibitors and ARAs II should not be used in patients with diabetic nephropathy.

Renal function impairment

Renal function impairment caused by enalapril has been reported, especially in patients with severe heart failure or kidney diseases, including renal artery stenosis. If diagnosed promptly and appropriate treatment is initiated, renal failure associated with enalapril therapy is usually reversible.

In some patients with arterial hypertension without pre-existing renal insufficiency, administration of enalapril together with a diuretic may lead to increased serum urea and creatinine levels. 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

Combination of enalapril with a low-dose diuretic may lead to hyperkalemia.

Lithium

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

Use in children

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

Elderly patients

The effectiveness and tolerability of enalapril maleate and hydrochlorothiazide used simultaneously are similar in elderly patients and younger adult patients with arterial hypertension.

Enalapril

Aortic or mitral stenosis / hypertrophic cardiomyopathy

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

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney who are taking ACE inhibitors have an increased risk of developing arterial hypotension. Even minor changes in serum creatinine may lead to worsening of renal function. In these patients, treatment should be initiated under strict medical supervision, starting with low doses and careful dose adjustment with close monitoring of renal function.

Patients undergoing hemodialysis

In patients undergoing dialysis using high-flux membranes (e.g., AN 69), angioedema-like reactions have occurred in some cases during treatment with ACE inhibitors. Therefore, for such patients, use of dialysis membranes of another type or antihypertensive agents from another class is recommended.

Kidney transplantation

There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Therefore, treatment with Enap®-H or Enap®-HL is not recommended for these patients.

Hepatic function 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) with fatal outcome. 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 monitoring.

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitor therapy. Neutropenia rarely occurs in patients with normal renal function and without special risk factors. Enalapril should be used with extreme caution in patients with collagenosis, undergoing immunosuppressive therapy, treatment with allopurinol or procainamide, or with a combination of the above risk factors, especially if renal function impairment has been previously established. In some of these patients, severe infections may develop, which sometimes do not respond to intensive antibiotic therapy.

When using enalapril in these patients, periodic monitoring of leukocytes is recommended, and patients should be warned to inform their physician about any signs of infection.

Hyperkalemia

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. The effect is usually insignificant in patients with normal renal function. The risk of hyperkalemia is increased in patients with renal insufficiency, impaired renal function, patients aged >70 years, patients with diabetes mellitus, transient conditions such as dehydration, patients with acute heart decompensation, metabolic acidosis, patients concomitantly taking potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride); use of dietary supplements or salt substitutes containing potassium; in patients taking other drugs that may cause increased serum potassium levels (e.g., heparin, trimethoprim or cotrimoxazole, also known as trimethoprim/sulfamethoxazole, and particularly aldosterone antagonists or ARAs). In particular, use of potassium-sparing diuretics, dietary supplements, or salt substitutes containing potassium in patients with impaired renal function may lead to significant elevation of serum potassium levels. Hyperkalemia may cause serious, sometimes fatal arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and renal function and serum potassium levels should be carefully monitored (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin require careful glycemic control, especially during the first month of treatment with ACE inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Increased sensitivity / angioedema

In patients treated with ACE inhibitors, including Enap®-H or Enap®-HL, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has occurred in some cases. It may occur at any time during treatment. In such cases, use of Enap®-H or Enap®-HL must be immediately discontinued and continuous monitoring of the patient established to ensure complete resolution of symptoms. Even if only tongue swelling is observed without respiratory distress, prolonged monitoring may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal angioedema of the larynx or tongue has been reported. If swelling of the tongue, glottis, or larynx occurs, airway obstruction is likely, especially in patients who have undergone surgery on respiratory organs. In these cases, emergency treatment is required, which may include subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) and/or measures to ensure airway patency.

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

Patients who previously experienced angioedema unrelated to ACE inhibitor use have an increased risk of its occurrence when using ACE inhibitors (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy must not be initiated 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 for use").

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

Caution is required when initiating racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already taking an ACE inhibitor.

Anaphylactoid reactions during desensitization therapy

Rarely, anaphylactoid reactions, potentially life-threatening, have occurred in patients receiving ACE inhibitors during allergen desensitization with Hymenoptera venom. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting hyposensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

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

Cough

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

Surgical procedures/anesthesia

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

Pregnancy

Initiation of ACE inhibitors during pregnancy is not recommended. Women planning pregnancy should be switched to alternative antihypertensive drugs with an established safety profile during pregnancy. If pregnancy is confirmed, treatment with ACE inhibitors should be immediately discontinued and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Racial differences

Like other ACE inhibitors, enalapril is less effective in lowering blood pressure in patients of non-Caucasian race compared to patients of other races, possibly due to higher prevalence of low-renin states among non-Caucasian race patients with hypertension.

Hydrochlorothiazide

Renal function impairment

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

Enap®-H or Enap®-HL tablets should not be prescribed to patients with renal insufficiency (creatinine clearance <80 mL/min) until titration of individual components reaches the dose of the drug in the combined tablet.

Hepatic function impairment

Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as even minor disturbances in water-electrolyte balance may lead to hepatic coma. Hydrochlorothiazide is contraindicated in patients with severe hepatic function impairment.

Metabolic and endocrine effects

Thiazide therapy may alter glucose tolerance. Adjustment of antidiabetic drug doses, including insulin, may be required. Thiazide treatment may provoke manifestation of latent 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 low-dose use (12.5 mg), minimal or no effect has been reported. Furthermore, in clinical studies of hydrochlorothiazide at a dose of 6 mg, no clinically significant effect on glucose, cholesterol, triglycerides, sodium, magnesium, or potassium levels was observed.

Thiazides may reduce calcium excretion in urine and cause occasional slight elevation of serum calcium. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before performing tests for thyroid function.

Thiazide diuretic therapy may cause hyperuricemia and/or exacerbation of gout in some patients. This effect on hyperuricemia is dose-dependent. However, enalapril may increase uric acid levels and thus may attenuate the hyperuricemic effect of hydrochlorothiazide.

In patients receiving diuretic therapy, serum electrolyte levels should be measured at appropriate intervals.

Thiazides (including hydrochlorothiazide) may cause fluid and electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Dangerous signs of fluid-electrolyte imbalance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, fatigue, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting).

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

In hot weather, hyponatremia may occur in patients prone to edema due to blood dilution. Chloride deficiency is usually mild and does not require treatment.

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

Effect on laboratory test results:

• the drug may reduce protein-bound iodine levels in plasma;
• drug treatment should be discontinued before laboratory testing to assess parathyroid function;
• the drug may increase free bilirubin concentration in serum;
• hydrochlorothiazide may yield a positive result in anti-doping tests.

Increased sensitivity

Reactions of increased sensitivity to hydrochlorothiazide may occur in patients prone to allergies or with a history of bronchial asthma.

Exacerbation or activation of systemic lupus erythematosus has been observed during use of thiazide diuretics.

Non-melanoma skin cancer

According to data from two epidemiological studies included in the Danish National Cancer Registry, there is an increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose 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 developing NMSC. Such patients should be advised to take preventive measures to reduce exposure to solar and artificial ultraviolet radiation. 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 "Side effects").

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion, visual disturbances, transient myopia, and acute angle-closure glaucoma. Symptoms include decreased visual acuity or eye pain, which usually occur within hours or weeks of taking the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, rapid medical or surgical treatment may be required. Risk factors for developing acute angle-closure glaucoma include a history of allergy to sulfonamides or penicillin.

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide intake. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide administration. 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 previously experienced ARDS after hydrochlorothiazide.

Special warnings regarding inactive components of the medicinal product

Enap®-H and Enap®-HL contain lactose. This drug should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy and breastfeeding.

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

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

Breastfeeding period

Enalapril and thiazide diuretics pass into breast milk. Use of enalapril/hydrochlorothiazide during breastfeeding is contraindicated. If use of the drug is absolutely necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Caution should be exercised when driving or operating machinery, considering the possibility of adverse reactions affecting the nervous system, including dizziness or drowsiness.

Dosage and Administration

Arterial Hypertension

Fixed-dose combination tablets of enalapril maleate and hydrochlorothiazide are prescribed to patients whose arterial pressure is not adequately controlled with enalapril alone.

The fixed combination of enalapril maleate and hydrochlorothiazide is not used for initial therapy. This combination is typically recommended after individual component doses have been adjusted. If clinically appropriate, transition from monotherapy to the fixed combination may be made directly.

Dosage regimens should be individually tailored depending on the patient's condition and severity of arterial hypertension. Treatment should be initiated with low doses, gradually increasing as needed. The drug should be taken orally, independently of food intake. The established daily dose should be taken in the morning with a large amount of fluid.

The usual dose is 1 tablet once daily. If necessary, the dose may be increased to 2 tablets once daily.

Fixed-dose combination tablets of 10 mg/25 mg and 10 mg/12.5 mg may replace therapy consisting of separate administration of 10 mg enalapril and 25 mg or 12.5 mg hydrochlorothiazide, respectively, in patients whose condition has been stabilized on individual components.

Prior Diuretic Therapy: Symptomatic hypotension may occur at the start of enalapril therapy. It is more commonly observed in patients whose prior diuretic therapy has caused disturbances in water-electrolyte balance. Diuretic therapy should be discontinued 2–3 days before initiating treatment with Enap®-H or Enap®-HL preparations.

Dosage in Renal Impairment

Creatinine clearance above 30 mL/min

For patients with renal impairment and creatinine clearance ≥ 30 mL/min, dose adjustment of enalapril via titration is required before switching to the fixed combination. In such patients, loop diuretics are preferred over thiazides. The dose of enalapril and hydrochlorothiazide should be the lowest possible. Periodic monitoring of potassium and creatinine levels is required, for example, every 2 months once the patient's condition has stabilized.

Creatinine clearance below 30 mL/min

Use of the drug is contraindicated.

Special Populations

For patients with reduced fluid/salt volume, the initial dose of enalapril is 5 mg (administered at the corresponding dosage strength) or lower. Titrating monocomponent therapy is recommended for such patients.

Elderly Patients

The drug should be administered to elderly patients at the same doses as to younger patients. In cases of physiological renal impairment, enalapril dose adjustment via titration is required before switching to the fixed combination.

There are no time limitations regarding the duration of treatment.

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

Overdose

Treatment is symptomatic and supportive. Drug administration should be discontinued, and the patient should be thoroughly examined. Induction of vomiting and/or gastric lavage, correction of dehydration and electrolyte imbalance, and management of arterial hypotension using standard measures are recommended.

Enalapril

Symptoms
The main manifestation of overdose is pronounced arterial hypotension occurring within 6 hours after drug intake, associated with blockade of the RAAS and stupor. Symptoms related to overdose of ACE inhibitors may include circulatory shock, electrolyte imbalance, pulmonary hyperventilation, tachycardia, rapid heartbeat, dizziness, anxiety, cough, muscle spasms, paresthesia, exhaustion, impaired consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal failure). Plasma enalaprilat levels exceeding 100- and 200-fold the maximum levels achieved with therapeutic doses were recorded after ingestion of 300 mg and 440 mg of enalapril, respectively.

Treatment After ingestion of a large number of tablets, drug administration should be discontinued, vital parameters should be monitored in a hospital setting, gastric lavage should be performed, and activated charcoal and a laxative should be administered. Treatment is symptomatic. Arterial hypotension should be corrected by infusion of physiological saline. Usually, placing the patient in a supine position with low head elevation is sufficient. In more severe cases, infusion of physiological saline is required; infusion of angiotensin II may also be beneficial. The patient's arterial pressure, pulse, respiration, serum urea, creatinine and electrolyte concentrations, and diuresis should be monitored.

In more severe cases, toxic amounts of enalapril and/or enalaprilat should be removed from the circulation via hemodialysis (see section "Special Instructions for Use"). In cases of bradycardia resistant to therapeutic agents, therapy with a cardiac pacemaker should be initiated. Vital signs and serum electrolyte and creatinine concentrations should be continuously monitored.

Hydrochlorothiazide
The most common symptoms are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If cardiac glycosides are also being used, hypokalemia may provoke cardiac arrhythmia.

Adverse reactions.

Enalapril/hydrochlorothiazide manufactured by KRKA is generally well tolerated. The most commonly reported adverse effects during clinical trials were headache and cough.

The following adverse reactions have been reported with the use of the medicinal product, enalapril monotherapy, or hydrochlorothiazide.

1. Non-melanoma skin cancer: epidemiological studies have shown a cumulative dose-dependent association between the use of hydrochlorothiazide and NMSC (see sections "Pharmacodynamics" and "Special instructions").
2. See section "Special instructions".
3. Observed only with the use of hydrochlorothiazide at doses of 12.5 and 25 mg.
4. The frequency rate was comparable to that in the placebo and active control groups in clinical trials.
5. The frequency of the adverse reaction "muscle cramps" was classified as "common" when hydrochlorothiazide was used at doses of 12.5 and 25 mg, although the frequency of this reaction when hydrochlorothiazide was used at a dose of 6 mg was classified as "uncommon".

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is of great importance. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life.

Enap®-HL: 4 years.

Enap®-H: 5 years.

Storage conditions.

Store in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

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

Prescription status. Prescription only.

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

Manufacturer's address and location of activity.

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