Enapril-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENAPRIL-H

Composition:

Active substances:

Each tablet contains: enalapril maleate 5 mg, hydrochlorothiazide 12.5 mg;

Excipients: anhydrous lactose (44.5 mg), microcrystalline cellulose, corn starch, povidone, sodium methylparahydroxybenzoate (E 219), sodium propylparahydroxybenzoate (E 217), talc, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, biconvex tablets with a score line on one side.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Enalapril and diuretics. ATC code C09BA02.

Pharmacological Properties

Pharmacodynamics

ENALAPRIL

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to suppression of the negative feedback 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 significance of this effect in mediating the therapeutic actions of enalapril remains unclear.

Mechanism of Action

Although 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 can exert antihypertensive effects even in patients with low-renin hypertension.

ENALAPRIL AND 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 leads to greater blood pressure reduction in these patients.

Double Blockade

Two large randomized controlled trials (ONTARGET – Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, and VA NEPHRON-D – Veterans Affairs Nephropathy in Diabetes trial) 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 benefit on renal 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 may also apply 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 Cardio-Renal Endpoints) was a study 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 terminated prematurely 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 and serious adverse events (hyperkalemia, hypotension, and renal impairment) occurred more frequently in the aliskiren group than in the placebo group.

HYDROCHLOROTHIAZIDE

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

Non-melanoma Skin Cancer

Based on available epidemiological data, a cumulative dose-dependent association has been observed 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 coefficient (RC) 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 outcomes for both 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 among 63,067 individuals in the control population using a random sampling strategy. A clear dose-response relationship was demonstrated for each patient, with an adjusted RC of 2.1 (95% CI: 1.7–2.6), RC 3.9 (3.0–4.9) for high cumulative dose (at least 25,000 mg), and RC 7.7 (5.7–10.5) for the highest cumulative dose (at least 100,000 mg) (see section "Special Warnings and Precautions for Use").

Pharmacokinetics

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 inhibitor of angiotensin-converting enzyme. 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 the absorption of enalapril in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril is similar across different doses within the recommended therapeutic range.

After oral administration, peak concentrations of hydrochlorothiazide are reached within 1–3 hours. Due to cumulative renal excretion, the absolute bioavailability of hydrochlorothiazide is approximately 60%.

Distribution

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

Biotransformation

Aside from its 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 20 mg dose in five postpartum women, the mean peak concentration of enalapril in breast milk was 1.7 µg/L (range: 0.54–5.9 µg/L) 4–6 hours after administration. The mean peak concentration of enalaprilat was 1.7 µg/L (range: 1.2–2.3 µg/L); peaks were observed at various times within 24 hours. Based on peak concentrations in breast milk, the calculated maximum dose received by a breastfed infant is approximately 0.16% of the maternal dose normalized to body weight. A woman who took enalapril 10 mg daily for 11 months had a peak concentration of enalapril in milk of 2 µg/L at 4 hours after dosing and a peak concentration of enalaprilat 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 also undetectable.

Clinical characteristics.

Indications.

Mild to moderate arterial hypertension in patients who have been stabilized on the individual components of the medicinal product in the same proportions.

Contraindications.

Hypersensitivity to enalapril and other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide and other sulfonamide derivatives, or to any other component of the medicinal product.

Severe renal impairment (creatinine clearance ≤ 30 mL/min) or serum creatinine levels exceeding 265 µmol/L (3 mg/100 mL).

Anuria.

History of angioedema associated with previous treatment with ACE inhibitors.

Hereditary or idiopathic angioedema.

Refractory hypokalemia or hyperkalemia.

Refractory hyponatremia.

Renal artery stenosis.

Period during hemodialysis.

Clinical condition following kidney transplantation.

Severe hepatic dysfunction.

Symptomatic hyperuricemia (gout).

Pregnancy or planned pregnancy, breastfeeding (see section "Use in pregnancy or breastfeeding").

Concomitant use of this medicinal product with agents containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamic properties").

The medicinal product should not be used in combination with a neprilysin inhibitor (e.g., sacubitril/valsartan) due to increased risk of angioedema. The medicinal product should not be administered within 36 hours before or after switching to or from sacubitril/valsartan (which contains a neprilysin inhibitor) (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

ENALAPRIL AND HYDROCHLOROTHIAZIDE

Other antihypertensive agents

Concomitant use of beta-blockers, methyldopa, or calcium channel blockers may enhance the antihypertensive effect of the medicinal product. Concurrent administration of nitroglycerin and other nitrates or vasodilators may additionally reduce blood pressure.

Ganglionic blockers or adrenergic blockers combined with enalapril should be administered only under close patient monitoring.

Lithium

Concomitant use of lithium and ACE inhibitors may reversibly increase serum lithium concentrations and its toxicity. Concurrent use with thiazide diuretics may further increase lithium levels and increase the risk of lithium toxicity caused by ACE inhibitors. Concomitant use of enalapril/hydrochlorothiazide with lithium is not recommended; however, if such combination is deemed necessary, serum lithium concentrations should be closely monitored.

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

Nonsteroidal anti-inflammatory drugs (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 diminished when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs (including COX-2 inhibitors) with angiotensin II receptor antagonists or ACE inhibitors may additionally increase serum potassium levels and may lead to renal dysfunction. These effects are usually reversible. Rarely, renal failure may develop, particularly in patients with impaired renal function (e.g., elderly patients or dehydrated patients, including those receiving diuretics). Therefore, such combinations should be prescribed with caution in patients with compromised renal function. Patients should maintain adequate fluid intake, and renal function should be closely monitored at the start and regularly during concomitant therapy.

Dual blockade of the renin-angiotensin-aldosterone system (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 monotherapy with a single RAAS-blocking agent (see sections "Pharmacodynamic properties", "Contraindications", and "Special precautions for use").

ENALAPRIL

Potassium-sparing diuretics or potassium supplements

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes 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 cautiously with regular monitoring of serum potassium levels (see section "Special precautions for use").

Diuretics (thiazide or loop diuretics)

Prior therapy with high-dose diuretics may lead to reduced intravascular volume and subsequently increase the risk of arterial hypotension at the initiation of enalapril therapy. The hypotensive effect can be minimized by discontinuing the diuretic, increasing fluid or salt intake, or starting treatment with a low dose of the medicinal product.

Tricyclic antidepressants/antipsychotics/anesthetics

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

Gold preparations

Isolated reactions resembling nitrite reactions (vasodilatory symptoms including flushing, facial swelling, dizziness, nausea, vomiting, and arterial hypotension) have been observed in patients receiving injectable gold preparations (sodium aurothiomalate) concomitantly with ACE inhibitors, including enalapril.

mTOR inhibitors (mammalian target of rapamycin inhibitors)

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

Neprilysin inhibitors

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

Cyclosporine

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

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol

Alcohol potentiates 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 renal impairment.

Acetylsalicylic acid, thrombolytics, beta-blockers

Enalapril may be used cautiously concomitantly with acetylsalicylic acid (when used as a thrombolytic agent), thrombolytic agents, and beta-blockers.

HYDROCHLOROTHIAZIDE

Non-depolarizing muscle relaxants

Thiazide diuretics may potentiate the response to tubocurarine.

Alcohol, barbiturates, narcotic analgesics

Orthostatic hypotension may be potentiated.

Antidiabetic agents (oral hypoglycemic agents and insulin)

Concomitant use of antidiabetic agents and thiazide diuretics may require dose adjustment of the antidiabetic agent (see sections "Special precautions for use" and "Adverse reactions").

Cholestyramine and colestipol resins

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

Cardiac glycosides

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

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone

Concomitant use with thiazide diuretics leads to pronounced electrolyte depletion, particularly hypokalemia.

Potassium-wasting diuretics (e.g., furosemide), carbenoxolone, or laxatives (in case of 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 types of interactions").

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

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

Antigout agents (probenecid, sulfinpyrazone, and allopurinol)

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

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

Bioavailability of thiazide diuretics may be increased due to reduced gastrointestinal motility and delayed gastric emptying.

Salicylates

Hydrochlorothiazide may potentiate the toxic effects of high-dose salicylates on the central nervous system.

Methyldopa

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

Cyclosporine

Concomitant use of cyclosporine increases the risk of hyperuricemia and gout-related complications.

Medicinal products promoting potassium loss and prolonging the QT interval

Regular monitoring of serum potassium levels and ECG is recommended when enalapril/hydrochlorothiazide is used concomitantly with agents that cause hypokalemia (e.g., cardiac glycosides and antiarrhythmic agents) and agents that increase the risk of torsades de pointes (ventricular tachycardia), including certain antiarrhythmic agents, as hypokalemia is a precipitating factor for torsades de pointes (ventricular tachycardia):

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide, procainamide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Some antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Others (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinca mine).

Calcium salts and vitamin D

Thiazide diuretics may increase serum calcium concentration due to reduced excretion. If calcium supplements are required, serum calcium levels should be monitored and the calcium dose adjusted accordingly.

Interaction with biological tests

Due to effects on calcium metabolism, thiazide diuretics may influence parathyroid function test results.

Carbamazepine

Risk of symptomatic hyponatremia. Clinical and laboratory monitoring is required.

Iodinated contrast agents

In cases of dehydration caused by diuretics, the risk of acute renal failure is increased, especially with high doses of iodinated contrast agents. Patients should have their fluid balance restored prior to administration of the medicinal product.

Children

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

ENALAPRIL AND HYDROCHLOROTHIAZIDE

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

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to specific cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with atherosclerotic vascular disease, heart failure, or diabetes with target 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 renin-angiotensin-aldosterone system. Enalapril should not be used concomitantly 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 should be avoided in patients with diabetic nephropathy.

Hypotension and disturbances of fluid and electrolyte balance

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving enalapril/hydrochlorothiazide, arterial hypotension occurs more frequently in patients with salt depletion/reduced fluid volume, e.g., due to diuretic therapy, salt restriction, dialysis, diarrhea, or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects"). Regular monitoring of serum electrolyte levels is required in such patients. Symptomatic arterial hypotension has been observed in patients with heart failure, with or without renal impairment. Arterial hypotension occurs more frequently in patients with severe heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should start treatment under medical supervision. Monitoring should be especially careful when adjusting the dose of enalapril/hydrochlorothiazide and/or diuretic. Similarly, patients with ischemic heart disease and cerebrovascular disorders should be closely monitored, as a sudden drop 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, 0.9% sodium chloride solution should be administered intravenously. Transient arterial hypotension upon taking the drug is not a contraindication for treatment, which can be continued after normalization of blood pressure and restoration of fluid volume.

In some patients with heart failure and normal or low blood pressure, the drug may further reduce blood pressure. This response to the drug is expected and should not be considered a reason to discontinue treatment. In cases where arterial hypotension becomes resistant to treatment, the dose should be reduced and/or diuretic and/or enalapril/hydrochlorothiazide therapy discontinued.

Renal function impairment

Renal function impairment has been reported with enalapril, 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.

Enalapril/hydrochlorothiazide should not be prescribed to patients with renal impairment (creatinine clearance < 80 mL/min and > 30 mL/min) until titration of enalapril reaches the dose of the combined tablet (see section "Dosage and administration").

In some patients with arterial hypertension without renal impairment, 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

The combination of enalapril and 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").

Elderly patients

The efficacy and tolerability of enalapril maleate and hydrochlorothiazide administered 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 mitral valve stenosis and left ventricular outflow tract obstruction. Their use should be avoided in cases of cardiogenic shock and left ventricular outflow tract obstruction.

Renal function 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, renal failure associated with enalapril use is usually reversible (see section "Dosage and administration").

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the aorta of a single healthy kidney who are taking ACE inhibitors have an increased risk of developing arterial hypotension. Even minor changes in serum creatinine may worsen 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

The use of enalapril is contraindicated in patients requiring dialysis due to renal failure. In patients undergoing dialysis with high-flux membranes (e.g., AN 69) and concomitant use of ACE inhibitors, anaphylactoid reactions have occurred in some cases. Therefore, for such patients, the use of other types of dialysis membranes or antihypertensive agents from another class is recommended.

Kidney transplantation

There is no experience with the use of enalapril/hydrochlorothiazide in patients with recently transplanted kidneys. Therefore, treatment with the drug is not recommended for them.

Hepatic function impairment

Very rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients receiving ACE inhibitors who develop jaundice or significant elevation of liver enzymes should discontinue the drug and seek appropriate medical care.

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, immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these risk factors, especially if renal function impairment has previously been established. Some of these patients develop severe infections, 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 advised to inform their physician of any signs of infection.

Hyperkalemia

In some patients receiving ACE inhibitors, including enalapril, increased serum potassium concentration has been observed. Risk factors for hyperkalemia include renal impairment or reduced renal function, age over 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes; or other drugs that increase serum potassium concentration (e.g., heparin). The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to a significant increase in serum potassium levels. Hyperkalemia may cause serious, sometimes fatal arrhythmias. When enalapril/hydrochlorothiazide is used concomitantly with any of these agents, serum potassium levels should be regularly 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 ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Increased sensitivity/angioedema

In patients treated with ACE inhibitors, including enalapril/hydrochlorothiazide, 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, enalapril/hydrochlorothiazide should be discontinued immediately, and the patient should be placed under continuous observation to ensure complete resolution of symptoms. Even if only tongue swelling is observed without respiratory distress, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal angioedema of the larynx or tongue has been reported. In case of swelling of the tongue, glottis, or larynx, airway obstruction is likely, especially in patients who have undergone surgery on the respiratory organs. In these cases, emergency therapy 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 African descent receiving ACE inhibitors compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema when using ACE inhibitors (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 within 36 hours after the last dose of enalapril. Enalapril therapy should 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 racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin increases 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 should be exercised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin in patients already taking an ACE inhibitor.

Anaphylactoid reactions during desensitization with hymenoptera venom

Rarely, patients receiving ACE inhibitors have developed anaphylactoid reactions, which could be life-threatening, during desensitization with hymenoptera venom allergen. 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 dextrin 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. Usually, the cough is 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.

Surgery/anesthesia

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

Pregnancy

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

Ethnic differences

Like other ACE inhibitors, enalapril is less effective in reducing blood pressure in patients of African descent compared to patients of other races. This may be explained by the higher prevalence of low-renin systems among hypertensive patients of African descent.

HYDROCHLOROTHIAZIDE

Renal function impairment

Thiazides may be insufficiently effective as diuretics in treating patients with renal impairment and when creatinine clearance is 30 mL/min or less (i.e., moderate to severe renal impairment).

Enalapril/hydrochlorothiazide tablets should not be prescribed to patients with renal impairment (creatinine clearance < 80 mL/min) until titration of individual components reaches the dose of the combined tablet.

Hepatic function impairment

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor disturbances in fluid and electrolyte balance may lead to hepatic coma.

Metabolic and endocrine effects

Thiazide therapy may alter glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required.

Latent diabetes mellitus may manifest during thiazide therapy.

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

Increased 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.

Thiazides may reduce calcium excretion in urine and cause intermittent, slight elevation of serum calcium. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before testing thyroid function.

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

Thiazide diuretic therapy may cause hyperuricemia and/or exacerbation of gout in some patients. However, enalapril may increase uric acid excretion in urine and thus mitigate the hyperuricemic effect of hydrochlorothiazide. In patients receiving diuretic therapy, serum electrolyte levels should be periodically measured at appropriate intervals.

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

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

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

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

Hydrochlorothiazide may affect laboratory test results.

• Hydrochlorothiazide may reduce iodine binding to plasma proteins.
• Treatment should be discontinued before laboratory testing assessing parathyroid function.
• Hydrochlorothiazide may increase free bilirubin levels in serum.
• A positive analytical result in anti-doping tests is possible.

Non-melanoma skin cancer

Based on two epidemiological studies included in the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] associated with cumulative doses of hydrochlorothiazide has been observed. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC, advised to regularly check their skin for new lesions, and to immediately report any suspicious skin lesions. Preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and appropriate protective measures, are recommended to minimize the risk of skin cancer. 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 "Undesirable effects").

Disorders of the visual organs (choroidal effusion, acute myopia, and secondary angle-closure glaucoma)

Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Although hydrochlorothiazide is a sulfonamide, only isolated cases related to hydrochlorothiazide-containing drugs have been documented to date. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting 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, medical or surgical treatment may be appropriate. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Increased sensitivity

Hypersensitivity reactions 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 with the use of thiazide diuretics.

Excipients

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

Sodium methylparaben (E 219) and sodium propylparaben (E 216), included in the medicinal product, may cause allergic reactions (possibly delayed-type).

Use during pregnancy or breastfeeding

Pregnancy

ACE INHIBITORS

ACE inhibitors are contraindicated in pregnant women and women planning pregnancy (see section "Contraindications").

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

Epidemiological conclusions regarding the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy may lead to fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ACE inhibitors were used during the second trimester of pregnancy, ultrasound assessment of embryonic kidney and skull function is recommended.

Newborns whose mothers received ACE inhibitors should be carefully monitored for arterial hypotension.

HYDROCHLOROTHIAZIDE

Experience with the use of hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. When used during the second and third trimesters of pregnancy, hydrochlorothiazide, due to its pharmacological action, may impair fetoplacental circulation and cause jaundice in the fetus or newborn, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used for the treatment of edema, arterial hypertension, or preeclampsia in pregnant women, as instead of a beneficial effect on the course of the disease, it increases the risk of plasma volume reduction and worsens fetoplacental circulation.

Hydrochlorothiazide should not be used for the treatment of essential arterial hypertension in pregnant women.

Hydrochlorothiazide should not be used during pregnancy.

Period of breastfeeding

ENALAPRIL

Limited pharmacokinetic data show very low concentrations in breast milk. Although these concentrations are not clinically significant, the use of enalapril/hydrochlorothiazide during breastfeeding is contraindicated due to the hypothetical risk of cardiovascular and renal effects and insufficient clinical experience.

HYDROCHLOROTHIAZIDE

Hydrochlorothiazide passes into breast milk; its use during breastfeeding is contraindicated.

The use of Enapril-N is contraindicated during breastfeeding.

If the use of this medicinal product 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 due to the possibility of adverse reactions affecting the nervous system, such as dizziness or drowsiness.

Method of administration and dosage.

Enapril-N is taken orally, regardless of meal times. The dosage regimen is determined individually by a physician depending on the patient's condition and the severity of arterial hypertension.

Arterial hypertension

Treatment should be initiated with low doses of the drug, gradually increasing the dosage. The established daily dose should be taken in the morning with a large amount of fluid.

Typically, adults are prescribed an initial dose of 1 tablet once daily. If necessary, the dose may be increased to 2 tablets once daily.

Prior diuretic therapy

Symptomatic arterial hypotension may occur at the beginning of Enapril-N therapy; it is more commonly observed in patients whose previous diuretic therapy caused disturbances in water-electrolyte balance. Diuretic therapy should be discontinued 2–3 days prior to initiating Enapril-N treatment.

Dosing in 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 or less (i.e., moderate to severe renal impairment).

Enapril-N should be administered to patients with creatinine clearance in the range of >30 to <60 mL/min only after prior dose titration of each component.

The duration of treatment depends on the severity and course of the disease.

Children

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

Overdose

Information regarding overdose of the medicinal product is lacking. In case of accidental or intentional overdose, symptomatic and supportive therapy should be administered. Recommended measures include induction of emesis, administration of activated charcoal, and use of laxatives if the drug was recently ingested, as well as correction of dehydration, electrolyte imbalance, and arterial hypotension using standard procedures.

ENALAPRIL MALEATE

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

Recommended treatment for overdose is intravenous administration of physiological saline. If arterial hypotension occurs, the patient should be placed in a supine position with legs elevated (anti-shock position). If possible, infusion of angiotensin II and/or intravenous administration of catecholamines should be considered. If the drug was recently ingested, measures aimed at eliminating enalapril maleate from the body should be undertaken (e.g., induction of emesis, gastric lavage, administration of adsorbents, and sodium sulfate). Enalapril can be removed from systemic circulation by hemodialysis (see section "Special instructions"). In cases of bradycardia resistant to treatment, cardiac pacing is indicated. Vital signs, serum electrolyte levels, and serum creatinine levels 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 precipitate cardiac arrhythmias. Other manifestations of overdose may include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances in consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal failure).

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

Adverse reactions.

The most commonly reported adverse reactions were dizziness and increased fatigue, which usually resolved with dose reduction and did not always require discontinuation of the medicinal product.

The adverse reactions listed below are classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000), including isolated cases.

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 precautions").
2. See section "Special precautions".
3. Observed only with hydrochlorothiazide doses of 12.5 and 25 mg.
4. The frequency rate was comparable to that in placebo and active control groups in clinical trials.
5. The frequency of the adverse reaction "muscle cramps" was classified as "common" with hydrochlorothiazide doses of 12.5 and 25 mg, although the frequency of this reaction with hydrochlorothiazide at a dose of 6 mg was classified as "uncommon".

Additional adverse effects associated with hydrochlorothiazide

Infections and infestations: sialadenitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): Unknown: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Based on available epidemiological data, a dose-dependent association has been observed between hydrochlorothiazide and non-melanoma skin cancer (NMSC) (see sections "Special precautions" and "Pharmacodynamics").

Metabolism and nutrition disorders: glucosuria.

Nervous system disorders: dizziness.

Skin and subcutaneous tissue disorders: anaphylaxis.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets per strip; 2 strips per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Genome Biotech Pvt. Ltd.

Manufacturer's address and location of its business operations.

Plot No. D-121, 122, 123, MIDC Malegaon, Tal. Sinnar, Nashik 422103, Maharashtra State, India.