Instructions Enap-HL tablets 10 mg + 12.5 mg blister No. 60
Composition
active ingredients: 1 tablet contains enalapril maleate 10 mg and hydrochlorothiazide 12.5 mg or enalapril maleate 10 mg and hydrochlorothiazide 25 mg;
excipients: sodium bicarbonate, lactose monohydrate, corn starch, pregelatinized starch, talc, magnesium stearate, quinoline yellow dye (E 104) – only in Enap®-N.
Dosage form
Pills.
Main physicochemical properties:
Enap®-HL: round, flat, white tablets with a score on one side, with beveled edges.
Enap®-H: round, flat, yellow tablets with a notch on one side, with beveled edges.
Pharmacotherapeutic group
Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. ATC code C09B A02.
Pharmacological properties
Pharmacodynamics.
The drug is a combination of an ACE inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).
ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in plasma angiotensin II levels, which leads to an increase in plasma renin activity (due to inhibition of the negative feedback loop on renin release) and a decrease in 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 fact in the realization of the therapeutic effects of enalapril remains unclear.
Mechanism of action
Although the mechanism by which enalapril lowers blood pressure is primarily associated with inhibition of the activity of the renin-angiotensin-aldosterone system (RAAS), which plays a major role in blood pressure regulation, enalapril may exert an antihypertensive effect even in patients with low-renin hypertension.
Enalapril maleate – hydrochlorothiazide
Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity. Although enalapril has antihypertensive effects even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide results in greater reductions in blood pressure in these patients.
Double blockade
Two large randomized controlled trials (ONTARGET - an ongoing international study of telmisartan alone and in combination with ramipril, VA NEPHRON-D - a study of diabetic nephropathy conducted by the US Department of Veterans Affairs) studied the use of a combination of an ACE inhibitor with an angiotensin receptor antagonist (ARB) II.
ONTARGET is a study conducted in patients with a history of cardiovascular or cerebrovascular disease or with type 2 diabetes mellitus accompanied by signs of target organ damage. VA NEPHRON-D is a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies did not show significant renal or cardiovascular outcomes and reduced mortality, while there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared with monotherapy. Given their similar pharmacodynamic properties, these findings may also apply to other ACE inhibitors and ARBs.
Therefore, ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE, a study of aliskiren in type 2 diabetes with cardiovascular and renal endpoints, was designed to test the benefits of adding aliskiren to standard therapy with ACE inhibitors or ARBs in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. The study was stopped early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke were higher in the aliskiren group than in the placebo group, and the listed adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more common in the aliskiren group than in the placebo group.
Epidemiological studies have shown 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 controls, respectively. High doses of hydrochlorothiazide (≥ 50,000 mg cumulative dose) were associated with an adjusted hazard ratio (HR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. There was a clear relationship between cumulative dose and BCC and SCC. Another study showed a possible association between lip cancer (LC) and hydrochlorothiazide exposure: 633 cases of lip cancer were identified in a control group of 63,067 subjects using a random population sampling strategy. A clear association with cumulative dose was demonstrated for each patient with an adjusted HR of 2.1 (95% CI: 1.7–2.6), HR of 3.9 (3.0–4.9) for the high cumulative dose (at least 25,000 mg) and HR of 7.7 (5.7–10.5) for the highest cumulative dose (at least 100,000 mg) (see section 4.4).
Pharmacokinetics.
Enalapril
Absorption: After oral administration, enalapril is rapidly absorbed, reaching peak serum concentrations within 1 hour. Based on urinary excretion, the extent of absorption of oral enalapril is approximately 60–70%.
After 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 eliminated primarily by the kidneys. The major components in the urine are enalaprilat, which accounts for approximately 40% of the dose, and unchanged enalapril. Apart from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat is characterized by a prolonged terminal phase, which is probably due to binding to ACE. In subjects with normal renal function, steady-state serum concentrations of enalaprilat are reached by the 4th day of oral administration of enalapril. Food intake does not affect the absorption of enalapril from the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar at different doses within the recommended therapeutic range.
Distribution
Studies in dogs indicate that enalapril does not cross the blood-brain barrier or does so in negligible amounts; 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
Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys.
Breeding
Enalaprilat is excreted primarily by the kidneys. The major components of the drug in the urine are enalaprilat, which accounts for about 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 of plasma concentrations of hydrochlorothiazide for at least 24 hours, the plasma half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. When administered orally, at least 61% of the dose is excreted unchanged within 24 hours.
Kidney failure
Enalaprilat is removed from the general circulation by hemodialysis.
Lactation
Following a single oral dose of 20 mg to 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 to 6 hours after dosing. The mean peak concentration of enalaprilat was 1.7 μg/L (range 1.2 to 2.3 μg/L); peaks occurred at various times during the 24-hour period. Based on the peak concentration in breast milk, the estimated maximum dose to the breastfed infant is approximately 0.16% of the maternal dose on a weight-based basis. A woman taking oral enalapril 10 mg daily for 11 months had a peak milk concentration of enalapril of 2 mcg/L 4 hours after dosing and a peak enalaprilat concentration of 0.75 mcg/L approximately 9 hours after dosing. The total amount of enalapril and enalaprilat detected in breast milk over 24 hours was 1.44 mcg/L and 0.63 mcg/L of milk, respectively. Enalaprilat concentrations in breast milk were undetectable (<0.2 mcg/L) 4 hours after a single dose of 5 mg enalapril in one woman and 10 mg in two women; enalapril levels were undetectable.
Indication
Arterial hypertension in patients for whom combination therapy is indicated.
Contraindication
Hypersensitivity to enalapril and other ACE inhibitors, hydrochlorothiazide and other sulfonamide derivatives or to other components of the drugs Enap®-H or Enap®-HL.
History of angioedema associated with previous treatment with ACE inhibitors.
Severe renal impairment [creatinine clearance less than 30 ml/min or serum creatinine level greater than 265 µmol/l (3 mg/100 ml)].
Renal artery stenosis.
During hemodialysis.
Clinical status after kidney transplantation.
Severe liver dysfunction.
Anuria, primary hyperaldosteronism.
Treatment-resistant hypokalemia or hyperkalemia.
Refractory hyponatremia.
Symptomatic hyperuricemia (gout).
Pregnancy or planning pregnancy (see "Use during pregnancy or breastfeeding").
Enalapril should not be used with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 5.1 and 5.4).
Concomitant use with sacubitril/valsartan therapy – due to increased risk of angioedema. The drug should not be used within 36 hours of the last dose of sacubitril/valsartan, a drug containing a neprilysin inhibitor, or after switching from it to another drug (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”).
Interaction with other medicinal products and other types of interactions
Enalpril maleate and hydrochlorothiazide
Other antihypertensive drugs
Concomitant use of such drugs may enhance the hypotensive effect of the drug. Concomitant use of nitroglycerin and other nitrates or vasodilators may further reduce blood pressure.
Lithium
Concomitant use of lithium and ACE inhibitors has been shown to reversibly increase serum lithium concentrations and increase lithium toxicity. Concomitant use of thiazide diuretics and ACE inhibitors may further increase lithium levels and increase the risk of lithium toxicity. The 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 reduce the antihypertensive effects of ACE inhibitors, diuretics and/or other antihypertensive drugs. In some patients with impaired renal function (e.g. elderly patients or patients with dehydration, including those receiving diuretic therapy) taking NSAIDs, including COX-2 inhibitors, the concomitant use of ARBs and ACE inhibitors has been shown to have an additive effect on serum potassium and further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution to patients with impaired renal function. Patients should consume sufficient fluids and require careful monitoring of renal function at the beginning of concomitant therapy and regularly during concomitant treatment.
Dual blockade of the renin-angiotensin-aldosterone system
Clinical studies have shown that dual blockade of the RAAS with the simultaneous use of ACE inhibitors, ARBs or aliskiren is associated with an increased risk of adverse events such as hypotension, hyperkalemia and deterioration of renal function (including acute renal failure) compared with the use of a single RAAS-blocking agent (see sections "Pharmacodynamic properties", "Contraindications", "Special instructions for use").
Enalapril
Potassium-sparing diuretics, potassium supplements, or potassium salt substitutes
Although serum potassium levels are usually within normal limits, hyperkalemia may occur in some patients receiving enalapril. The use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride) and the use of potassium-containing food supplements or salt substitutes may lead to a significant increase in serum potassium. Caution should also be exercised when using enalapril with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, the combination of enalapril with the above drugs is not recommended. If the above agents are indicated in connection with hypokalemia, they should be used with caution, with regular determination of serum potassium levels (see section "Special warnings and precautions for use").
Drugs that increase the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special warnings and precautions for use").
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin increases the risk of angioedema (see section 4.4).
Cotrimoxazole (trimethoprim/sulfamethoxazole)
Cyclosporine: Concomitant use of cyclosporine may increase hyperkalemia, which may precipitate gout attacks in asymptomatic patients.
Heparin
Hyperkalemia may occur with concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Diuretics (thiazide or loop diuretics)
Previous treatment with high doses of diuretics may lead to volume depletion and an increased risk of hypotension at the start of enalapril therapy (see section 4.4). Hypotensive effects can be reduced 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 a further decrease in blood pressure.
Gold preparations
Isolated reactions similar to those to nitrites (symptoms of vasodilation, including flushing, facial edema, dizziness, nausea, vomiting, and hypotension) have been observed in patients treated with injectable gold (sodium aurothiomalate) and concomitantly with an ACE inhibitor, including enalapril.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Alcohol
Alcohol enhances the hypotensive effect of ACE inhibitors.
Antidiabetic drugs
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycaemic agents) may increase the blood glucose-lowering effect with a risk of hypoglycaemia. This effect is more likely to occur during the first weeks of concomitant treatment and in patients with impaired renal function (see section 4.8).
Acetylsalicylic acid, thrombolytics, beta-blockers
Enalapril can be used with caution together with acetylsalicylic acid (in cardiological doses), thrombolytic agents and beta-blockers.
Concomitant therapy with an ACE inhibitor and angiotensin receptor antagonist
In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and an ARB has been reported to be associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of the RAAS agent alone. Dual blockade (e.g., combining an ACE inhibitor with an ARB) should be limited to individually defined cases and accompanied by close monitoring of renal function, potassium levels, and blood pressure.
Hydrochlorothiazide
Non-depolarizing muscle relaxants
Increased sensitivity to the effects of muscle relaxants is possible.
Alcohol, barbiturates, narcotic analgesics
Potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral antidiabetic agents and insulin)
During thiazide therapy, glucose tolerance may be impaired. Dosage adjustment may be necessary. Metformin should be used with caution due to the risk of lactic acidosis due to possible renal failure associated with hydrochlorothiazide.
Other antihypertensive drugs
Additive effect.
Cholestyramine and colestipol resins
Anion exchange resins may reduce the absorption of hydrochlorothiazide. Single doses of cholestyramine or colestipol resins reduce the absorption of hydrochlorothiazide from the gastrointestinal tract by 85% and 43%, respectively.
QT prolongation (e.g., procainamide, amiodarone, sotalol)
Increased risk of torsades de pointes.
Cardiac glycosides
Hypokalemia may increase the sensitivity or clinical response of the heart to digitalis toxicity (e.g., increased ventricular excitability).
Corticosteroids, adrenocorticotropic hormone
Hydrochlorothiazide may exacerbate electrolyte imbalance, mainly hypokalemia.
Kaliuretic diuretics (e.g., furosemide), carbenoxolone, or laxative abuse
Hydrochlorothiazide may cause increased loss of potassium and/or magnesium.
Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol)
Dose adjustment of drugs that promote the excretion of uric acid may be necessary, since hydrochlorothiazide may increase the concentration of uric acid in the blood serum. It may be necessary to increase the dose of probenecid or sulfinpyrazone. Concomitant use of thiazides may increase the incidence of hypersensitivity to allopurinol.
Pressor amines (e.g., adrenaline)
Thiazides may reduce the response to pressor amines, but not enough to preclude concomitant use.
Anticholinergics (e.g., atropine, biperiden)
Increases the bioavailability of thiazide diuretics due to a decrease in gastrointestinal motility and gastric emptying rate.
Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Long-term use of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.
Salicylates
When taking high doses of salicylates, hydrochlorothiazide may enhance their toxic effect on the central nervous system.
Methyldopa
There are isolated reports of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa.
Cyclosporine
Concomitant use of cyclosporine may exacerbate hyperuricemia and increase the risk of complications such as gout.
Drugs affected by changes in serum potassium
Periodic monitoring of serum potassium and ECG is recommended when enalapril/hydrochlorothiazide is co-administered with medicinal products affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmics) and with the following medicinal products (including antiarrhythmics) that induce torsades de pointes, hypokalaemia being a predisposing factor for torsades de pointes (ventricular tachycardia):
Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide);
some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine,
triflupyrazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
other drugs (e.g., bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincomycin).
Calcium salts
Thiazide diuretics may increase serum calcium levels by decreasing its excretion. If calcium supplements are required, the dose should be adjusted under the control of serum calcium levels.
Impact on laboratory test results
Due to their effect on calcium metabolism, thiazides may interfere with the results of parathyroid function tests (see section 4.4).
Carbamazepine
Given the risk of symptomatic hyponatremia, clinical and biological monitoring is necessary.
Iodine-containing contrast agents
In case of diuretic-induced dehydration, the risk of acute renal failure increases, especially when using high doses of contrast media. Patients need to be rehydrated before the administration of iodine-containing drugs.
Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone (ACTH), or stimulant laxatives
Hydrochlorothiazide may exacerbate 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 side effects caused by amantadine.
Application features
Enalapril and hydrochlorothiazide
Arterial hypotension and electrolyte imbalance
Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. In patients with hypertension receiving Enap®-H or Enap®-HL, hypertension develops more often in the presence of salt/volume depletion, for example, due to diuretic therapy, salt restriction, dialysis, diarrhea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions"). In such patients, regular monitoring of serum electrolyte levels is necessary. Symptomatic hypotension has developed more often in patients with more severe forms of heart failure, which is reflected in 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 carefully adhere to the adjusted doses of the drug and/or diuretic. Similar attention should be paid to the treatment of patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure could lead to myocardial infarction or stroke.
In some patients with heart failure and normal or low blood pressure, the drug may cause an additional decrease in systemic blood pressure. This reaction to the drug is to be expected and should not be considered a reason for discontinuation of treatment. If hypotension becomes symptomatic, it may be necessary to reduce the dose and/or discontinue the diuretic and/or the enalapril/hydrochlorothiazide drug.
Dual blockade of the renin-angiotensin-aldosterone system
There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren in patients increases the risk of developing arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure). In this regard, dual blockade of the RAAS through the simultaneous use of ACE inhibitors, ARBs or aliskiren is not recommended (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamic properties").
If dual blockade is considered absolutely necessary, it should be carried out under medical supervision with close monitoring of renal function, fluid and electrolyte balance, and blood pressure.
ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
Kidney dysfunction
Renal impairment has been reported with enalapril, particularly in patients with severe heart failure or renal disease, including renal artery stenosis. If diagnosed promptly and treated appropriately, renal impairment associated with enalapril therapy is usually reversible.
In some hypertensive patients without pre-existing renal insufficiency, increases in serum urea and creatinine have been observed when enalapril is administered with a diuretic. A reduction in the dose of enalapril and/or discontinuation of the diuretic may be necessary. In such cases, the possibility of renal artery stenosis should be considered.
Hyperkalemia
The combination of enalapril and a diuretic in low doses may cause hyperkalemia.
Lithium
Concomitant use of enalapril and lithium is generally not recommended (see sections "Interaction with other medicinal products and other types of interactions").
Use in children
The safety and effectiveness of the drug in children have not been established.
Elderly patients
The efficacy and tolerability of enalapril maleate and hydrochlorothiazide administered concomitantly are similar in both elderly and younger adult patients with arterial hypertension.
Enalapril
Aortic or mitral stenosis/hypertrophic cardiomyopathy
As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow obstruction and should be avoided in cardiogenic shock and hemodynamically significant obstruction.
Renovascular hypertension
Patients with bilateral renal artery stenosis or aortic stenosis of a single healthy kidney who are taking ACE inhibitors are at increased risk of developing arterial hypotension. Even with small changes in serum creatinine, renal function may deteriorate. In these patients, treatment should be initiated under strict medical supervision, with low doses and with careful dose adjustments and monitoring of renal function.
Patients on hemodialysis
In patients dialyzed with high-flux membranes (e.g. AN 69), anaphylactoid reactions have been reported in some cases during treatment with ACE inhibitors. Therefore, the use of a different type of dialysis membrane or a different class of antihypertensive agent is recommended for these patients.
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.
Liver dysfunction
Rarely, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant necrotizing hepatitis (sometimes fatal). The mechanism of this syndrome is unknown. Patients taking ACE inhibitors who develop jaundice or significant elevations of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical supervision.
Neutropenia/agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and no specific risk factors. Enalapril should be used with great caution in patients with collagen vascular disease, immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of the above risk factors, especially if there is a history of impaired renal function. Some of these patients have developed severe infections, which sometimes do not respond to intensive antibiotic therapy.
When using enalapril in these patients, periodic monitoring of leukocytes is recommended, and the patient should be warned to inform the doctor of any signs of infection.
ACE inhibitors may cause hyperkalemia because they inhibit the release of aldosterone. The effect is generally insignificant in patients with normal renal function. The risk of hyperkalemia is increased in patients with renal failure, with impaired renal function, patients > 70 years of age, patients with diabetes mellitus, transient conditions, in particular dehydration, patients with acute cardiac decompensation, metabolic acidosis, patients taking concomitant potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride); when using dietary supplements or salt substitutes containing potassium; in patients taking other drugs that may cause increases in serum potassium (e.g. heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, and especially aldosterone antagonists or ARBs). In particular, the use of potassium-sparing diuretics, dietary supplements or salt substitutes containing potassium in patients with impaired renal function may lead to a significant increase in serum potassium. 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 should be closely monitored (see section 4.5).
Hypoglycemia.
Diabetic patients taking oral antidiabetic agents or insulin require close glycemic control, especially during the first month of treatment with ACE inhibitors (see section "Interaction with other medicinal products and other types of interactions").
Hypersensitivity/angioedema
In patients treated with ACE inhibitors, including Enap®-N or Enap®-HL, angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in some cases. It may occur at any time during treatment. In such cases, Enap®-N or Enap®-HL should be discontinued immediately and the patient should be monitored closely to ensure complete resolution of symptoms. Even if only tongue swelling is present in the absence of respiratory distress, the patient may require prolonged monitoring, as treatment with antihistamines and corticosteroids may be inadequate.
Fatal angioedema of the larynx or tongue has been reported very rarely. If swelling of the tongue, glottis or larynx occurs, airway obstruction is likely, particularly in patients who have undergone respiratory surgery. In these cases, emergency treatment is required, which may include subcutaneous administration of 1:1000 adrenaline (0.3-0.5 ml) and/or measures to maintain a patent airway.
Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.
Patients who have previously experienced angioedema unrelated to the use of ACE inhibitors are at increased risk of developing it when taking 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 of the last dose of enalapril. Enalapril should not be initiated within 36 hours of the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
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 4.5).
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 therapy
Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom have developed anaphylactoid reactions, which may be life-threatening. Such reactions can be avoided by temporarily stopping the ACE inhibitor before the start of the 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
